ORCID Profile
0000-0003-0324-0205
Current Organisations
Lee Kong Chian School of Medicine
,
Royal College of Physicians of Edinburgh
,
National University Singapore Yong Loo Lin School of Medicine
,
National Centre for Infectious Diseases
,
Tan Tock Seng Hospital
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Publications
Administrative data is as good as medical chart review for comorbidity ascertainment in patients with infections in Singapore
Publisher: Cambridge University Press (CUP)
Date: 13-01-2016
DOI: 10.1017/S0950268815003271
Abstract: The Charlson comorbidity index (CCI) is widely used for control of confounding from comorbidities in epidemiological studies. International Classification of Diseases (ICD)-coded diagnoses from administrative hospital databases is potentially an efficient way of deriving CCI. However, no studies have evaluated its validity in infectious disease research. We aim to compare CCI derived from administrative data and medical record review in predicting mortality in patients with infections. We conducted a cross-sectional study on 199 inpatients. Correlation analyses were used to compare comorbidity scores from ICD-coded administrative databases and medical record review. Multivariable regression models were constructed and compared for discriminatory power for 30-day in-hospital mortality. Overall agreement was fair [weighted kappa 0·33, 95% confidence interval (CI) 0·23–0·43]. Kappa coefficient ranged from 0·17 (95% CI 0·01–0·36) for myocardial infarction to 0·85 (95% CI 0·59–1·00) for connective tissue disease. Administrative data-derived CCI was predictive of CCI ⩾5 from medical record review, controlling for age, gender, resident status, ward class, clinical speciality, illness severity, and infection source ( C = 0·773). Using the multivariable model comprising age, gender, resident status, ward class, clinical speciality, illness severity, and infection source to predict 30-day in-hospital mortality, administrative data-derived CCI ( C = 0·729) provided a similar C statistic as medical record review ( C = 0·717, P = 0·8548). In conclusion, administrative data-derived CCI can be used for assessing comorbidities and confounding control in infectious disease research.
External validation of the PRIORITY model in predicting COVID-19 critical illness in vaccinated and unvaccinated patients
Publisher: Elsevier BV
Date: 06-2022
Severity of Plasma Leakage Is Associated With High Levels of Interferon γ–Inducible Protein 10, Hepatocyte Growth Factor, Matrix Metalloproteinase 2 (MMP-2), and MMP-9 During Dengue Virus Infection
Publisher: Oxford University Press (OUP)
Date: 17-10-2016
Abstract: Dengue virus infection typically causes mild dengue fever, but, in severe cases, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur. The pathophysiological hallmark of DHF and DSS is plasma leakage that leads to enhanced vascular permeability, likely due to a cytokine storm. Ninety patients with dengue during 2010-2012 in Singapore were prospectively recruited and stratified according to their disease phase, primary and secondary infection status, and disease severity, measured by plasma leakage. Clinical parameters were recorded throughout the disease progression. The levels of various immune mediators were quantified using comprehensive multiplex microbead-based immunoassays for 46 immune mediators. Associations between clinical parameters and immune mediators were analyzed using various statistical methods. Potential immune markers, including interleukin 1 receptor antagonist, interferon γ-inducible protein 10, hepatocyte growth factor, soluble p75 tumor necrosis factor α receptor, vascular cell adhesion molecule 1, and matrix metalloproteinase 2, were significantly associated with significant plasma leakage. Secondary dengue virus infections were also shown to influence disease outcome in terms of disease severity. This study identified several key markers for exacerbated dengue pathogenesis, notably plasma leakage. This will allow a better understanding of the molecular mechanisms of DHF and DSS in patients with dengue.
Clinical and microbiological characteristics of cryptococcosis in Singapore: predominance of Cryptococcus neoformans compared with Cryptococcus gattii
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.IJID.2014.05.019
Abstract: To describe the clinical features, treatments, outcomes, and subtype prevalence of cryptococcosis in Singapore. All patients with laboratory confirmed cryptococcal infections admitted from 1999 to 2007 to a teaching hospital in Singapore were reviewed retrospectively. Identification and molecular types of Cryptococcus neoformans variants and Cryptococcus gattii were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serotypes were inferred with a multiplex PCR method. Of 62 patients with cryptococcosis, C. neoformans var. grubii was the predominant subtype (in 95%), affecting mainly immunocompromised hosts (91%) with HIV infection (80%). Patients with HIV were younger (median age 36.5 vs. 49.5 years, p=0.006) and less likely to present with an altered mental status (14% vs. 50%, p=0.013). In contrast, delayed treatment (median 7 days vs. 2 days, p=0.03), pulmonary involvement (58% vs. 14%, p=0.03), and initial treatment with fluconazole (25% vs. 2%, p=0.02) were more common in HIV-negative patients. C. gattii was uncommon, affecting only three patients, all of whom were immunocompetent and had disseminated disease with pulmonary and neurological involvement. All C. gattii were RFLP type VG II, serotype B and all C. neoformans var. grubii were RFLP type VN I, serotype A, except for one that was RFLP type VN II. C. neoformans var. grubii, subtype VN I, was the predominant subtype in Singapore, infecting younger, mainly immunocompromised hosts with HIV. C. gattii was uncommon, causing pulmonary manifestations in older, immunocompetent patients and were RFLP type VG II.
Comparative effectiveness of 3 or 4 doses of mRNA and inactivated whole-virus vaccines against COVID-19 infection, hospitalization and severe outcomes among elderly in Singapore
Publisher: Elsevier BV
Date: 12-2022
Monitoring and predicting viral dynamics in SARS-CoV-2-infected Patients
Publisher: Cold Spring Harbor Laboratory
Date: 17-04-2020
DOI: 10.1101/2020.04.14.20060491
Abstract: This study is based on the a simple but robust model we developed urgently to accurately monitor and predict viral dynamics for each SARS-CoV-2-infected patient, given the limited number of RT-PCR tests and the complexity of each in idual’s physical health situation. We used the mathematical model to monitor and predict the changes of viral loads from different nasal and throat swab of clinical specimens collected from diagnosed patients. We also tested this real-time model by using the data from the SARS-CoV-2-infected patients with different severity. By using this model ( 58.87.113.187:8080/ ), we can predict the viral dynamics of patients, minimize false-negative test results, and screen the patients who are at risk of testing positive again after recovery. We sincerely thank those who are on the front lines battling SARS-CoV-2 virus. We hope this model will be useful for SARS-CoV-2-infected patients.
Risk factors and treatment outcomes of severe Clostridioides difficile infection in Singapore
Publisher: Springer Science and Business Media LLC
Date: 17-09-2019
DOI: 10.1038/S41598-019-49794-7
Abstract: Severe Clostridioides difficile infection (CDI) is associated with poorer outcomes. We aimed to identify risk factors and treatment outcomes of severe CDI. This was a retrospective cohort study. Eligible patients from January to December 2012 were recruited. Severity definitions were in accordance with SHEA/IDSA 2010 guideline. Treatment outcomes were (1) diarrhoea persistence, (2) CDI recurrence, (3) major complications despite treatment and (4) 30-day mortality. Two hundred and seventy-two patients were included and 40% had severe CDI. High APACHE II score (aOR 1.112, 95% CI 1.014–1.219 p 0.05), high C-reactive protein (aOR 1.011 95% CI 1.004–1.019 p 0.01) and carbapenem usage in past 90 days (aOR 3.259 95% CI 1.105–9.609 p 0.05) were independent risk factors of severe CDI. Majority received oral metronidazole as sole treatment (92.6% for mild-moderate, 83.9% for severe, 77% for severe-complicated). Diarrhoea persistence was 32% versus 50% (p 0.01), CDI recurrence 16.6% versus 16.5% (p 0.05), major complications 1.2% versus 11% (p 0.001) and 30-day mortality 7.4% versus 20.2% (p 0.01) in mild-moderate CDI and severe CDI groups respectively. Oral metronidazole for severe CDI was associated with persistent diarrhoea, major complications and mortality. Risk factors for severe CDI can guide doctors in diagnosing severe CDI earlier and instituting oral vancomycin treatment to improve outcomes from severe CDI.
Clinical trials on the pharmacological treatment of long COVID: A systematic review
Publisher: Wiley
Date: 18-11-2022
DOI: 10.1002/JMV.28289
Abstract: The postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection (PASC), also known as post‐acute coronavirus disease 19 (COVID‐19) or the long COVID syndrome (long COVID) is an emerging public health concern. A substantial proportion of in iduals may remain symptomatic months after initial recovery. An updated review of published and ongoing trials focusing on managing long COVID will help identify gaps and address the unmet needs of patients suffering from this potentially debilitating syndrome. A comprehensive literature search was conducted on the international databases and clinical trial registries from inception to 31 July 2022. This review included 6 published trials and 54 trial registration records. There is significant heterogeneity in the characterization of long COVID and ascertainment of primary outcomes. Most of the trials are focused on in idual symptoms of long COVID or isolated organ dysfunction, classified according to cardiovascular, respiratory and functional capacity, neurological and psychological, fatigue, and olfactory dysfunction. Most of the interventions are related to the mechanisms causing the in idual symptoms. Although the six published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability. This review provides an update of the pharmacological agents that could be used to treat long COVID. Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.
Chikungunya Outbreak, Singapore, 2008
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 05-2009
Risk factors for nephrotoxicity associated with continuous vancomycin infusion in outpatient parenteral antibiotic therapy
Publisher: Oxford University Press (OUP)
Date: 04-2008
DOI: 10.1093/JAC/DKN080
Abstract: Continuous vancomycin infusion is increasingly used for outpatient management of infections, but the relationship between vancomycin and nephrotoxicity is controversial. We investigated the risk factors associated with nephrotoxicity in this setting. A retrospective cohort study of patients receiving continuous vancomycin infusion as outpatient parenteral antibiotic therapy (OPAT) was performed. The likelihood of developing nephrotoxicity (> or =50% increase in serum creatinine from baseline) was evaluated in relation to demographic variables, underlying co-morbidities, infectious disease diagnoses, concomitant drug exposures and vancomycin concentration. Logistic regression was used to determine the association of various variables. Classification and regression tree analysis was used to determine the most significant breakpoint for continuous variables. We examined 102 adult patients between January 2004 and June 2007. The mean +/- SD age, baseline serum creatinine and steady-state vancomycin concentration were 48.2 +/- 17.6 years, 78.0 +/- 32.5 micromol/L and 15.5 +/- 10.8 mg/L, respectively. The majority of the patients (66.7%) were treated for bone and joint infection. The cumulative incidence of nephrotoxicity was 15.7%. Nephrotoxicity was found to be associated with hypertension [odds ratio (OR) 5.302 (95% confidence interval (CI) 1.159-24.246), P = 0.031], exposure to aminoglycosides [OR 6.594 (95% CI 1.026-42.385), P = 0.047], loop diuretics [OR 8.123 (95% CI 1.449-45.528), P = 0.017], and steady-state vancomycin concentration > or =28 mg/L [OR 21.236 (95% CI 2.687-167.857), P = 0.004]. We have identified independent risk factors for nephrotoxicity in patients receiving continuous infusion vancomycin in OPAT. A serum steady-state vancomycin concentration > or =28 mg/L markedly increases the risk.
Two linear epitopes on the SARS-CoV-2 spike protein that elicit neutralising antibodies in COVID-19 patients
Publisher: Springer Science and Business Media LLC
Date: 06-2020
DOI: 10.1038/S41467-020-16638-2
Abstract: Given the ongoing SARS-CoV-2 pandemic, identification of immunogenic targets against the coronavirus spike glycoprotein will provide crucial advances towards the development of sensitive diagnostic tools and potential vaccine candidate targets. In this study, using pools of overlapping linear B-cell peptides, we report two IgG immunodominant regions on SARS-CoV-2 spike glycoprotein that are recognised by sera from COVID-19 convalescent patients. Notably, one is specific to SARS-CoV-2, which is located in close proximity to the receptor binding domain. The other region, which is localised at the fusion peptide, could potentially function as a pan-SARS target. Functionally, antibody depletion assays demonstrate that antibodies targeting these immunodominant regions significantly alter virus neutralisation capacities. Taken together, identification and validation of these neutralising B-cell epitopes will provide insights towards the design of diagnostics and vaccine candidates against this high priority coronavirus.
Differential Targeting of Viral Components by CD4+versus CD8+T Lymphocytes in Dengue Virus Infection
Publisher: American Society for Microbiology
Date: 03-2013
DOI: 10.1128/JVI.02675-12
Abstract: Dengue virus (DENV) is the principal arthropod-borne viral pathogen afflicting human populations. While repertoires of antibodies to DENV have been linked to protection or enhanced infection, the role of T lymphocytes in these processes remains poorly defined. This study provides a comprehensive overview of CD4 + and CD8 + T cell epitope reactivities against the DENV 2 proteome in adult patients experiencing secondary DENV infection. Dengue virus-specific T cell responses directed against an overlapping 15mer peptide library spanning the DENV 2 proteome were analyzed ex vivo by enzyme-linked immunosorbent spot assay, and recognition of in idual peptides was further characterized in specific T cell lines. Thirty novel T cell epitopes were identified, 9 of which are CD4 + and 21 are CD8 + T cell epitopes. We observe that whereas CD8 + T cell epitopes preferentially target nonstructural proteins (NS3 and NS5), CD4 + epitopes are skewed toward recognition of viral components that are also targeted by B lymphocytes (envelope, capsid, and NS1). Consistently, a large proportion of dengue virus-specific CD4 + T cells have phenotypic characteristics of circulating follicular helper T cells (CXCR5 expression and production of interleukin-21 or gamma interferon), suggesting that they are interacting with B cells in vivo . This study shows that during a dengue virus infection, the protein targets of human CD4 + and CD8 + T cells are largely distinct, thus highlighting key differences in the immunodominance of DENV proteins for these two cell types. This has important implications for our understanding of how the two arms of the human adaptive immune system are differentially targeted and employed as part of our response to DENV infection.
Inappropriate carbapenem use in Singapore public hospitals: opportunities for antimicrobial stewardship
Publisher: Elsevier BV
Date: 2011
Promotion of Testa Rupture during Garden Cress Germination Involves Seed Compartment-Specific Expression and Activity of Pectin Methylesterases
Publisher: Oxford University Press (OUP)
Date: 26-11-2014
Abstract: Pectin methylesterase (PME) controls the methylesterification status of pectins and thereby determines the biophysical properties of plant cell walls, which are important for tissue growth and weakening processes. We demonstrate here that tissue-specific and spatiotemporal alterations in cell wall pectin methylesterification occur during the germination of garden cress (Lepidium sativum). These cell wall changes are associated with characteristic expression patterns of PME genes and resultant enzyme activities in the key seed compartments CAP (micropylar endosperm) and RAD (radicle plus lower hypocotyl). Transcriptome and quantitative real-time reverse transcription-polymerase chain reaction analysis as well as PME enzyme activity measurements of separated seed compartments, including CAP and RAD, revealed distinct phases during germination. These were associated with hormonal and compartment-specific regulation of PME group 1, PME group 2, and PME inhibitor transcript expression and total PME activity. The regulatory patterns indicated a role for PME activity in testa rupture (TR). Consistent with a role for cell wall pectin methylesterification in TR, treatment of seeds with PME resulted in enhanced testa permeability and promoted TR. Mathematical modeling of transcript expression changes in germinating garden cress and Arabidopsis (Arabidopsis thaliana) seeds suggested that group 2 PMEs make a major contribution to the overall PME activity rather than acting as PME inhibitors. It is concluded that regulated changes in the degree of pectin methylesterification through CAP- and RAD-specific PME and PME inhibitor expression play a crucial role during Brassicaceae seed germination.
Global haemostatic tests demonstrate the absence of parameters of hypercoagulability in non-hypoxic mild COVID-19 patients: a prospective matched study
Publisher: Springer Science and Business Media LLC
Date: 28-09-2021
First report of emergence of OXA-48 carbapenemase-producing Enterobacteriaceae in Singapore: Proactive or reactive infection control strategy?
Publisher: Elsevier BV
Date: 05-2014
Duration of Carbapenemase-Producing Enterobacteriaceae Carriage in Hospital Patients
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 09-2020
When to Test for Anti–Interferon-γ Autoantibody?
Publisher: Oxford University Press (OUP)
Date: 13-02-2020
DOI: 10.1093/CID/CIAA129
Empiric piperacillin-tazobactam versus carbapenems in the treatment of bacteraemia due to extended-spectrum beta-lactamase-producing enterobacteriaceae
Publisher: Public Library of Science (PLoS)
Date: 22-04-2016
Utility of 16S ribosomal DNA sequencing in the diagnosis of Staphylococcus lugdunensis native valve infective endocarditis: case report and literature review
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.IJID.2009.02.019
Abstract: We report a case of possible infective endocarditis without fever presenting with an acutely ischemic limb with prior antimicrobial therapy preventing identification by culture of a microorganism. 16S ribosomal DNA sequencing led to the identification of Staphylococcus lugdunensis from an embolus removed at surgery and subsequent successful antibiotic treatment. We review the utility of 16S ribosomal DNA sequencing in diagnosing infective endocarditis and other infectious conditions.
Mutations of SARS-CoV-2 variants of concern escaping Spike-specific T cells
Publisher: Cold Spring Harbor Laboratory
Date: 25-01-2020
DOI: 10.1101/2022.01.20.477163
Abstract: The amino acid (AA) mutations that characterise the different variants of concern (VOCs), which replaced the ancestral SARS-CoV-2 Wuhan-Hu-1 isolate worldwide, provide biological advantages such as increased infectivity and partial escape from humoral immunity. Here we analysed the impact of these mutations on vaccination- and infection-induced Spike-specific T cells. We confirmed that, in the majority of infected or vaccinated in iduals, different mutations present in a single VOC (Delta) or a combined mosaic of more than 30 AA substitutions and deletions found in Alpha, Beta, Gamma, Delta and Omicron VOCs cause modest alteration in the global Spike-specific T cell response. However, distinct numerically dominant Spike-specific CD4 and CD8 T cells preferentially targeted regions affected by AA mutations and do not recognise the mutated peptides. Importantly, some of these mutations, such as N501Y (present in Alpha, Beta, Gamma, and Omicron) and L452R (present in Delta), known to provide biological advantage to SARS-CoV-2 in terms of infectivity also abolished CD8 T cell recognition. Taken together, our data show that while global mRNA vaccine- and infection-induced Spike-specific T cells largely tolerate the erse mutations present in VOCs, single Spike-specific T cells might contribute to the natural selection of SARS-CoV-2 variants.
Early clinical and laboratory risk factors of intensive care unit requirement during 2004–2008 dengue epidemics in Singapore: a matched case–control study
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Severe Neutropenia in Dengue Patients: Prevalence and Significance
Publisher: American Society of Tropical Medicine and Hygiene
Date: 04-06-2014
Pharmacokinetics of ertapenem in outpatients with complicated urinary tract infections
Publisher: Oxford University Press (OUP)
Date: 05-05-2014
DOI: 10.1093/JAC/DKU143
Abstract: Ertapenem is a broad-spectrum carbapenem antibiotic used to treat severe bacterial infections. In view of its dosing convenience, it is increasingly used as outpatient therapy. The objective of this study was to determine the pharmacokinetics and renal disposition of ertapenem in outpatients with complicated urinary tract infections. Ertapenem was administered as a daily intravenous infusion of 1 g over 30 min. At steady-state, blood and urine s les were collected over one dosing interval. Drug concentrations in serum and urine were determined using a validated liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was used to characterize ertapenem serum and urine profiles. The likelihood of the standard dosing achieving a favourable pharmacokinetic-pharmacodynamic exposure was evaluated using Monte Carlo simulations. Ten adult male patients were studied. Concentration-time profiles of ertapenem in both serum (r(2) =0.997) and urine (r(2) =0.982) were captured satisfactorily. Mean values for volume of distribution, clearance and elimination t½ were 4.8 L, 0.7 L/h and 6.1 h, respectively. A high ertapenem concentration (>128 mg/L) could be attained in the urine at 40% of the dosing interval. The pharmacokinetics of ertapenem in serum and urine were characterized. Our simulations suggested that a sufficiently high ertapenem concentration could be achieved in urine to overcome low to intermediate resistance. Clinical investigations to validate our findings are warranted.
Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures
Publisher: Elsevier BV
Date: 03-2020
Hot topics in necrotising skin and soft tissue infections
Publisher: Elsevier BV
Date: 07-2018
Human neutralising antibodies elicited by SARS‐CoV‐2 non‐D614G variants offer cross‐protection against the SARS‐CoV‐2 D614G variant
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1241
Lack of cross-neutralization by SARS patient sera towards SARS-CoV-2
Publisher: Informa UK Limited
Date: 2020
Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals
Publisher: Frontiers Media SA
Date: 14-11-2022
DOI: 10.3389/FIMMU.2022.1031852
Abstract: The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all in iduals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of in iduals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of in iduals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of in iduals (18.8 – 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly in iduals may require a fourth dose to provide protection against SARS-CoV-2.
IDentif.AI-Omicron: Harnessing an AI-Derived and Disease-Agnostic Platform to Pinpoint Combinatorial Therapies for Clinically Actionable Anti-SARS-CoV-2 Intervention
Publisher: American Chemical Society (ACS)
Date: 17-08-2022
Abstract: Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For ex le, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested
Severe dengue and liver involvement: an overview and review of the literature
Publisher: Informa UK Limited
Date: 03-02-2020
Staphylococcus aureus and topical fusidic acid use: results of a clinical audit on antimicrobial resistance
Publisher: Wiley
Date: 22-02-2013
DOI: 10.1111/J.1365-4632.2012.05747.X
Abstract: Fusidic acid (FA) resistance in Staphylococcus aureus poses a problem for treating systemic methicillin-resistant S. aureus infection, in which FA may otherwise remain a viable option. It can also result in treatment failure of common dermatological conditions such as impetigo and infected atopic eczema. Several studies have linked trends in prescribing medication and topical use of FA to development of resistance. However, few case-control studies have evaluated risk factors for developing FA resistance in S. aureus. A clinical audit for antimicrobial resistance was performed in dermatology patients from the National Skin Centre who were admitted for inpatient care from 2006 to 2008 and had positive bacterial cultures for S. aureus. Each FA-resistant S. aureus (FRSA) case was compared with four randomly selected FA-susceptible (FSSA) cases. Medical records were reviewed retrospectively, and potential risk factors for development of resistance were analyzed. Thirteen of 37 patients with FRSA (35.1%) had used FA topically compared with 11 of 148 patients with FSSA (7.4%). Findings from multivariate analysis indicate that previous use of topical FA was the only independent risk factor of FA resistance (adjusted OR 7.46, 95% CI [2.60-21.41], P < 0.001). Patients' coexisting illnesses, recent hospitalization, or systemic antibiotic use were not significant risks. Previous recent topical FA use correlated positively with FA resistance in S. aureus. Prescribing physicians must be vigilant of the rise of FA resistance and its resultant problems and prescribe topical FA discerningly.
Resistance of SARS-CoV-2 Delta variant to neutralization by BNT162b2-elicited antibodies in Asians
Publisher: Elsevier BV
Date: 10-2021
Current management of severe dengue infection
Publisher: Informa UK Limited
Date: 27-10-2016
DOI: 10.1080/14787210.2017.1248405
Abstract: Traditionally a disease mainly affecting the pediatric population, dengue burden has increased significantly in recent decades and adults with severe disease may become more common. There is currently no effective anti-viral agent available for the treatment of dengue and supportive care is the mainstay of management. Areas covered: We present a review of current literature on dengue severity classification systems and the management of severe dengue in adults. In particular, emphasis was placed on organ impairment in dengue and management of elderly in iduals with multiple medical problems. Expert commentary: There is an urgent need to search for an effective anti-viral agent to treat infected in iduals. The commercial availability of a dengue vaccine in older children has provided optimism in reducing the disease burden but long term efficacy and safety are unknown. The results from phase III trials of two new candidate vaccines are eagerly awaited.
The higher prevalence of extended spectrum beta-lactamases among Escherichia coli ST131 in Southeast Asia is driven by expansion of a single, locally prevalent subclone
Publisher: Springer Science and Business Media LLC
Date: 13-09-2019
DOI: 10.1038/S41598-019-49467-5
Abstract: The ST131 multilocus sequence type (MLST) of Escherichia coli is a globally successful pathogen whose dissemination is increasing rates of antibiotic resistance. Numerous global surveys have demonstrated the pervasiveness of this clone in some regions ST131 accounts for up to 30% of all E . coli isolates. However, many regions are underrepresented in these published surveys, including Africa, South America, and Asia. We collected consecutive bloodstream E . coli isolates from three countries in Southeast Asia ST131 was the most common MLST type. As in other studies, the C2/H30Rx clade accounted for the majority of ST131 strains. Clinical risk factors were similar to other reported studies. However, we found that nearly all of the C2 strains in this study were closely related, forming what we denote the SEA-C2 clone. The SEA-C2 clone is enriched for strains from Asia, particularly Southeast Asia and Singapore. The SEA-C2 clone accounts for all of the excess resistance and virulence of ST131 relative to non-ST131 E . coli . The SEA-C2 strains appear to be locally circulating and dominant in Southeast Asia, despite the intuition that high international connectivity and travel would enable frequent opportunities for other strains to establish themselves.
Sensitive Detection of Total Anti-Spike Antibodies and Isotype Switching in Asymptomatic and Symptomatic COVID-19 Patients
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3713507
Stool metagenome analysis of patients with Klebsiella pneumoniae liver abscess and their domestic partners
Publisher: Elsevier BV
Date: 06-2021
Klebsiella pneumoniae liver abscesses
Publisher: Elsevier BV
Date: 05-2013
Clinical features and predictors of severity in COVID-19 patients with critical illness in Singapore
Publisher: Springer Science and Business Media LLC
Date: 05-04-2021
DOI: 10.1038/S41598-021-81377-3
Abstract: We aim to describe a case series of critically and non-critically ill COVID-19 patients in Singapore. This was a multicentered prospective study with clinical and laboratory details. Details for fifty uncomplicated COVID-19 patients and ten who required mechanical ventilation were collected. We compared clinical features between the groups, assessed predictors of intubation, and described ventilatory management in ICU patients. Ventilated patients were significantly older, reported more dyspnea, had elevated C-reactive protein and lactate dehydrogenase. A multivariable logistic regression model identified respiratory rate (aOR 2.83, 95% CI 1.24–6.47) and neutrophil count (aOR 2.39, 95% CI 1.34–4.26) on admission as independent predictors of intubation with area under receiver operating characteristic curve of 0.928 (95% CI 0.828–0.979). Median APACHE II score was 19 (IQR 17–22) and PaO2/FiO2 ratio before intubation was 104 (IQR 89–129). Median peak FiO2 was 0.75 (IQR 0.6–1.0), positive end-expiratory pressure 12 (IQR 10–14) and plateau pressure 22 (IQR 18–26) in the first 24 h of ventilation. Median duration of ventilation was 6.5 days (IQR 5.5–13). There were no fatalities. Most COVID-19 patients in Singapore who required mechanical ventilation because of ARDS were extubated with no mortality.
Vaccine effectiveness against Delta, Omicron BA.1, and BA.2 in a highly vaccinated Asian setting: a test-negative design study
Publisher: Elsevier BV
Date: 2023
Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine breakthrough infections: a multicentre cohort study
Publisher: Elsevier BV
Date: 04-2022
Clinical utility of chest radiography for severe COVID-19
Publisher: AME Publishing Company
Date: 07-2020
DOI: 10.21037/QIMS-20-642
Clinical Predictors for Abnormal ALT in Patients Infected with COVID-19—A Retrospective Single Centre Study
Publisher: MDPI AG
Date: 16-03-2023
DOI: 10.3390/PATHOGENS12030473
Abstract: Objective: Abnormal liver tests have been associated with worse clinical outcomes in patients infected with COVID-19. This retrospective observational study from Singapore aims to elucidate simple clinical predictors of abnormal alanine aminotransferase (ALT) in COVID-19 infections. Design: 717 patients hospitalised with COVID-19 at the National Centre for Infectious Diseases (NCID), Singapore, from 23 January–15 April 2020 were screened, of which 163 patients with baseline normal alanine transferase (ALT) and at least two subsequent ALTs performed were included in the final analysis. Information on baseline demographics, clinical characteristics and biochemical laboratory tests were collected. Results: 30.7% of patients developed abnormal ALT. They were more likely to be older (60 vs. 55, p = 0.022) and have comorbidities of hyperlipidaemia and hypertension. The multivariate logistic regression showed that R-factor ≥1 on admission (adjusted odds ratio (aOR) 3.13, 95% Confidence Interval (CI) 1.41–6.95) and hypoxia (aOR 3.54, 95% CI 1.29–9.69) were independent risk factors for developing abnormal ALT. The patients who developed abnormal ALT also ran a more severe course of illness with a greater proportion needing supplementary oxygen (58% vs. 18.6%, p 0.0005), admission to the Intensive Care Unit (ICU)/High Dependency Unit (HDU) (32% vs. 11.5%, p = 0.003) and intubation (20% vs. 2.7%, p 0.0005). There was no difference in death rate between the two groups. Conclusions: Liver injury is associated with poor clinical outcomes in patients with COVID-19. R-factor ≥1 on admission and hypoxia are independent simple clinical predictors for developing abnormal ALT in COVID-19.
Safety and potential efficacy of cyclooxygenase‐2 inhibitors in coronavirus disease 2019
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1159
Association between lung compliance phenotypes and mortality in COVID-19 patients with acute respiratory distress syndrome
Publisher: Academy of Medicine, Singapore
Date: 30-09-2021
DOI: 10.47102/ANNALS-ACADMEDSG.2021129
Abstract: ABSTRACT Introduction: Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with a high mortality rate, though outcomes of the different lung compliance phenotypes are unclear. We aimed to measure lung compliance and examine other factors associated with mortality in COVID-19 patients with ARDS. Methods: Adult patients with COVID-19 ARDS who required invasive mechanical ventilation at 8 hospitals in Singapore were prospectively enrolled. Factors associated with both mortality and differences between high ( mL/cm H2O) and low ( mL/cm H2O) compliance were analysed. Results: A total of 102 patients with COVID-19 who required invasive mechanical ventilation were analysed 15 (14.7%) did not survive. Non-survivors were older (median 70 years, interquartile range [IQR] 67–75 versus median 61 years, IQR 52–66 P .01), and required a longer duration of ventilation (26 days, IQR 12–27 vs 8 days, IQR 5–15 P .01) and intensive care unit support (26 days, IQR 11–30 vs 11.5 days, IQR 7–17.3 P=0.01), with a higher incidence of acute kidney injury (15 patients [100%] vs 40 patients [46%] P .01). There were 67 patients who had lung compliance data 24 (35.8%) were classified as having high compliance and 43 (64.2%) as having low compliance. Mortality was higher in patients with high compliance (33.3% vs 11.6% P=0.03), and was associated with a drop in compliance at day 7 (-9.3mL/cm H2O (IQR -4.5 to -15.4) vs 0.2mL/cm H2O (4.7 to -5.2) P=0.04). Conclusion: COVID-19 ARDS patients with higher compliance on the day of intubation and a longitudinal decrease over time had a higher risk of death. Keywords: ARDS, COVID-19-associated respiratory failure, high-flow nasal cannula therapy, HFNC, post-intubation, ventilation strategies
Empowerment of nurses in antibiotic stewardship: a social ecological qualitative analysis
Publisher: Elsevier BV
Date: 11-2020
Outpatient parenteral antibiotic therapy in Singapore
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.IJANTIMICAG.2006.08.018
Abstract: Outpatient parenteral antibiotic therapy (OPAT) remains in its infancy in Singapore, with the first patients enrolled 4 years ago. Singapore's three largest hospitals, with over 3000 inpatient beds, now have designated and approved OPAT services. This study reviews the demographic, clinical and cost data of all patients enrolled in 2005 to facilitate benchmarking between services in Singapore and abroad and also to identify common needs for further development. In 2005, 225 OPAT enrollments in 208 different patients resulted in 4050 days of OPAT care. Orthopaedic diagnoses constituted 40% of admissions. Vancomycin was the most frequently used antibiotic (34%). The re-admission rate was 8.9%, but complications of OPAT care were only occasionally implicated. An estimated $207,200 was saved by patients despite there being significant financial disincentives to subsidised patients. OPAT is a safe, cost-efficient system that is becoming increasingly accepted in Singapore by patients, clinicians and management. Our three services have evolved independently into very similar practices. There is potential for further innovation, including outreach and carer-delivered dosing. However, major financial disincentives require review.
No association between resistance mutations, empiric antibiotic, and mortality in ceftriaxone-resistant Escherichia coli and Klebsiella pneumoniae bacteremia
Publisher: Springer Science and Business Media LLC
Date: 24-08-2018
DOI: 10.1038/S41598-018-31081-6
Abstract: The objective of this study was to correlate resistance mutations of extended spectrum beta-lactamases (ESBL) and AmpC beta-lactamases and virulence factors (VF) with 30-day mortality in patients treated with either piperacillin-tazobactam or carbapenems. A post-hoc analysis on 123 patients with ceftriaxone-resistant Escherichia coli and Klebsiella pneumoniae bacteremia treated empirically with piperacillin-tazobactam and carbapenems was performed. Beta-lactamase resistance mutations and VF were identified by whole genome sequencing (WGS). The primary endpoint was 30-day mortality. Multivariate analyses were performed using logistic regression. WGS showed erse multilocus sequence types (MLST) in 43 K. pneumoniae strains, while ST131 predominated in E. coli strains (57/80). CTX-M was most commonly detected (76/80 [95%] of E. coli 39/43 [91%] of K pneumoniae .), followed by OXA (53/80 [66%] of E. coli 34/43 [79%] of K. pneumoniae ). A significant correlation was found between the number of genes encoding third-generation cephalosporin-resistant beta-lactamases and 30-day mortality (p = 0.045). The positive association was not significant after controlling for empiric carbapenem, Pitt score 3 and K. pneumoniae (OR 2.43, P = 0.073). None of the VF was associated with 30-day mortality. No association was found between 30-day mortality and any ESBL and AmpC beta-lactamases or VF when piperacillin-tazobactam or carbapenems were given. No significant association between 30-day mortality and active empiric therapy was found.
Investigator-Driven Randomised Controlled Trial of Cefiderocol versus Standard Therapy for Healthcare-Associated and Hospital-Acquired Gram-negative Bloodstream Infection: Study protocol (the GAME CHANGER trial): study protocol for an open-label, randomised controlled trial
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1186/S13063-021-05870-W
Abstract: Increasing rates of antibiotic resistance in Gram-negative organisms due to the presence of extended-spectrum beta-lactamases (ESBL), hyperproduction of AmpC enzymes, carbapenemases and other mechanisms of resistance are identified in common hospital- and healthcare-associated pathogens including Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii . Cefiderocol is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Cefiderocol has been shown to be potent in vitro against a broad range of Gram-negative organisms, including carbapenem-resistant Enterobacteriaceae (CRE) and multi-drug-resistant (MDR) P. aeruginosa and A. baumannii . Recent clinical data has shown cefiderocol to be effective in the setting of complicated urinary tract infections and nosocomial pneumonia, but it has not yet been studied as treatment of bloodstream infection. This study will use a multicentre, open-label non-inferiority trial design comparing cefiderocol and standard of care antibiotics. Eligible participants will be adult inpatients who are diagnosed with a bloodstream infection with a Gram-negative organism on the basis of a positive blood culture result where the acquisition meets the definition for healthcare-associated or hospital-acquired. It will compare cefiderocol with the current standard of care (SOC) antibiotic regimen according to the patient’s treating clinician. Eligible participants will be randomised 1:1 to cefiderocol or SOC and receive 5–14 days of antibiotic therapy. Trial recruitment will occur in at least 20 sites in ten countries (Australia, Malaysia, Singapore, Thailand, Turkey and Greece). The s le size has been derived from an estimated 14 day, all-cause mortality rate of 10% in the control group, and a non-inferiority margin of 10% difference in the two groups. A minimum of 284 patients are required in total to achieve 80% power with a two-sided alpha level of 0.05. Data describing demographic information, risk factors, concomitant antibiotics, illness scores, microbiology, multidrug-resistant organism screening, discharge and mortality will be collected. With increasing antimicrobial resistance, there is a need for the development of new antibiotics with broad activity against Gram-negative pathogens such as cefiderocol. By selecting a population at risk for multi-drug-resistant pathogens and commencing study treatment early in the clinical illness (within 48 h of index blood culture) the trial hopes to provide guidance to clinicians of the efficacy of this novel agent. The GAME CHANGER trial is registered under the US National Institute of Health ClinicalTrials.gov register, reference number NCT03869437 . Registered on March 11, 2019.
Risk Factors for Development of Acute Kidney Injury in COVID-19 Patients: A Retrospective Observational Cohort Study
Publisher: S. Karger AG
Date: 2021
DOI: 10.1159/000514064
Abstract: b i Introduction: /i /b Acute kidney injury (AKI) in coronavirus infection disease (COVID-19) is associated with disease severity. We aimed to evaluate risk factors associated with AKI beyond COVID-19 severity. b i Methods: /i /b A retrospective observational study of COVID-19 patients admitted to a tertiary hospital in Singapore. Logistic regression was used to evaluate associations between risk factors and AKI (based on Kidney Disease Improving Global Outcomes criteria). Dominance analysis was performed to evaluate the relative importance of in idual factors. b i Results: /i /b Seven hundred seven patients were included. Median age was 46 years (interquartile range [IQR]: 29–57) and 57% were male with few comorbidities (93%, Charlson Comorbidity Index [CCI] & #x3c ). AKI occurred in 57 patients (8.1%) 39 were in AKI stage 1 (68%), 9 in stage 2 (16%), and 9 in stage 3 (16%). Older age (adjusted odds ratio [aOR] 1.04 95% confidence interval [CI]: 1.01–1.07), baseline use of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) (aOR 2.86 95% CI: 1.20–6.83), exposure to vancomycin (aOR 5.84 95% CI: 2.10–16.19), use of nonsteroidal anti-inflammatory drugs (NSAIDs) (aOR 3.04 95% CI: 1.15–8.05), and severe COVID-19 with hypoxia (aOR 13.94 95% CI: 6.07–31.98) were associated with AKI in the multivariable logistic regression model. The 3 highest ranked predictors were severe COVID-19 with hypoxia, vancomycin exposure, and age, accounting for 79.6% of the predicted variance (41.6, 23.1, and 14.9%, respectively) on dominance analysis. b i Conclusion: /i /b Severe COVID-19 is independently associated with increased risk of AKI beyond premorbid conditions and age. Appropriate avoidance of vancomycin and NSAIDs are potentially modifiable means to prevent AKI in patients with COVID-19.
Increasing Experience With Melioidosis and Critical Care: Medical and Military Implications*
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2016
Comparative in situ analysis reveals the dynamic nature of sclerenchyma cell walls of the fern Asplenium rutifolium
Publisher: Oxford University Press (OUP)
Date: 23-12-2017
DOI: 10.1093/AOB/MCX167
Making meaningful journalism
Publisher: Routledge
Date: 15-08-2017
Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial.
Publisher: American College of Physicians
Date: 12-2022
DOI: 10.7326/M22-2116
Prevalence of Healthcare-Associated Infections and Antimicrobial Use Among Adult Inpatients in Singapore Acute-Care Hospitals: Results From the First National Point Prevalence Survey
Publisher: Oxford University Press (OUP)
Date: 29-04-2017
DOI: 10.1093/CID/CIX103
Abstract: We conducted a national point prevalence survey (PPS) to determine the prevalence of healthcare-associated infections (HAIs) and antimicrobial use (AMU) in Singapore acute-care hospitals. Trained personnel collected HAI, AMU, and baseline hospital- and patient-level data of adult inpatients from 13 private and public acute-care hospitals between July 2015 and February 2016, using the PPS methodology developed by the European Centre for Disease Prevention and Control. Factors independently associated with HAIs were determined using multivariable regression. Of the 5415 patients surveyed, there were 646 patients (11.9% 95% confidence interval [CI], 11.1%-12.8%) with 727 distinct HAIs, of which 331 (45.5%) were culture positive. The most common HAIs were unspecified clinical sepsis (25.5%) and pneumonia (24.8%). Staphylococcus aureus (12.9%) and Pseudomonas aeruginosa (11.5%) were the most common pathogens implicated in HAIs. Carbapenem nonsusceptibility rates were highest in Acinetobacter species (71.9%) and P. aeruginosa (23.6%). Male sex, increasing age, surgery during current hospitalization, and presence of central venous or urinary catheters were independently associated with HAIs. A total of 2762 (51.0% 95% CI, 49.7%-52.3%) patients were on 3611 systemic antimicrobial agents 462 (12.8%) were prescribed for surgical prophylaxis and 2997 (83.0%) were prescribed for treatment. Amoxicillin/clavulanate was the most frequently prescribed (24.6%) antimicrobial agent. This survey suggested a high prevalence of HAIs and AMU in Singapore's acute-care hospitals. While further research is necessary to understand the causes and costs of HAIs and AMU in Singapore, repeated PPSs over the next decade will be useful to gauge progress at controlling HAIs and AMU.
Author Correction: The higher prevalence of extended spectrum beta-lactamases among Escherichia coli ST131 in Southeast Asia is driven by expansion of a single, locally prevalent subclone
Publisher: Springer Science and Business Media LLC
Date: 14-04-2021
DOI: 10.1038/S41598-021-87312-W
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Efficient recall of SARS‐CoV‐2 variant‐reactive B cells and T responses in the elderly upon heterologous mRNA vaccines as boosters
Publisher: Wiley
Date: 16-11-2022
DOI: 10.1002/JMV.28258
Abstract: Waning antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and the emergence of variants of concern highlight the need for booster vaccinations. This is particularly important for the elderly population, who are at a higher risk of developing severe coronavirus disease 2019 (COVID‐19) disease. While studies have shown increased antibody responses following booster vaccination, understanding the changes in T and B cell compartments induced by a third vaccine dose remains limited. We analyzed the humoral and cellular responses in subjects who received either a homologous messenger RNA(mRNA) booster vaccine (BNT162b2 + BNT162b2 + BNT162b2 ‘‘BBB”) or a heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA‐1273 ‘‘BBM”) at Day 0 (prebooster), Day 7, and Day 28 (postbooster). Compared with BBB, elderly in iduals (≥60 years old) who received the BBM vaccination regimen display higher levels of neutralizing antibodies against the Wuhan and Delta strains along with a higher boost in immunoglobulin G memory B cells, particularly against the Omicron variant. Circulating T helper type 1(Th1), Th2, Th17, and T follicular helper responses were also increased in elderly in iduals given the BBM regimen. While mRNA vaccines increase antibody, T cell, and B cell responses against SARS‐CoV‐2 1 month after receiving the third dose booster, the efficacy of the booster vaccine strategies may vary depending on age group and regimen combination.
Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19
Publisher: Springer Science and Business Media LLC
Date: 16-10-2020
DOI: 10.1038/S41467-020-19080-6
Abstract: SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood s les from 54 COVID-19 patients reveals a dramatic increase in the number of immature neutrophils. This increase strongly correlates with disease severity and is associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts is observed for CD8 T-cells and VD2 γδ T-cells, which both exhibit increased differentiation and activation. ROC analysis reveals that the count ratio of immature neutrophils to VD2 (or CD8) T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.
Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation
Publisher: Cold Spring Harbor Laboratory
Date: 18-11-2020
DOI: 10.1101/2020.11.16.20232835
Abstract: The rapid rise of coronavirus disease 2019 patients who suffer from vascular events after their initial recovery is expected to lead to a worldwide shift in disease burden. We aim to investigate the impact of COVID-19 on the pathophysiological state of blood vessels in convalescent patients. Here, convalescent COVID-19 patients with or without preexisting conditions (i.e. hypertension, diabetes, hyperlipidemia) were compared to non-COVID-19 patients with matched cardiovascular risk factors or healthy participants. Convalescent patients had elevated circulating endothelial cells (CECs), and those with underlying cardiovascular risk had more pronounced endothelial activation hallmarks (ICAM1, P-selectin or CX3CL1) expressed by CECs. Multiplex microbead-based immunoassays revealed some levels of cytokine production sustained from acute infection to recovery phase. Several proinflammatory and activated T lymphocyte-associated cytokines correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Finally, the activation markers detected on CECs mapped to the counter receptors (i.e. ITGAL, SELPLG , and CX3CR1 ) found primarily on CD8+ T cells and natural killer cells, suggesting that activated endothelial cells could be targeted by cytotoxic effector cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.
Ertapenem for the treatment of extended-spectrum β-lactamase-producing Gram-negative bacterial infections
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.IJANTIMICAG.2007.05.016
Abstract: Ertapenem is indicated for complicated intra-abdominal, skin and skin-structure, urinary tract and acute pelvic infections as well as community-acquired pneumonia, for which there are cheaper and more narrow-spectrum antibiotics. It is active against extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria, but report of its clinical efficacy is lacking. We evaluated our experience with the use of ertapenem for ESBL-producing Gram-negative bacterial infections over 13 months. Forty-seven patients were treated with 50 courses of ertapenem. Thirty-nine courses were for ESBL-producing Gram-negative bacterial infections, 33% of which were bacteraemia. The clinical response rate was 92% and survival to hospital discharge was 94%. We propose that ertapenem has a role in the first-line treatment of these infections.
Data-driven analysis of COVID-19 reveals specific severity patterns distinct from the temporal immune response
Publisher: Cold Spring Harbor Laboratory
Date: 11-02-2021
DOI: 10.1101/2021.02.10.430668
Abstract: Key immune signatures of SARS-CoV-2 infection may associate with either adverse immune reactions (severity) or simply an ongoing anti-viral response (temporality) how immune signatures contribute to severe manifestations and/or temporal progression of disease and whether longer disease duration correlates with severity remain unknown. Patient blood was comprehensively immunophenotyped via mass cytometry and multiplex cytokine arrays, leading to the identification of 327 basic subsets that were further stratified into more than 5000 immunotypes and correlated with 28 plasma cytokines. Low-density neutrophil abundance was closely correlated with hepatocyte growth factor levels, which in turn correlated with disease severity. Deep analysis also revealed additional players, namely conventional type 2 dendritic cells, natural killer T cells, plasmablasts and CD16 + monocytes, that can influence COVID-19 severity independent of temporal progression. Herein, we provide interactive network analysis and data visualization tools to facilitate data mining and hypothesis generation for elucidating COVID-19 pathogenesis.
Observation and analysis of creation, decay, and regeneration of annular soliton clusters in a lossy cubic-quintic optical medium
Publisher: American Physical Society (APS)
Date: 23-09-2020
Carriage duration of carbapenemase-producing Enterobacteriaceae in a hospital cohort - implications for infection control measures
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2019
DOI: 10.1101/19001479
Abstract: Carriage duration of carbapenemase-producing Enterobacteriaceae (CPE) is uncertain. We followed 21 CPE carriers over one year. Mean carriage duration was 86 (95%CrI= [60, 122]) days, with 98.5% (95%CrI= [95.0, 99.8]) probability of decolonization in one year. Antibiotic consumption was associated with prolonged carriage. CPE-carriers’ status should be reviewed yearly.
Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long‐term outcomes in COVID ‐19 patients
Publisher: Wiley
Date: 28-04-2022
DOI: 10.1002/AJH.26575
Abstract: Sustained hypercoagulability and endotheliopathy are present in convalescent COVID‐19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID‐19 patients were evaluated up to 16 months after recovery from COVID‐19. These values were compared with a control group of healthy volunteers ( n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID‐19 acute ischaemic limb. Elevated D‐dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D‐dimer 0.34 FEU μg/mL (IQR 0.28, 0.46) ( p .001) and Factor VIII 150% (IQR 171, 203) ( p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) ( p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) ( p = 0.01) and delayed lag time 2.4 min (1.42–2.97) ( p = 0.0002) versus controls. Raised vWF:Ag and ICAM‐1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) ( p = 0.02) and ICAM‐1 54.1 ng/mL (IQR 43.8, 64.1) ( p = .004) than controls. IL‐6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL‐6 of 1.5 pg/mL (IQR 0.6, 3.0) ( p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID‐19 severity and COVID‐19 vaccination preceding SARS‐CoV‐2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID‐19.
SARS-CoV-2 Omicron variant emerged under immune selection
Publisher: Springer Science and Business Media LLC
Date: 04-10-2022
DOI: 10.1038/S41564-022-01246-1
Abstract: The SARS-CoV-2 Omicron variant (B.1.1.529 lineage) escapes antibodies that neutralize the ancestral virus. We tested human serum panels from participants with differing infection and vaccination status using a multiplex surrogate virus neutralization assay targeting 20 sarbecoviruses. We found that bat and pangolin sarbecoviruses showed significantly less neutralization escape than the Omicron variant. We propose that SARS-CoV-2 variants have emerged under immune selection pressure and are evolving differently from animal sarbecoviruses.
Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation
Publisher: eLife Sciences Publications, Ltd
Date: 23-03-2021
DOI: 10.7554/ELIFE.64909
Abstract: Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8 + T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.
Prosthetic joints: shining lights on challenging blind spots
Publisher: Elsevier BV
Date: 02-2017
Organ‐specific immune response in lethal SARS‐CoV‐2 infection by deep spatial phenotyping
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1384
Abstract: Immunopathology of ongoing COVID‐19 global pandemic is not limited solely to pulmonary tissue, but is often associated with multi‐organ complications, mechanisms of which are intensely being investigated. In this regard, the interplay between immune, stromal cells and cytokines in pulmonary and extrapulmonary infected tissues, especially in young adults (median age 46 years, range 30–53 years) without comorbidities, remains poorly characterised. We profiled lung, heart and intestinal autopsy s les from five SARS‐CoV‐2‐infected cases for 18–20 targets to detect immune, cytokine and stromal cell status at subcellular resolution by a novel IHC‐based deep‐phenotyping technique, iSPOT (immunoSpatial histoPhenOmics using TSA‐IHC), to assess spatial and functional patterns of immune response in situ , in lethal COVID‐19 infection. SARS‐CoV‐2‐infected autopsy s les exhibit skewed counts of immune populations in all s les with organ‐specific dysfunctions. Lung and ileal tissue reveal altered architecture with marked loss of tissue integrity, while lung and heart tissue show severe hyperinflammation marked by elevated TNF‐α in heart tissue and additionally IL‐6, IFN‐γ and IL‐10 cytokines in lung s les. With resurgence of infection in younger populations, single‐cell cytokine localisation in immune and stromal structures provides important mechanistic insights into organ‐specific immunopathology of naïve SARS‐CoV‐2 infection in the absence of other comorbidities.
A comparative characterization of SARS-CoV-2-specific T cells induced by mRNA or inactive virus COVID-19 vaccines
Publisher: Elsevier BV
Date: 11-2022
ZIKV-Specific NS1 Epitopes as Serological Markers of Acute Zika Virus Infection
Publisher: Oxford University Press (OUP)
Date: 04-04-2019
Abstract: Zika virus (ZIKV) infections have reemerged as a global health issue due to serious clinical complications. Development of specific serological assays to detect and differentiate ZIKV from other cocirculating flaviviruses for accurate diagnosis remains a challenge. We investigated antibody responses in 51 acute ZIKV-infected adult patients from C inas, Brazil, including 7 pregnant women who later delivered during the study. Using enzyme-linked immunosorbent assays, levels of antibody response were measured and specific epitopes identified. Several antibody-binding hot spots were identified in ZIKV immunogenic antigens, including membrane, envelope (E) and nonstructural protein 1 (NS1). Interestingly, specific epitopes (2 from E and 2 from NS1) strongly recognized by ZIKV-infected patients' antibodies were identified and were not cross-recognized by dengue virus (DENV)-infected patients' antibodies. Corresponding DENV peptides were not strongly recognized by ZIKV-infected patients' antibodies. Notably, ZIKV-infected pregnant women had specific epitope recognition for ZIKV NS1 (amino acid residues 17-34), which could be a potential serological marker for early ZIKV detection. This study identified 6 linear ZIKV-specific epitopes for early detection of ZIKV infections. We observed differential epitope recognition between ZIKV-infected and DENV-infected patients. This information will be useful for developing diagnostic methods that differentiate between closely related flaviviruses.
Dynamic dengue haemorrhagic fever calculators as clinical decision support tools in adult dengue
Publisher: Oxford University Press (OUP)
Date: 15-11-2019
Abstract: The objective of this study was to develop multiple prediction tools that calculate the risk of developing dengue haemorrhagic fever. Training data consisted of 1771 in iduals from 2006–2008 admitted with dengue fever whereby 304 developed dengue haemorrhagic fever during hospitalisation. Least absolute shrinkage and selection operator regression was used to construct three types of calculators, static admission calculators and dynamic calculators that predict the risk of developing dengue haemorrhagic fever for a subsequent day (DAily Risk Tomorrow [DART]) or for any future point after a specific day since fever onset (DAily Risk Ever [DARE]). From 119 admission covariates, 35 were in at least one of the calculators, which reported area under the curve (AUC) values of at least 0.72. Addition of person-time data for DART improved AUC to 0.76. DARE calculators displayed a large increase in AUC to 0.79 past day 7 with the inclusion of a strong predictor, maximum temperature on day 6 since onset, indicative of a saddleback fever. All calculators performed well when validated with 2005 data. Addition of daily variables further improved the accuracy. These calculators can be used in tandem to assess the risk of dengue haemorrhagic fever upon admission and updated daily to obtain more precise risk estimates.
Rapidly growing mycobacteria in Singapore, 2006–2011
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.CMI.2014.10.018
Abstract: Nontuberculous mycobacteria infection is a growing global concern, but data from Asia are limited. This study aimed to describe the distribution and antibiotic susceptibility profiles of rapidly growing mycobacterium (RGM) isolates in Singapore. Clinical RGM isolates with antibiotic susceptibility tests performed between 2006 and 2011 were identified using microbiology laboratory databases and minimum inhibitory concentrations of amikacin, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, imipenem, linezolid, moxifloxacin, sulfamethoxazole or trimethoprim-sulfamethoxazole, tigecycline and tobramycin were recorded. Regression analysis was performed to detect changes in antibiotic susceptibility patterns over time. A total of 427 isolates were included. Of these, 277 (65%) were from respiratory specimens, 42 (10%) were related to skin and soft tissue infections and 36 (8%) were recovered from blood specimens. The two most common species identified were Mycobacterium abscessus (73%) and Mycobacterium fortuitum group (22%), with amikacin and clarithromycin being most active against the former, and quinolones and trimethoprim-sulfamethoxazole against the latter. Decreases in susceptibility of M. abscessus to linezolid by 8.8% per year (p 0.001), M. fortuitum group to imipenem by 9.5% per year (p 0.023) and clarithromycin by 4.7% per year (p 0.033) were observed. M. abscessus in respiratory specimens is the most common RGM identified in Singapore. Antibiotic options for treatment of RGM infections are increasingly limited.
Heterologous mRNA vaccine boosters induce a stronger and longer-lasting antibody response against Omicron XBB variant
Publisher: Elsevier BV
Date: 04-2023
Association Between Increased Vascular Nitric Oxide Bioavailability and Progression to Dengue Hemorrhagic Fever in Adults
Publisher: Oxford University Press (OUP)
Date: 02-03-2015
Abstract: In a prospective longitudinal adult study, vascular nitric oxide bioavailability measured as reactive hyperemia index was significantly higher at enrollment in patients who developed dengue hemorrhagic fever (DHF) (n = 11), compared with the non-DHF group (n = 63) and those with other febrile illnesses (n = 25) (P = .01). After adjustment for age, fever day, and body mass index, enrollment reactive hyperemia index was associated with a 4-fold increased risk for DHF, and predicted DHF with an area under the receiver operating curve of 0.86. Increased vascular nitric oxide in dengue is associated with increased vascular permeability and impaired homeostasis and may have utility as a predictor of DHF.
Association of Homologous and Heterologous Vaccine Boosters With COVID-19 Incidence and Severity in Singapore
Publisher: American Medical Association (AMA)
Date: 22-03-2022
Draft Genome Sequence of a Multidrug-Resistant New Delhi Metallo-β-Lactamase-1 (NDM-1)-Producing Escherichia coli Isolate Obtained in Singapore
Publisher: American Society for Microbiology
Date: 26-12-2013
Abstract: We report the draft genome sequence of a New Delhi metallo-β-lactamase-1 (NDM-1)-positive Escherichia coli isolate obtained from a surgical patient. The assembled data indicate the presence of 3 multidrug resistance plasmids, 1 of which shares 100% identity with an NDM-1 plasmid isolated previously from a nearby hospital, suggesting possible local transmission.
Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19
Publisher: Massachusetts Medical Society
Date: 04-03-2021
The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.
Publisher: Oxford University Press (OUP)
Date: 19-06-2022
DOI: 10.1093/CID/CIAC476
Abstract: Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%–30%. Despite this, & people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target s le size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.
Derivation and validation of an accurate estimation of CD4 counts from the absolute lymphocyte count in virologically suppressed and immunologically reconstituted HIV infected adults
Publisher: Springer Science and Business Media LLC
Date: 13-08-2015
Identifying Adult Dengue Patients at Low Risk for Clinically Significant Bleeding
Publisher: Public Library of Science (PLoS)
Date: 05-02-2016
Vancomycin monotherapy vs. combination therapy for the treatment of persistent methicillin-resistantStaphylococcus aureusbacteremia
Publisher: Informa UK Limited
Date: 15-11-2013
DOI: 10.4161/VIRU.26909
Whole genome analysis of cephalosporin-resistant Escherichia coli from bloodstream infections in Australia, New Zealand and Singapore: high prevalence of CMY-2 producers and ST131 carrying blaCTX-M-15
Publisher: Oxford University Press (OUP)
Date: 14-12-2017
DOI: 10.1093/JAC/DKX466
Abstract: To characterize MDR Escherichia coli from bloodstream infections (BSIs) in Australia, New Zealand and Singapore. We collected third-generation cephalosporin-resistant (3GC-R) E. coli from blood cultures in patients enrolled in a randomized controlled trial from February 2014 to August 2015. WGS was used to characterize antibiotic resistance genes, MLST, plasmids and phylogenetic relationships. Antibiotic susceptibility was determined using disc diffusion and Etest. A total of 70 3GC-R E. coli were included, of which the majority were ST131 (61.4%). BSI was most frequently from a urinary source (69.6%), community associated (62.9%) and in older patients (median age 71 years). The median Pitt score was 1 and ICU admission was infrequent (3.1%). ST131 possessed more acquired resistance genes than non-ST131 (P = 0.003). Clade C1/C2 ST131 predominated (30.2% and 53.5% of ST131, respectively) and these were all ciprofloxacin resistant. All clade A ST131 (n = 6) were community associated. The predominant ESBL types were blaCTX-M (80.0%) and were strongly associated with ST131 (95% carried blaCTX-M), with the majority blaCTX-M-15. Clade C1 was associated with blaCTX-M-14 and blaCTX-M-27, whereas blaCTX-M-15 predominated in clade C2. Plasmid-mediated AmpC genes (mainly blaCMY-2) were frequent (17.1%) but were more common in non-ST131 (P < 0.001) isolates from Singapore and Brisbane. Two strains carried both blaCMY-2 and blaCTX-M. The majority of plasmid replicon types were IncF. In a prospective collection of 3GC-R E. coli causing BSI, community-associated Clade C1/C2 ST131 predominate in association with blaCTX-M ESBLs, although a significant proportion of non-ST131 strains carried blaCMY-2.
Providing outpatient parenteral antibiotic therapy (OPAT) to facilitate effective treatment of melioidosis
Publisher: Elsevier BV
Date: 06-2013
Challenges in Dengue Fever in the Elderly: Atypical Presentation and Risk of Severe Dengue and Hospita-Acquired Infection
Publisher: Public Library of Science (PLoS)
Date: 03-04-2014
Confirmed adult dengue deaths in Singapore: 5-year multi-center retrospective study
Publisher: Springer Science and Business Media LLC
Date: 12-05-2011
Interaction between Antibiotic Resistance, Resistance Genes, and Treatment Response for Urinary Tract Infections in Primary Care
Publisher: American Society for Microbiology
Date: 09-2019
DOI: 10.1128/JCM.00143-19
Abstract: Given increasing antimicrobial resistance, we aimed to determine antibiotic susceptibility and presence of resistance genes in uropathogens in primary care, factors associated with resistance to commonly prescribed antibiotics, and effect of treatment on early symptom resolution. We conducted a prospective study of primary care patients with urinary tract infection (UTI) symptoms and culture-confirmed UTI in Singapore from 2015 to 2016.
Clinical features of patients with Zika and dengue virus co-infection in Singapore
Publisher: Elsevier BV
Date: 06-2017
Hospital Pharmacists and Antimicrobial Stewardship: A Qualitative Analysis
Publisher: MDPI AG
Date: 24-11-2021
DOI: 10.3390/ANTIBIOTICS10121441
Abstract: Antimicrobial stewardship programmes (ASPs) in hospitals are predominantly led by specific ASP physicians and pharmacists. Limited studies have been conducted to appreciate non-ASP-trained hospital pharmacists’ perspectives on their roles in antimicrobial stewardship. Focus group discussions (FGDs) were conducted with 74 pharmacists, purposively s led from the 3 largest acute-care public hospitals in Singapore, to explore facilitators and barriers faced by them in antimicrobial stewardship. Applied thematic analysis was conducted and codes were categorised using the social–ecological model (SEM). At the intrapersonal level, pharmacists identified themselves as reviewers for drug safety before dispensing, confining to a restricted advisory role due to lack of clinical knowledge, experience, and empowerment to contribute actively to physicians’ prescribing decisions. At the interpersonal level, pharmacists expressed difficulties conveying their opinions and recommendations on antibiotic therapy to physicians despite frequent communications, but they assumed critical roles as educators for patients and their caregivers on proper antibiotic use. At the organisational level, in-house antibiotic guidelines supported pharmacists’ antibiotic interventions and recommendations. At the community level, pharmacists were motivated to improve low public awareness and knowledge on antibiotic use and antimicrobial resistance. These findings provide important insights into the gaps to be addressed in order to harness the untapped potential of hospital pharmacists and fully engage them in antimicrobial stewardship.
Sustaining Antimicrobial Stewardship in a High–Antibiotic Resistance Setting
Publisher: American Medical Association (AMA)
Date: 03-05-2022
Gut Microbiota Modulation: Implications for Infection Control and Antimicrobial Stewardship
Publisher: Springer Science and Business Media LLC
Date: 07-08-2020
Gut microbiome recovery after antibiotic usage is mediated by specific bacterial species
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2018
DOI: 10.1101/350470
Abstract: Dysbiosis in the gut microbiome due to antibiotic usage can persist for extended periods of time, impacting host health and increasing the risk for pathogen colonization. The specific factors associated with variability in gut microbiome recovery remain unknown. Using data from 4 different cohorts in 3 continents comprising microbiome profiles from 117 subjects, we identified 20 bacterial species exhibiting robust association with gut microbiome recovery post antibiotic therapy. Functional and growth analysis showed that microbiome recovery is supported by enrichment in carbohydrate degradation and energy production capabilities. Association rule mining on 782 microbiome profiles from the MEDUSA database enabled reconstruction of the gut microbial ‘food-web’, identifying many recovery-associated bacteria (RABs) as primary colonizing species, with the ability to use both host and diet-derived energy sources, and to break down complex carbohydrates to support the growth of other bacteria. Experiments in a mouse model recapitulated the ability of RABs ( Bacteroides thetaiotamicron and Bifidobacterium adolescentis ) to promote microbiome recovery with synergistic effects, providing a two orders of magnitude boost to microbial abundance in early time-points and faster maturation of microbial ersity. The identification of specific microbial factors promoting microbiome recovery opens up opportunities for rationally fine-tuning pre- and probiotic formulations that prevent pathogen colonization and promote gut health.
Severe community‐acquired Acinetobacter baumannii pneumonia: An emerging highly lethal infectious disease in the Asia–Pacific
Publisher: Wiley
Date: 22-10-2009
DOI: 10.1111/J.1440-1843.2009.01630.X
Abstract: Patients with community-acquired Acinetobacter baumannii (AB) pneumonia have been reported from subtropical countries. We investigated the epidemiology, clinical and microbiological characteristics of community-acquired pneumonia (CAP) due to AB in Singapore. A retrospective case series was performed over a 21-month period at two institutions. From 1 January 2007 to 30 September 2008, eight patients were diagnosed with CAP due to AB. Seven had bacteraemia and five were sputum culture-positive. The median age at presentation was 58.5 years (range 45-76 years). Five patients (71.4%) acquired the pneumonia in the warmer months of June to September. Presentation was acute, with a median duration of 2.5 days (range 1-7 days). The median Acute Physiology and Chronic Health Evaluation II score was 28.5 (range 6-36). Six patients presented with septic shock, lactic acidosis, acute kidney injury and respiratory failure, necessitating ICU care five of these patients eventually died. All patients received empirical antibiotics, including third-generation cephalosporins, which were inactive against the organism. All isolates were susceptible to icillin/sulbactam, ciprofloxacin, co-trimoxazole, aminoglycosides and imipenem. Community-acquired AB pneumonia have a fulminant course. In a region endemic for melioidosis and severe community-acquired Klebsiella pneumoniae, the challenge lies in rapid identification and initiation of appropriate empirical antibiotics to improve the survival of patients with AB CAP.
Implementation hurdles of an interactive, integrated, point-of-care computerised decision support system for hospital antibiotic prescription
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.IJANTIMICAG.2015.12.006
Abstract: Antimicrobial stewardship is used to combat antimicrobial resistance. In Singapore, a tertiary hospital has integrated a computerised decision support system, called Antibiotic Resistance Utilisation and Surveillance-Control (ARUSC), into the electronic inpatient prescribing system. ARUSC is launched either by the physician to seek guidance for an infectious disease condition or via auto-trigger when restricted antibiotics are prescribed. This paper describes the implementation of ARUSC over three phases from 1 May 2011 to 30 April 2013, compared factors between ARUSC launches via auto-trigger and for guidance, examined factors associated with acceptance of ARUSC recommendations, and assessed user acceptability. During the study period, a monthly average of 9072 antibiotic prescriptions was made, of which 2370 (26.1%) involved ARUSC launches. Launches via auto-trigger comprised 48.1% of ARUSC launches. In phase 1, 23% of ARUSC launches were completed. This rose to 38% in phase 2, then 87% in phase 3, as escapes from the ARUSC programme were sequentially disabled. Amongst completed launches for guidance, 89% of ARUSC recommendations were accepted versus 40% amongst completed launches via auto-trigger. Amongst ARUSC launches for guidance, being from a medical department [adjusted odds ratio (aOR)=1.20, 95% confidence interval (CI) 1.04-1.37] and ARUSC launch during on-call (aOR=1.81, 95% CI 1.61-2.05) were independently associated with acceptance of ARUSC recommendations. Junior physicians found ARUSC useful. Senior physicians found ARUSC reliable but admitted to having preferences for antibiotics that may conflict with ARUSC. Hospital-wide implementation of ARUSC encountered hurdles from physicians. With modifications, the completion rate improved.
Diagnostic lumbar puncture: Minimizing complications
Publisher: Wiley
Date: 07-2008
DOI: 10.1111/J.1445-5994.2008.01631.X
Abstract: Diagnostic lumbar puncture (LP) is essential to the diagnosis of central nervous system infections and subarachnoid haemorrhage. Life or limb-threatening adverse events due to the procedure are rare, but less severe complications may be common. Clinical practice in diagnostic LP is often not evidenced based. The aim of the study was to use best available published evidence to address questions on minimizing complications associated with diagnostic LP. We searched PubMed for studies in the English language using key words relevant to the complications of diagnostic LP. We emphasized randomized controlled trials and systematic reviews enrolling adult patients undergoing diagnostic LP. Uncontrolled studies and studies involving children or spinal anaesthesia were considered when no other evidence was available. There were nine prospective studies and three systematic reviews on reducing complications from LP. Recommendations on interventions to minimize complications of LP are graded based on the quality and strength of evidence.
Associations of viral ribonucleic acid (RNA) shedding patterns with clinical illness and immune responses in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) infection
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1160
Antibody Response of Heterologous vs Homologous Messenger RNA Vaccine Boosters Against the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant: Interim Results from the PRIBIVAC Study, a R
Publisher: Oxford University Press (OUP)
Date: 11-05-2022
DOI: 10.1093/CID/CIAC345
Abstract: Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity have raised the need for booster vaccinations. However, which combination of coronavirus disease 2019 (COVID-19) vaccines offers the strongest immune response against the Omicron variant is unknown. This randomized, participant-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. A total of 100 BNT162b2-vaccinated in iduals were enrolled and randomized 1:1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2 “BBB”) or heterologous messenger RNA (mRNA) (BNT162b2 + BNT162b2 + mRNA-1273 “BBM”) booster vaccine. The primary end point was the level of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and VOCs at day 28. A total of 51 participants were allocated to BBB and 49 to BBM 50 and 48, respectively, were analyzed for safety and immunogenicity outcomes. At day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22 382 IU/mL 95% confidence interval [CI], 18 210 to 27 517) vs BBM (29 751 IU/mL 95% CI, 25 281 to 35 011 P = .034) as was the median level of neutralizing antibodies: BBB 99.0% (interquartile range [IQR], 97.9% to 99.3%) vs BBM 99.3% (IQR, 98.8% to 99.5% P = .021). On subgroup analysis, significant higher mean spike antibody titer, median surrogate neutralizing antibody level against all VOCs, and live Omicron neutralization titer were observed only in older adults receiving BBM. Both vaccines were well tolerated. Heterologous mRNA-1273 booster vaccination compared with homologous BNT123b2 induced a stronger neutralizing response against the Omicron variant in older in iduals. NCT05142319.
The association of hypertension and diabetes pharmacotherapy with COVID-19 severity and immune signatures: an observational study
Publisher: Oxford University Press (OUP)
Date: 07-08-2020
Stomatal Function Requires Pectin De-methyl-esterification of the Guard Cell Wall
Publisher: Elsevier BV
Date: 11-2016
Efficacy of continuous infusion of vancomycin for the outpatient treatment of methicillin-resistant Staphylococcus aureus infections
Publisher: Oxford University Press (OUP)
Date: 21-08-2012
DOI: 10.1093/JAC/DKS328
Abstract: Recently published guidelines on the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend against administering vancomycin by continuous infusion on the basis of insufficient studies comparing this with intermittent infusion. We compared outcomes of patients treated with continuous infusion and intermittent infusion of vancomycin. Data for outpatients treated with continuous infusion and intermittent infusion of vancomycin were compared utilizing rates of clinical failure defined as the need for unplanned re-admission, change of antibiotics or extension of therapy. A total of 244 patients met the inclusion criteria, with 188 receiving continuous infusion and 56 intermittent infusion of vancomycin. The endpoint occurred in 21.3% and 30.4% of those receiving continuous infusion and intermittent infusion, respectively (relative risk 0.701, 95% CI 0.432-1.136, P = 0.159). Patient characteristics differed slightly between the two groups however, logistic regression to adjust for differences in age, co-morbidity, subtherapeutic levels and prosthetic devices did not substantially alter this result. No difference in rates of clinical failure of continuous infusion and intermittent infusion of vancomycin was observed in this outpatient cohort.
Clinical Relevance and Discriminatory Value of Elevated Liver Aminotransferase Levels for Dengue Severity
Publisher: Public Library of Science (PLoS)
Date: 05-06-2012
Virus-specific T lymphocytes home to the skin during natural dengue infection
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-03-2015
DOI: 10.1126/SCITRANSLMED.AAA0526
Abstract: Circulating virus-specific T lymphocytes may contribute to immune surveillance against dengue in the skin.
Safety of temporary interruption of antiplatelet therapy in dengue fever with thrombocytopenia
Publisher: Elsevier BV
Date: 02-2021
Assessing Viral Shedding and Infectivity of Tears in Coronavirus Disease 2019 (COVID-19) Patients
Publisher: Elsevier BV
Date: 07-2020
Sensitive detection of total anti-Spike antibodies and isotype switching in asymptomatic and symptomatic individuals with COVID-19
Publisher: Elsevier BV
Date: 02-2021
A Virus-Specific Immune Rheostat in the Immunome of Patients Recovering From Mild COVID-19
Publisher: Frontiers Media SA
Date: 25-05-2021
DOI: 10.3389/FIMMU.2021.674279
Abstract: An accurate depiction of the convalescent COVID-19 immunome will help delineate the immunological milieu crucial for disease resolution and protection. Using mass cytometry, we characterized the immune architecture in patients recovering from mild COVID-19. We identified a virus-specific immune rheostat composed of an effector T (T eff ) cell recall response that is balanced by the enrichment of a highly specialized regulatory T (T reg ) cell subset. Both components were reactive against a peptide pool covering the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein. We also observed expansion of IFNγ + memory CD4 + T cells and virus-specific follicular helper T (T FH ) cells. Overall, these findings pinpoint critical immune effector and regulatory mechanisms essential for a potent, yet harmless resolution of COVID-19 infection.
Asymptomatic COVID‐19: disease tolerance with efficient anti‐viral immunity against SARS‐CoV‐2
Publisher: EMBO
Date: 27-05-2021
The impact of multidrug resistance in healthcare-associated and nosocomial Gram-negative bacteraemia on mortality and length of stay: cohort study
Publisher: Elsevier BV
Date: 05-2012
Remdesivir for the Treatment of Covid-19 — Final Report
Publisher: Massachusetts Medical Society
Date: 05-11-2020
Efficacy and safety of abacavir/lamivudine plus rilpivirine as a first-line regimen in treatment-naïve HIV-1 infected adults
Publisher: Springer Science and Business Media LLC
Date: 21-05-2020
DOI: 10.1186/S12981-020-00272-5
Abstract: The anti-retroviral combination of abacavir/lamivudine plus rilpivirine (ABC/3TC/RPV) is not recommended by international guidelines as the first-line regimen. However, it is potent, well-tolerated, and affordable, especially in resource-limited settings. This study evaluates the efficacy and safety of ABC/3TC/RPV as an initial regimen for treatment-naïve HIV-1 infected patients. A retrospective study was conducted in the largest HIV care centre in Singapore, with data collected June 2011 to September 2017. All treatment-naïve HIV-1 infected adults prescribed ABC/3TC as part of their initial anti-retroviral therapy regimen were included. The third drug was a non-nucleoside reverse-transcriptase inhibitor (NNRTI) such as RPV or efavirenz (EFV), or boosted protease-inhibitor (PI). Patients were followed up for 48 weeks. The primary end-point was the percentage of patients achieving virologic suppression, analysed using on-treatment analysis. Secondary outcomes included CD4-count change, treatment discontinuation and treatment-related adverse events. 170 patients were included in the study, 66 patients in the RPV group, 104 patients in the comparator group (EFV or boosted PI). 96% (n = 24) in the RPV group and 87% (n = 26) in the comparator group achieved viral suppression at 48 weeks (p = 0.28). Median (interquartile range) time to viral suppression was similar: 17 (14–24) weeks in the RPV group, and 21 (13–26) weeks in the comparator group. There were no statistically significant differences in the CD4 count between the two groups. 14% (n = 9) of patients on RPV discontinued treatment before 48 weeks, compared to 30% (n = 31) from the comparator group (p = 0.053). Of these, 23 discontinuations were due to drug adverse effects, and only 1 attributed to RPV (p 0.01). One patient in each group had virologic failure. RPV is effective, safe and considerably more tolerable than compared to NNRTI or boosted PI in ABC/3TC-containing regimens for treatment-naïve patients. It offers an affordable and attractive option, especially in resource-limited settings.
Fever Patterns, Cytokine Profiles, and Outcomes in COVID-19
Publisher: Oxford University Press (OUP)
Date: 24-08-2020
DOI: 10.1093/OFID/OFAA375
Abstract: Prolonged fever is associated with adverse outcomes in dengue viral infection. Similar fever patterns are observed in COVID-19 with unclear significance. We conducted a hospital-based case–control study of patients admitted for COVID-19 with prolonged fever (fever & days) and saddleback fever (recurrence of fever, lasting & hours, after defervescence beyond day 7 of illness). Fever was defined as a temperature of ≥38.0°C. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. A total of 142 patients were included in the study 12.7% (18/142) of cases had prolonged fever, and 9.9% (14/142) had saddleback fever. Those with prolonged fever had a median duration of fever (interquartile range [IQR]) of 10 (9–11) days for prolonged fever cases, while fever recurred at a median (IQR) of 10 (8–12) days for those with saddleback fever. Both prolonged (27.8% vs 0.9% P & .01) and saddleback fever (14.3% vs 0.9% P = .03) were associated with hypoxia compared with controls. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9% P = .05). Patients with prolonged fever had higher induced protein–10 and lower interleukin-1α levels compared with those with saddleback fever at the early acute phase of disease. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Patients with saddleback fever appeared to have good outcomes regardless of the fever.
Effective Antimicrobial StewaRdship StrategIES (ARIES): Cluster randomised trial of computerised decision support system and prospective review and feedback
Publisher: Oxford University Press (OUP)
Date: 29-06-2020
DOI: 10.1093/OFID/OFAA254
Abstract: Prospective review and feedback (PRF) of antibiotic prescriptions and compulsory computerized decision support system (CDSS) are 2 strategies of antimicrobial stewardship. There are limited studies investigating their combined effects. We hypothesized that the use of on-demand (voluntary) CDSS would achieve similar patient outcomes compared with automatically triggered (compulsory) CDSS whenever broad-spectrum antibiotics are ordered. A parallel-group, 1:1 block cluster randomized crossover study was conducted in 32 medical and surgical wards from March to August 2017. CDSS use for piperacillin-tazobactam or carbapenem in the intervention clusters was at the demand of the doctor, while in the control clusters CDSS use was compulsory. PRF was continued for both arms. The primary outcome was 30-day mortality. Six hundred forty-one and 616 patients were randomized to voluntary and compulsory CDSS, respectively. There were no differences in 30-day mortality (hazard ratio [HR], 0.87 95% CI, 0.67–1.12), re-infection and re-admission rates, antibiotic duration, length of stay, or hospitalization cost. The proportion of patients receiving PRF recommendations was not significantly lower in the voluntary CDSS arm (62 [10%] vs 81 [13%] P = .05). Appropriate indication of antibiotics was high in both arms (351/448 [78%] vs 330/433 [74%] P = .18). However, in geriatric medicine patients where antibiotic appropriateness was & %, prescription via compulsory CDSS resulted in a shorter length of stay and lower hospitalization cost. Voluntary broad-spectrum antibiotics with PRF via CDSS did not result in differing clinical outcomes, antibiotic duration, or length of stay. However, in the setting of low antibiotic appropriateness, compulsory CDSS may be beneficial.
Early pathogenesis profiles across SARS-CoV-2 variants in K18-hACE2 mice revealed differential triggers of lung damages
Publisher: Frontiers Media SA
Date: 27-10-2022
DOI: 10.3389/FIMMU.2022.950666
Abstract: The on-going COVID-19 pandemic has given rise to SARS-CoV-2 clades and variants with differing levels of symptoms and severity. To this end, we aim to systematically elucidate the changes in the pathogenesis as SARS-CoV-2 evolved from ancestral to the recent Omicron VOC, on their mechanisms (e.g. cytokine storm) resulting in tissue damage, using the established K18-hACE2 murine model. We reported that among the SARS-CoV-2 viruses tested, infection profiles were initially similar between viruses from early clades but started to differ greatly starting from VOC Delta, where the trend continues in Omicron. VOCs Delta and Omicron both accumulated a significant number of mutations, and when compared to VOCs Alpha, Beta, and earlier predecessors, showed reduced neurotropism and less apparent gene expression in cytokine storm associated pathways. They were shown to leverage on other pathways to cause tissue damage (or lack of in the case of Omicron). Our study highlighted the importance of elucidating the response profiles of in idual SARS-CoV-2 iterations, as their propensity of severe infection via pathways like cytokine storm changes as more variant evolves. This will then affect the overall threat assessment of each variant as well as the use of immunomodulatory treatments as management of severe infections of each variant.
Metagenome-wide association analysis identifies microbial determinants of post-antibiotic ecological recovery in the gut
Publisher: Springer Science and Business Media LLC
Date: 06-07-2020
DOI: 10.1038/S41559-020-1236-0
Abstract: Loss of ersity in the gut microbiome can persist for extended periods after antibiotic treatment, impacting microbiome function, antimicrobial resistance and probably host health. Despite widespread antibiotic use, our understanding of the species and metabolic functions contributing to gut microbiome recovery is limited. Using data from 4 discovery cohorts in 3 continents comprising >500 microbiome profiles from 117 in iduals, we identified 21 bacterial species exhibiting robust association with ecological recovery post antibiotic therapy. Functional and growth-rate analysis showed that recovery is supported by enrichment in specific carbohydrate-degradation and energy-production pathways. Association rule mining on 782 microbiome profiles from the MEDUSA database enabled reconstruction of the gut microbial 'food web', identifying many recovery-associated bacteria as keystone species, with the ability to use host- and diet-derived energy sources, and support repopulation of other gut species. Experiments in a mouse model recapitulated the ability of recovery-associated bacteria (Bacteroides thetaiotaomicron and Bifidobacterium adolescentis) to promote recovery with synergistic effects, providing a boost of two orders of magnitude to microbial abundance in early time points and faster maturation of microbial ersity. The identification of specific species and metabolic functions promoting recovery opens up opportunities for rationally determining pre- and probiotic formulations offering protection from long-term consequences of frequent antibiotic usage.
Psychosocial determinants of physicians’ acceptance of recommendations by antibiotic computerised decision support systems: A mixed methods study
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.IJANTIMICAG.2014.10.009
Abstract: Antibiotic computerised decision support systems (CDSSs) were developed to facilitate optimal prescribing, but acceptance of their recommendations has remained low. We aimed to evaluate physicians' perceptions and attitudes toward antibiotic CDSSs and determine psychosocial factors associated with acceptance of CDSS recommendations for empirical therapy. A mixed methods study was conducted in an adult tertiary-care hospital in Singapore, with its in-house antibiotic CDSS that integrates antimicrobial stewardship with electronic prescribing. Focus group discussions were conducted among purposively s led physicians and data were analysed using the framework approach. Emerging themes were included in the questionnaire with newly developed scales for the subsequent cross-sectional survey involving all physicians. Principal components analysis was performed to derive the latent factor structure that was later applied in multivariate analyses. Physicians expressed confidence in the credibility of CDSS recommendations. Junior physicians accepted CDSS recommendations most of the time, whilst senior physicians acknowledged overriding recommendations in complex patients with multiple infections or allergies. Willingness to consult the CDSS for common and complex infections (OR=1.68, 95% CI 1.16-2.44) and preference for personal or team decision (OR=0.61, 95% CI 0.43-0.85) were associated with acceptance of CDSS recommendations. Cronbach's α for scales measuring physicians' attitudes and perceptions towards acceptance of CDSS recommendations ranged from 0.64 to 0.88. Physicians' willingness to consult an antibiotic CDSS determined acceptance of its recommendations. Physicians would choose to exercise their own or clinical team's decision over CDSS recommendations in complex patient situations when the antibiotic prescribing needs were not met.
Effects of coronavirus disease 2019 (COVID-19) pandemic on antimicrobial prevalence and prescribing in a tertiary hospital in Singapore
Publisher: Springer Science and Business Media LLC
Date: 03-02-2021
DOI: 10.1186/S13756-021-00898-8
Abstract: The deployment of antimicrobial stewardship (AMS) teams to deal with the COVID-19 pandemic can lead to a loss of developed frameworks, best practices and leadership resulting in adverse impact on antimicrobial prescribing and resistance. We aim to investigate effects of reduction in AMS resources during the COVID-19 pandemic on antimicrobial prescribing. One of 5 full-time equivalent AMS pharmacists was deployed to support pandemic work and AMS rounds with infectious disease physicians were reduced from 5 to 2 times a week. A survey in acute inpatients was conducted using the Global Point Prevalence Survey methodology in July 2020 and compared with those in 2015 and 2017–2019. The prevalence of antimicrobial prescribing (55% in 2015 to 49% in 2019 and 47% in 2020, p = 0.02) and antibacterials (54% in 2015 to 45% in 2019 and 42% in 2020, p 0.01) have been reducing despite the pandemic. Antimicrobial prescribing in infectious disease wards with suspected or confirmed COVID-19 cases was 29% in 2020. Overall, antimicrobial prescribing quality indicators continued to improve (e.g. reasons in notes, 91% in 2015 to 94% in 2019 and 97% in 2020, p 0.01) or remained stable (compliance to guideline, 71% in 2015 to 62% in 2019 and 73% in 2020, p = 0.08). During the COVID-19 pandemic, there was no increase in antimicrobial prescribing and no significant differences in antimicrobial prescribing quality indicators.
Clinical impact of non-antibiotic recommendations by a multi-disciplinary antimicrobial stewardship team
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.IJANTIMICAG.2017.01.046
Abstract: The multi-disciplinary antimicrobial stewardship team at the study hospital conducts prospective review and feedback on all inpatient orders of piperacillin-tazobactam and carbapenems. In addition, the team provides non-antibiotic recommendations (i.e. additional investigations and infectious disease reviews). This study aimed to describe the impact of these recommendations on patient outcomes. Patients on carbapenem and piperacillin-tazobactam who received at least one non-antibiotic recommendation between January 2012 and August 2014 were included in this study. Acceptance and rejection of non-antibiotic recommendations by the managing physician were compared. The primary outcome was 30-d mortality. Non-antibiotic recommendations were made in 166 patients. There were no differences in baseline characteristics between patients for whom recommendations were accepted and patients for whom recommendations were rejected. Thirty-day mortality (18.0% vs. 34.5%, P = 0.02) was significantly lower in patients who had at least one non-antibiotic recommendation accepted. Multi-variate analysis found that Charlson's comorbidity score [odds ratio (OR) 1.20, 95% confidence interval (CI) 1.03-1.42, P = 0.03], APACHE II score (OR 1.10, 95% CI 1.01-1.19, P < 0.01), hepatobiliary source of infection (OR 10.19, 95% CI 1.44-72.13, P = 0.02) and acceptance of at least one non-antibiotic recommendation (OR 0.39, 95% CI 0.17-0.88, P = 0.02) were independently associated with 30-d mortality. During prospective review and feedback of piperacillin-tazobactam and carbapenems, acceptance of non-antibiotic recommendations was found to be associated with a reduction in 30-d mortality.
A prospective case-control study to investigate retinal microvascular changes in acute dengue infection
Publisher: Springer Science and Business Media LLC
Date: 25-11-2015
DOI: 10.1038/SREP17183
Abstract: Dengue infection can affect the microcirculation by direct viral infection or activation of inflammation. We aimed to determine whether measured retinal vascular parameters were associated with acute dengue infection. Patients with acute dengue were recruited from Communicable Diseases Center, Singapore and age-gender-ethnicity matched healthy controls were selected from a population-based study. Retinal photographs were taken on recruitment and convalescence. A spectrum of quantitative retinal microvascular parameters (retinal vascular caliber, fractal dimension, tortuosity and branching angle) was measured using a semi-automated computer-based program. (Singapore I Vessel Assessment, version 3.0). We included 62 dengue patients and 127 controls. Dengue cases were more likely to have wider retinal arteriolar and venular calibers (158.3 μm vs 144.3 μm, p 0.001 227.7 μm vs 212.8 μm, p 0.001 respectively), higher arteriolar and venular fractal dimensions (1.271 vs 1.249, p = 0.002 1.268 vs. 1.230, p 0.001, respectively), higher arteriolar and venular tortuosity (0.730 vs 0.546 [x10 4 ], p 0.001 0.849 vs 0.658 [x10 4 ], p 0.001 respectively), compared to controls. Resolution of acute dengue coincided with decrease in retinal vascular calibers and venular fractal dimension. Dengue patients have altered microvascular network in the retina these changes may reflect pathophysiological processes in the immune system.
Facile synthesis of CeO2/g-C3N4 nanocomposites with significantly improved visible-light photocatalytic activity for hydrogen evolution
Publisher: Elsevier BV
Date: 06-2019
The IDentif.AI 2.0 Pandemic Readiness Platform: Rapid Prioritization of Optimized COVID-19 Combination Therapy Regimens
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2021
DOI: 10.1101/2021.06.23.21259321
Abstract: We aimed to harness IDentif.AI 2.0, a clinically actionable AI platform to rapidly pinpoint and prioritize optimal combination therapy regimens against COVID-19. A pool of starting candidate therapies was developed in collaboration with a community of infectious disease clinicians and included EIDD-1931 (metabolite of EIDD-2801), baricitinib, ebselen, selinexor, masitinib, nafamostat mesylate, telaprevir (VX-950), SN-38 (metabolite of irinotecan), imatinib mesylate, remdesivir, lopinavir, and ritonavir. Following the initial drug pool assessment, a focused, 6-drug pool was interrogated at 3 dosing levels per drug representing nearly 10,000 possible combination regimens. IDentif.AI 2.0 paired prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus (propagated, original strain, B.1.351 and B.1.617.2 variants) and Vero E6 assay with a quadratic optimization workflow. Within 3 weeks, IDentif.AI 2.0 realized a list of combination regimens, ranked by efficacy, for clinical go/no-go regimen recommendations. IDentif.AI 2.0 revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived. IDentif.AI 2.0 rapidly revealed promising drug combinations for clinical translation. It pinpointed dose-dependent drug synergy behavior to play a role in trial design and realizing positive treatment outcomes. IDentif.AI 2.0 represents an actionable path towards rapidly optimizing combination therapy following pandemic emergence. - When novel pathogens emerge, the immediate strategy is to repurpose drugs. - Good drugs delivered together in suboptimal combinations and doses can yield low or no efficacy, leading to misperception that the drugs are ineffective. - IDentif.AI 2.0 does not use in silico modeling or pre-existing data. - IDentif.AI 2.0 pairs optimization with prospectively acquired experimental data using a SARS-CoV-2/Vero E6 assay. - IDentif.AI 2.0 pinpoints EIDD-1931 as a foundation for optimized anti-SARS-CoV-2 combination therapies.
Exercise and Sports Cardiology
Publisher: WORLD SCIENTIFIC (EUROPE)
Date: 2018
DOI: 10.1142/Q0045
Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-08-2021
DOI: 10.1126/SCIIMMUNOL.ABL4340
Abstract: Autoantibodies neutralizing type I IFNs increase in prevalence over 60 years of age and underlie about 20% of all fatal COVID-19 cases.
Implications of Discordance in World Health Organization 1997 and 2009 Dengue Classifications in Adult Dengue
Publisher: Public Library of Science (PLoS)
Date: 04-2013
Defining Factors that Influence vaccine-induced, cross-variant neutralizing antibodies for SARS-CoV-2 in Asians
Publisher: Cold Spring Harbor Laboratory
Date: 08-03-2022
DOI: 10.1101/2022.03.06.22271809
Abstract: The scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced neutralizing antibody responses for key variants in an Asian volunteer cohort. We demonstrate a reduction in neutralizing antibody titres across all groups six months post-vaccination and show a marked reduction in the serological binding and neutralizing response targeting Omicron compared to other viral variants. We also highlight the increase in cross-protective neutralizing antibody responses against Omicron induced by a third dose (booster) of vaccine. These data illustrate how key virological factors such as immune escape mutation combined with host factors such as age and sex of the vaccinated in iduals influence the strength and duration of cross-protective serological immunity for COVID-19.
Sleep
Publisher: Springer International Publishing
Date: 2018
Capacity for antimicrobial stewardship in the Asia Pacific
Publisher: Elsevier BV
Date: 09-2021
The “timeless” use of influenza-like illness criteria for influenza detection in the tropics
Publisher: Elsevier BV
Date: 05-2021
Teicoplanin hypersensitivity syndrome
Publisher: Elsevier BV
Date: 04-2007
Blood pressure trend in hospitalized adult dengue patients
Publisher: Public Library of Science (PLoS)
Date: 07-2020
Membrane feeding of dengue patient’s blood as a substitute for direct skin feeding in studying Aedes-dengue virus interaction
Publisher: Springer Science and Business Media LLC
Date: 15-04-2016
A Multicenter Case-Case Control Study for Risk Factors and Outcomes of Extensively Drug-ResistantAcinetobacter baumanniiBacteremia
Publisher: Cambridge University Press (CUP)
Date: 2014
DOI: 10.1086/674387
Abstract: Extensively drug resistant (XDR) Acinetobacter baumannii infections are increasing. Knowledge of risk factors can help to prevent these infections. We designed a 1: 1: 1 case-case-control study to identify risk factors for XDR A. baumannii bacteremia in Singapore and Thailand. Case group 1 was defined as having infection due to XDR A. baumannii , and case group 2 was defined as having infection due to non-XDR A. baumannii . The control group comprised patients with blood cultures obtained to determine possible infection. There were 93 patients in each group. Pitt bacteremia score (adjusted odds ratio [aOR], 2.570 [95% confidence interval (CI), 1.528–4.322]), central venous catheters (CVCs aOR, 12.644 [95% CI, 2.143–74.620]), use of carbapenems (aOR, 54.391 [95% CI, 3.869–764.674]), and piperacillin-tazobactam (aOR, 55.035 [95% CI, 4.803–630.613]) were independently associated with XDR A. baumannii bacteremia. In case group 2, Pitt bacteremia score (aOR, 1.667 [95% CI, 1.265–2.196]) and third-generation cephalosporins (aOR, 2.965 [95% CI, 1.224–7.182]) were independently associated with non-XDR A. baumannii bacteremia. Concurrent infections (aOR, 3.527 [95% CI, 1.479–8.411]), cancer (aOR, 3.172 [95% CI, 1.135–8.865]), and respiratory source (aOR, 2.690 [95% CI, 1.160–6.239]) were associated with an increased risk of 30-day mortality. Survivors received more active empirical therapy (16.7% vs 9.6% P = .157), had fewer cases of XDR bacteremia (45.8% vs 52.6% P = .452), and received higher median definitive polymyxin B doses (840,000 units vs 700,000 units P = .339) Use of CVC and broad spectrum antibiotics were unique risk factors of XDR A. baumannii bacteremia. Effective antimicrobial stewardship together with use of a CVC bundle may reduce the incidence of these infections. Risk factors of acquisition and mortality may help identify patients for early initiation of polymyxin B therapy.
High-risk chest radiographic features associated with COVID-19 disease severity
Publisher: Public Library of Science (PLoS)
Date: 14-01-2021
DOI: 10.1371/JOURNAL.PONE.0245518
Abstract: High-risk CXR features in COVID-19 are not clearly defined. We aimed to identify CXR features that correlate with severe COVID-19. All confirmed COVID-19 patients admitted within the study period were screened. Those with suboptimal baseline CXR were excluded. CXRs were reviewed by three independent radiologists and opacities recorded according to zones and laterality. The primary endpoint was defined as hypoxia requiring supplemental oxygen, and CXR features were assessed for association with this endpoint to identify high-risk features. These features were then used to define criteria for a high-risk CXR, and clinical features and outcomes of patients with and without baseline high-risk CXR were compared using logistic regression analysis. 109 patients were included. In the initial analysis of 40 patients (36.7%) with abnormal baseline CXR, presence of bilateral opacities, multifocal opacities, or any upper or middle zone opacity were associated with supplemental oxygen requirement. Of the entire cohort, 29 patients (26.6%) had a baseline CXR with at least one of these features. Having a high-risk baseline CXR was significantly associated with requiring supplemental oxygen in univariate (odds ratio 14.0, 95% confidence interval 3.90–55.60) and multivariate (adjusted odds ratio 8.38, 95% CI 2.43–28.97, P = 0.001) analyses. We identified several high-risk CXR features that are significantly associated with severe illness. The association of upper or middle zone opacities with severe illness has not been previously emphasized. Recognition of these specific high-risk CXR features is important to prioritize limited healthcare resources for sicker patients.
A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction
Publisher: Springer Science and Business Media LLC
Date: 23-07-2020
Antimicrobial stewardship capacity and manpower needs in the Asia Pacific
Publisher: Elsevier BV
Date: 03-2021
NK cells are activated and primed for skin-homing during acute dengue virus infection in humans
Publisher: Springer Science and Business Media LLC
Date: 29-08-2019
DOI: 10.1038/S41467-019-11878-3
Abstract: Despite animal models showing that natural killer (NK) cells are important players in the early defense against many viral infections, the NK cell response is poorly understood in humans. Here we analyze the phenotype, temporal dynamics, regulation and trafficking of NK cells in a patient cohort with acute dengue virus infection. NK cells are robustly activated and proliferate during the first week after symptom debut. Increased IL-18 levels in plasma and in induced skin blisters of DENV-infected patients, as well as concomitant signaling downstream of the IL-18R, suggests an IL-18-dependent mechanism in driving the proliferative NK cell response. Responding NK cells have a less mature phenotype and a distinct chemokine-receptor imprint indicative of skin-homing. A corresponding NK cell subset can be localized to skin early during acute infection. These data provide evidence of an IL-18-driven NK cell proliferation and priming for skin-homing during an acute viral infection in humans.
Neutralizing antibodies from early cases of SARS-CoV-2 infection offer cross-protection against the SARS-CoV-2 D614G variant
Publisher: Cold Spring Harbor Laboratory
Date: 09-10-2020
DOI: 10.1101/2020.10.08.332544
Abstract: The emergence of a SARS-CoV-2 variant with a point mutation in the spike (S) protein, D614G, has taken precedence over the original Wuhan isolate by May 2020. With an increased infection and transmission rate, it is imperative to determine whether antibodies induced against the D614 isolate may cross-neutralize against the G614 variant. In this report, profiling of the anti-SARS-CoV-2 humoral immunity reveals similar neutralization profiles against both S protein variants, albeit waning neutralizing antibody capacity at the later phase of infection. These findings provide further insights towards the validity of current immune-based interventions. Random mutations in the viral genome is a naturally occurring event that may lead to enhanced viral fitness and immunological resistance, while heavily impacting the validity of licensed therapeutics. A single point mutation from aspartic acid (D) to glycine (G) at position 614 of the SARS-CoV-2 spike (S) protein, termed D614G, has garnered global attention due to the observed increase in transmissibility and infection rate. Given that a majority of the developing antibody-mediated therapies and serological assays are based on the S antigen of the original Wuhan reference sequence, it is crucial to determine if humoral immunity acquired from the original SARS-CoV-2 isolate is able to induce cross-detection and cross-protection against the novel prevailing D614G variant.
Omicron reactive multi protein specific CD4 T cells defines cellular immune response induced by inactivated virus vaccines
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2022
DOI: 10.1101/2022.05.25.22275616
Abstract: Unlike mRNA vaccines based only on the Spike protein, inactivated SARS-CoV-2 vaccines should induce a ersified T cell response recognizing distinct structural proteins. Here we performed a comparative analysis of SARS-CoV-2 specific T cells in healthy in iduals following vaccination with inactivated SARS-CoV-2 or mRNA vaccines. Relative to Spike mRNA vaccination, inactivated vaccines elicited a lower magnitude of Spike-specific T cells, but the combined Membrane, Nucleoprotein and Spike-specific T cell response was quantitatively comparable to the sole Spike T cell response induced by mRNA vaccines, and they efficiently tolerate the mutations characterizing the Omicron lineage. However, this multi-protein specific T cell response was not mediated by a coordinated CD4 and CD8 T cell expansion but by selected priming of CD4 T cells. These findings can help in defining the role of CD4 and CD8 T cells in the efficacy of the different vaccines to control severe COVID-19 after Omicron infection.
Evaluation of the safety and immunogenicity of different COVID-19 vaccine combinations in healthy individuals: study protocol for a randomized, subject-blinded, controlled phase 3 trial [PRIBIVAC]
Publisher: Springer Science and Business Media LLC
Date: 16-06-2022
DOI: 10.1186/S13063-022-06345-2
Abstract: Over 2021, COVID-19 vaccination programs worldwide focused on raising population immunity through the primary COVID-19 vaccine series. In Singapore, two mRNA vaccines (BNT162b2 and mRNA-1273) and the inactivated vaccine CoronaVac are currently authorized under the National Vaccination Programme for use as the primary vaccination series. More than 90% of the Singapore population has received at least one dose of a COVID-19 vaccine as of December 2021. With the demonstration that vaccine effectiveness wanes in the months after vaccination, and the emergence of Omicron which evades host immunity from prior infection and/or vaccination, attention in many countries has shifted to how best to maintain immunity through booster vaccinations. The objectives of this phase 3, randomized, subject-blinded, controlled clinical trial are to assess the safety and immunogenicity of heterologous boost COVID-19 vaccine regimens (intervention groups 1–4) compared with a homologous boost regimen (control arm) in up to 600 adult volunteers. As non-mRNA vaccine candidates may enter the study at different time points depending on vaccine availability and local regulatory approval, participants will be randomized at equal probability to the available intervention arms at the time of randomization. Eligible participants will have received two doses of a homologous mRNA vaccine series with BNT162b2 or mRNA-1273 at least 6 months prior to enrolment. Participants will be excluded if they have a history of confirmed SARS or SARS-CoV-2 infection, are immunocompromised, or are pregnant. Participants will be monitored for adverse events and serious adverse events by physical examinations, laboratory tests and self-reporting. Blood s les will be collected at serial time points [pre-vaccination/screening (day − 14 to day 0), day 7, day 28, day 180, day 360 post-vaccination] for assessment of antibody and cellular immune parameters. Primary endpoint is the level of anti-SARS-CoV-2 spike immunoglobulins at day 28 post-booster and will be measured against wildtype SARS-CoV-2 and variants of concern. Comprehensive immune profiling of the humoral and cellular immune response to vaccination will be performed. This study will provide necessary data to understand the quantity, quality, and persistence of the immune response to a homologous and heterologous third booster dose of COVID-19 vaccines. This is an important step in developing COVID-19 vaccination programs beyond the primary series. ClinicalTrials.gov NCT05142319 . Registered on 2 Dec 2021.
CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: Study protocol for a randomised controlled trial
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
Implementation of patient education for patients with atrial fibrillation: nationwide cross-sectional survey and one-year follow-up
Publisher: Oxford University Press (OUP)
Date: 25-07-2023
Abstract: Clinical practice guidelines recommend patient education for patients with atrial fibrillation (AF) as a part of holistic care, however, clinical guidelines lack detailed specification on the content, structure, and delivery of AF education programmes. To examine the implementation of education for patients with AF in Denmark in relation to coverage, organization, and content. A cross-sectional survey was conducted from February to May 2021. The survey contained questions on the organization, delivery, and content of education for patients with AF from all 29 AF outpatient hospital sites in Denmark. The survey was conducted by email and telephone. One-year follow-up was done in May 2022 by email. Patient education was provided by healthcare professionals in 16 (55%) hospitals. Nurse workforce issues, management, non-prioritization, and lack of guidance for implementation were reasons for the absence of patient education in 13 (45%) hospitals. The structure of patient education differed in relation to group or in idual teaching methods and six different education models were used. Content of the AF disease education was generally similar. At 1-year follow-up, another four hospitals reported offering patient education (69% in total). Initially, almost half of the hospitals did not provide patient education, but at 1-year follow-up, 69% of hospitals delivered patient education. Patient education was heterogeneous in relation to delivery, frequency, and duration. Future research should address in idualized patient education that may demonstrate superiority in relation to quality of life, less hospital admissions, and increased longevity.
Diagnostic performance of COVID‐19 serological assays during early infection: A systematic review and meta‐analysis of 11 516 samples
Publisher: Wiley
Date: 20-02-2021
DOI: 10.1111/IRV.12841
Abstract: The use of coronavirus disease 2019 (COVID‐19) serological testing to diagnose acute infection or determine population seroprevalence relies on understanding assay accuracy during early infection. We aimed to evaluate the diagnostic performance of serological testing in COVID‐19 by providing summary sensitivity and specificity estimates with time from symptom onset. A systematic search of Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed was performed up to May 13, 2020. All English language, original peer‐reviewed publications reporting the diagnostic performance of serological testing vis‐à‐vis virologically confirmed SARS‐CoV‐2 infection were included. Our search yielded 599 unique publications. A total of 39 publications reporting 11 516 s les from 8872 human participants met eligibility criteria for inclusion in our study. Pooled percentages of IgM and IgG seroconversion by Day 7, 14, 21, 28 and after Day 28 were 37.5%, 73.3%, 81.3%, 72.3% and 73.3%, and 35.4%, 80.6%, 93.3%, 84.4% and 98.9%, respectively. By Day 21, summary estimate of IgM sensitivity was 0.872 (95% CI: 0.784‐0.928) and specificity 0.973 (95% CI: 0.938‐0.988), while IgG sensitivity was 0.913 (95% CI: 0.823‐0.959) and specificity 0.960 (95% CI: 0.919‐0.980). On meta‐regression, IgM and IgG test accuracy was significantly higher at Day 14 using enzyme‐linked immunosorbent assay (ELISA) compared to other methods. Serological assays offer imperfect sensitivity for the diagnosis of acute SARS‐CoV‐2 infection. Estimates of population seroprevalence during or shortly after an outbreak will need to adjust for the delay between infection, symptom onset and seroconversion.
Differential Clinical Outcome of Dengue Infection Among Patients With and Without HIV Infection: A Matched Case–Control Study
Publisher: American Society of Tropical Medicine and Hygiene
Date: 03-06-2015
Decreased memory B cell frequencies in COVID‐19 delta variant vaccine breakthrough infection
Publisher: EMBO
Date: 21-01-2022
Abstract: The SARS-CoV-2 Delta (B.1.617.2) variant is capable of infecting vaccinated persons. An open question remains as to whether deficiencies in specific vaccine-elicited immune responses result in susceptibility to vaccine breakthrough infection. We investigated 55 vaccine breakthrough infection cases (mostly Delta) in Singapore, comparing them against 86 vaccinated close contacts who did not contract infection. Vaccine breakthrough cases showed lower memory B cell frequencies against SARS-CoV-2 receptor-binding domain (RBD). Compared to plasma antibodies, antibodies secreted by memory B cells retained a higher fraction of neutralizing properties against the Delta variant. Inflammatory cytokines including IL-1β and TNF were lower in vaccine breakthrough infections than primary infection of similar disease severity, underscoring the usefulness of vaccination in preventing inflammation. This report highlights the importance of memory B cells against vaccine breakthrough and suggests that lower memory B cell levels may be a correlate of risk for Delta vaccine breakthrough infection.
X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-08-2021
DOI: 10.1126/SCIIMMUNOL.ABL4348
Abstract: TLR7 and plasmacytoid dendritic cells are essential for type I IFN–dependent immunity to SARS-CoV-2 in the lungs.
Risk Factors for Fatality among Confirmed Adult Dengue Inpatients in Singapore: A Matched Case-Control Study
Publisher: Public Library of Science (PLoS)
Date: 22-11-2013
Chest radiography in coronavirus disease 2019 (Covid-19): Correlation with clinical course
Publisher: Academy of Medicine, Singapore
Date: 30-07-2020
DOI: 10.47102/ANNALS-ACADMEDSG.2020106
Abstract: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 and was declared a global pandemic by the World Health Organization on 11 March 2020. A definitive diagnosis of COVID-19 is made after a positive result is obtained on reverse transcription-polymerase chain reaction assay. In Singapore, rigorous contact tracing was practised to contain the spread of the virus. Nasal swabs and chest radiographs (CXR) were also taken from in iduals who were suspected to be infected by COVID-19 upon their arrival at a centralised screening centre. From our experience, about 40% of patients who tested positive for COVID-19 had initial CXR that appeared “normal”. In this case series, we described the temporal evolution of COVID-19 in patients with an initial “normal” CXR. Since CXR has limited sensitivity and specificity in COVID-19, it is not suitable as a first-line diagnostic tool. However, when CXR changes become unequivocally abnormal, close monitoring is recommended to manage potentially severe COVID-19 pneumonia. Key words: Diagnostic Radiology, Infectious Diseases, Pulmonary
Discovery of a 382-nt deletion during the early evolution of SARS-CoV-2
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2020
DOI: 10.1101/2020.03.11.987222
Abstract: To date, the SARS-CoV-2 genome has been considered genetically more stable than SARS-CoV or MERS-CoV. Here we report a 382-nt deletion covering almost the entire open reading frame 8 (ORF8) of SARS-CoV-2 obtained from eight hospitalized patients in Singapore. The deletion also removes the ORF8 transcription-regulatory sequence (TRS), which in turn enhances the downstream transcription of the N gene. We also found that viruses with the deletion have been circulating for at least four weeks. During the SARS-CoV outbreak in 2003, a number of genetic variants were observed in the human population [1], and similar variation has since been observed across SARS-related CoVs in humans and bats. Overwhelmingly these viruses had mutations or deletions in ORF8, that have been associated with reduced replicative fitness of the virus [2]. This is also consistent with the observation that towards the end of the outbreak sequences obtained from human SARS cases possessed an ORF8 deletion that may be associated with host adaptation [1]. We therefore hypothesise that the major deletion revealed in this study may lead to an attenuated phenotype of SARS-CoV-2.
Dengue Serotype-Specific Differences in Clinical Manifestation, Laboratory Parameters and Risk of Severe Disease in Adults, Singapore
Publisher: American Society of Tropical Medicine and Hygiene
Date: 06-05-2015
Cefazolin versus ceftriaxone as definitive treatment forKlebsiella pneumoniaebacteraemia: a retrospective multicentre study in Singapore
Publisher: Oxford University Press (OUP)
Date: 27-01-2021
DOI: 10.1093/JAC/DKAB009
Abstract: Ceftriaxone is the preferred treatment for bacteraemia caused by non-MDR (antibiotic-susceptible) Klebsiella pneumoniae. Excessive and widespread ceftriaxone use creates selection pressure for ESBLs. Cefazolin is an alternative, although there are theoretical concerns that SHV-1 β-lactamase in K. pneumoniae may inactivate cefazolin in an inoculum-dependent manner. In this retrospective study, we investigated the outcomes in K. pneumoniae bacteraemia patients treated with IV cefazolin versus IV ceftriaxone as definitive therapy. A total of 917 patients infected with K. pneumoniae from 1 January to 31 December 2016 in three public acute care hospitals in Singapore were screened for study eligibility. Consecutive unique episodes of monomicrobial bacteraemia caused by cefazolin- and/or ceftriaxone-susceptible K. pneumoniae were analysed (n = 284). There were 143 patients (50.4%) in the cefazolin group and 141 patients (49.6%) in the ceftriaxone group. Demographics, baseline illness severity and risk factors for healthcare-associated bacteraemia were comparable in the two treatment groups. The primary outcome of 28 day all-cause mortality was not significantly different between the cefazolin and ceftriaxone groups (10.5% versus 7.1%, P = 0.403). Both in the crude analysis and using a multivariable logistic regression model with inverse probability weighting based on propensity score, cefazolin treatment was not associated with increased risk of 28 day mortality (OR 1.51 with ceftriaxone as the reference group, 95% CI 0.67–3.53 adjusted OR 1.55, 95% CI 0.33–7.40). Cefazolin may be a ceftriaxone-sparing alternative treatment for antibiotic-susceptible K. pneumoniae bacteraemia. This observation may provide sufficient clinical equipoise for a randomized controlled trial.
Effectiveness of structured, hospital-based, nurse-led atrial fibrillation clinics: a comparison between a real-world population and a clinical trial population
Publisher: BMJ
Date: 2016
Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore
Publisher: American Medical Association (AMA)
Date: 21-04-2020
Mathematical Model To Quantify the Effects of Risk Factors on Carbapenem-Resistant Acinetobacter baumannii
Publisher: American Society for Microbiology
Date: 09-2014
DOI: 10.1128/AAC.02791-14
Abstract: Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are increasing, and they are associated with an increased risk of mortality in hospitalized patients. Linear regression is commonly used to identify concurrent trends, but it cannot quantify the relationship between risk factors and resistance. We developed a model to quantify the impact of antibiotic consumption on the prevalence of CRAB over time. Data were collected from January 2007 to June 2013 from our institution. Quarterly antibiotic consumption was expressed as defined daily dose/1,000 inpatient days. Six-month prevalence of CRAB was expressed as a percentage of all nonrepeat A. baumannii isolates tested. In idual trends were identified using linear regression. Antibiotic consumption from 2007 to 2011 was input as a step function in a relationship with CRAB. Model fit was evaluated by visual inspection and the residual sum of squares. The final model was validated using the best-fit (95% confidence interval) parameter estimates and antibiotic consumption to predict CRAB prevalence from January 2012 to June 2013. Cefepime, ertapenem, and piperacillin-tazobactam consumption and CRAB prevalence increased significantly over time. CRAB prevalence was best correlated to ertapenem (use sensitive r 2 = 0.76), and accounting for additional concurrent antibiotic use did not significantly improve model fit. Prospective validation with ertapenem consumption correlated well with CRAB observations, suggesting good predicting ability of the model. Our model provided the quantitative impact of antibiotic consumption on CRAB. We plan to further refine this model to account for multiple risk factors. Interventions should focus on controlling risk factors with the highest impact on resistance.
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-10-2020
Abstract: The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). In iduals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system d ens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified in iduals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy in iduals. Together, these studies identify a means by which in iduals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570 , p. eabd4585 see also p. 404
An interactive, point-of-care, computerised antibiotic prescription decision support system and quality of antibiotic prescription in the management of complicated urinary tract infection
Publisher: Elsevier BV
Date: 06-2014
The benign nature of acute dengue infection in hospitalized older adults in Singapore
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.IJID.2009.06.026
Abstract: In Singapore, dengue primarily affects adults. This study aimed to determine if older dengue patients in Singapore have greater morbidity and mortality. All laboratory diagnosed dengue patients admitted to Tan Tock Seng Hospital in 2004 were retrospectively reviewed. Cases were re-classified into dengue fever and dengue hemorrhagic fever based on World Health Organization criteria. Demographic, clinical, laboratory, and outcome data of patients aged > or = 60 years and or = 60 years. Older patients were significantly less likely to be male (44% vs. 64%), and more likely to have diabetes (17% vs. 2%), hypertension (48% vs. 4%), ischemic heart disease (6% vs. 0.1%), hyperlipidemia (18% vs. 1%), and secondary dengue infections (64% vs. 34%). Clinical features were similar except older patients were significantly less likely to report fever (92% vs. 99%), or have leukopenia (32% vs. 51%) or hemoconcentration (0 vs. 5%) on admission. Older patients had similar dengue hemorrhagic fever, bleeding, hypotension, severe thrombocytopenia, and elevated transaminase rates. Length of hospital stay, risk of intensive care unit admission, and outcome of death were not statistically different. Despite greater co-morbidity and secondary dengue infection, older dengue patients in Singapore did not have greater morbidity or mortality.
Contemporary narrative review of treatment options for COVID ‐19
Publisher: Wiley
Date: 08-07-2021
DOI: 10.1111/RESP.14106
Abstract: The coronavirus disease 2019 (COVID‐19) pandemic is ongoing and many drugs have been studied in clinical trials. From a pathophysiological perspective, anti‐viral drugs may be more effective in the early stage while immunomodulators may be more effective in severe patients in later stages of infection. While drugs such as lopinavir‐ritonavir, hydroxychloroquine and azithromycin have proved to be ineffective in randomized controlled trials, corticosteroids, neutralizing monoclonal antibodies, remdesivir, tocilizumab and baricitinib have been reported to benefit certain groups of patients with COVID‐19. In this review, we will present the key clinical evidence and progress in promising COVID‐19 therapeutics, as well as summarize the experience and lessons learned from the development of the current therapeutics.
Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study
Publisher: Elsevier BV
Date: 08-2020
Rapid determination of the wide dynamic range of SARS-CoV-2 Spike T cell responses in whole blood of vaccinated and naturally infected
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2021
DOI: 10.1101/2021.06.29.450293
Abstract: Antibodies and T cells cooperate to control virus infections. The definition of the correlates of protection necessary to manage the COVID-19 pandemic, require both immune parameters but the complexity of traditional tests limits virus-specific T cell measurements. We test the sensitivity and performance of a simple and rapid SARS-CoV-2 Spike-specific T cell test based on stimulation of whole blood with peptides covering the SARS-CoV-2 Spike protein followed by cytokine (IFN-γ, IL-2) measurement in different cohorts including BNT162b2 vaccinated (n=112 201 s les), convalescent asymptomatic (n=62 62 s les) and symptomatic (n=68 115 s les) COVID-19 patients and SARS-CoV-1 convalescent in iduals (n=12 12 s les). The sensitivity of the rapid cytokine whole blood test equates traditional methods of T cell analysis (ELISPOT, Activation Induced Markers). Utilizing this test we observed that Spike-specific T cells in vaccinated preferentially target the S2 region of Spike and that their mean magnitude is similar between them and SARS-CoV-2 convalescents at 3 months after vaccine or virus priming respectively. However, a wide heterogeneity of Spike-specific T cell magnitude characterizes the in idual responses irrespective of the time of analysis. No correlation between neutralizing antibody levels and Spike-specific T cell magnitude were found. Rapid measurement of cytokine production in whole blood after peptide activation revealed a wide dynamic range of Spike-specific T cell response after vaccination that cannot be predicted from neutralizing antibody quantities. Both Spike-specific humoral and cellular immunity should be tested after vaccination to define the correlates of protection necessary to evaluate current vaccine strategies.
Correction to: Robust Virus‐Specific Adaptive Immunity in COVID‐19 Patients with SARS‐CoV‐2 Δ382 Variant Infection
Publisher: Springer Science and Business Media LLC
Date: 27-11-2021
Potent neutralizing antibodies in the sera of convalescent COVID-19 patients are directed against conserved linear epitopes on the SARS-CoV-2 spike protein
Publisher: Cold Spring Harbor Laboratory
Date: 31-03-2020
DOI: 10.1101/2020.03.30.015461
Abstract: The ongoing SARS-CoV-2 pandemic demands rapid identification of immunogenic targets for the design of efficient vaccines and serological detection tools. In this report, using pools of overlapping linear peptides and functional assays, we present two immunodominant regions on the spike glycoprotein that were highly recognized by neutralizing antibodies in the sera of COVID-19 convalescent patients. One is highly specific to SARS-CoV-2, and the other is a potential pan-coronavirus target.
Candida glabrata prosthetic valve endocarditis treated successfully with fluconazole plus caspofungin without surgery: a case report and literature review
Publisher: Springer Science and Business Media LLC
Date: 11-2005
DOI: 10.1007/S10096-005-0038-2
Abstract: Reported here is the case of a 72-year-old man who was diagnosed with Candida glabrata prosthetic mitral valve endocarditis and treated successfully with fluconazole plus caspofungin after he refused and was determined unfit for surgery. Initial treatment with intravenous hotericin B resulted in acute renal impairment. Despite 8 days of intravenous fluconazole therapy, he remained fungemic. Caspofungin was added to the treatment regimen with subsequent sterilisation of blood culture. The patient was treated for 34 days with caspofungin and 41 days with fluconazole. He continued oral fluconazole after hospital discharge and remained well at follow-up 11 months later. The role of fluconazole and caspofungin in the treatment of Candida endocarditis is discussed.
Diabetes, cardiac disorders and asthma as risk factors for severe organ involvement among adult dengue patients: A matched case-control study
Publisher: Springer Science and Business Media LLC
Date: 03-01-2017
DOI: 10.1038/SREP39872
Abstract: Progression to severe organ involvement due to dengue infection has been associated with severe dengue disease, intensive care treatment, and mortality. However, there is a lack of understanding of the impact of pre-existing comorbidities and other risk factors of severe organ involvement among dengue adults. The aim of this retrospective case-control study is to characterize and identify risk factors that predispose dengue adults at risk of progression with severe organ involvement. This study involved 174 dengue patients who had progressed with severe organ involvement and 865 dengue patients without severe organ involvement, matched by the year of presentation of the cases, who were admitted to Tan Tock Seng Hospital between year 2005 and 2008. Age group of 60 years or older, diabetes, cardiac disorders, asthma, and having two or more pre-existing comorbidities were independent risk factors of severe organ involvement. Abdominal pain, clinical fluid accumulation, and hematocrit rise and rapid platelet count drop at presentation were significantly associated with severe organ involvement. These risk factors, when validated in a larger study, will be useful for triage by clinicians for prompt monitoring and clinical management at first presentation, to minimize the risk of severe organ involvement and hence, disease severity.
Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a multicentre, open-label, randomised, superiority trial
Publisher: Elsevier BV
Date: 04-2017
Predictive Tools for Severe Dengue Conforming to World Health Organization 2009 Criteria
Publisher: Public Library of Science (PLoS)
Date: 10-07-2014
Diabetes with Hypertension as Risk Factors for Adult Dengue Hemorrhagic Fever in a Predominantly Dengue Serotype 2 Epidemic: A Case Control Study
Publisher: Public Library of Science (PLoS)
Date: 05-2012
Higher rates of carbapenem‐related seizures in older hospitalised adults
Publisher: Wiley
Date: 2020
DOI: 10.1111/IMJ.14693
Abstract: Clinical experience suggests higher occurrence of carbapenem-associated seizures in the elderly than what is reported in the available literature (range between 0.2% and 0.7%). An audit of 1345 patients with age 60 years or older, who received imipenem, ertapenem or meropenem during their acute hospitalisation found 32 (2.4%) subjects developed seizures. Subjects with more than one central nervous system disorders were 11.6 times more likely to develop seizures (odds ratio 11.61, P < 0.001) and subjects with prior history of seizures is associated with four times greater risks (odds ratio 4.02, P = 0.005). Physicians should exercise caution when prescribing carbapenems in elderly, especially those with known epilepsy and a high number of intracranial pathologies.
Lower vaccine-acquired immunity in the elderly population following two-dose BNT162b2 vaccination is alleviated by a third vaccine dose
Publisher: Springer Science and Business Media LLC
Date: 08-08-2022
DOI: 10.1038/S41467-022-32312-1
Abstract: Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 in iduals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most in iduals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where in iduals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while in iduals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older in iduals against the ancestral Wuhan strain, Delta and Omicron variants.
Ertapenem in outpatient parenteral antimicrobial therapy for complicated urinary tract infections
Publisher: Informa UK Limited
Date: 30-05-2016
Differences in clinical features and dengue severity between local and migrant Chinese with dengue infection in Singapore
Publisher: Public Library of Science (PLoS)
Date: 15-08-2018
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-10-2020
Abstract: The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). In iduals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system d ens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified in iduals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy in iduals. Together, these studies identify a means by which in iduals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570 , p. eabd4585 see also p. 404
Acute Onset of Bilateral Follicular Conjunctivitis in two Patients with Confirmed SARS-CoV-2 Infections
Publisher: Informa UK Limited
Date: 06-10-2020
Clinical Outcome and Genetic Differences within a Monophyletic Dengue Virus Type 2 Population
Publisher: Public Library of Science (PLoS)
Date: 26-03-2015
Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia
Publisher: American Medical Association (AMA)
Date: 11-02-2020
Resistance of SARS-CoV-2 variants to neutralization by convalescent plasma from early COVID-19 outbreak in Singapore
Publisher: Springer Science and Business Media LLC
Date: 25-10-2021
DOI: 10.1038/S41541-021-00389-2
Abstract: The rapid spreading of SARS-CoV-2 variants B.1.1.7 originated from the United Kingdom and B.1.351 from South Africa has contributed to the second wave of COVID-19 cases in the respective countries and also around the world. In this study, we employed advanced biochemical and virological methodologies to evaluate the impact of Spike mutations of these strains on the degree of protection afforded by humoral immune responses following natural infection of the ancestral SARS-CoV-2 strain during the early stages of the outbreak. We found that antibody-mediated neutralization activity was partially reduced for B.1.1.7 variant and significantly attenuated for the B.1.351 strain. We also found that mutations outside the receptor-binding domain (RBD) can strongly influence antibody binding and neutralization, cautioning the use of solely RBD mutations in evaluating vaccine efficacy. These findings highlight an urgent need to develop new SARS-CoV-2 vaccines that are not based exclusively on the ancestral SARS-CoV-2 Spike gene sequence.
Reactive Infection Control Strategy for Control of New Delhi Metallo-β-Lactamase (NDM)-Producing Enterobacteriaceae Analyzed Using Whole-Genome Sequencing: Hits and Misses
Publisher: Cambridge University Press (CUP)
Date: 04-05-2016
DOI: 10.1017/ICE.2016.92
Abstract: Genetically distinct isolates of New Delhi metallo-β-lactamase (NDM)–producing Enterobacteriaceae were identified from the clinical cultures of 6 patients. Screening of shared-ward contacts identified 2 additional NDM-positive patients. Phylogenetic analysis proved that 1 contact was a direct transmission while the other was unrelated to the index, suggesting hidden routes of transmission. Infect Control Hosp Epidemiol 2016 :987–990
Early induction of SARS-CoV-2 specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients
Publisher: Cold Spring Harbor Laboratory
Date: 16-10-2020
DOI: 10.1101/2020.10.15.341958
Abstract: Virus-specific humoral and cellular immunity act synergistically to protect the host from viral infection. We interrogated the dynamic changes of virological and immunological parameters in 12 patients with symptomatic acute SARS-CoV-2 infection from disease onset to convalescence or death. We quantified SARS-CoV-2 viral RNA in the respiratory tract in parallel with antibodies and circulating T cells specific for various structural (NP, M, ORF3a and spike) and non-structural proteins (ORF7/8, NSP7 and NSP13). We observed that while rapid induction and quantity of humoral responses were associated with increased disease severity, an early induction of SARS-CoV-2 specific T cells was present in patients with mild disease and accelerated viral clearance. These findings provide further support for a protective role of SARS-CoV-2 specific T cells over antibodies during SARS-CoV-2 infection with important implications in vaccine design and immune-monitoring.
Pandemic (H1N1) 2009 influenza in HIV-infected adults: Clinical features, severity, and outcome
Publisher: Elsevier BV
Date: 11-2010
Methicillin-sensitive Staphylococcus aureus tricuspid valve endocarditis with annular abscess cured with oral levofloxacin and rifampicin
Publisher: Elsevier BV
Date: 09-2007
Cure of Candida glabrata native tricuspid valve endocarditis by continuous infusion of conventional amphotericin B in a patient with nephrotic syndrome
Publisher: Elsevier BV
Date: 08-2007
Potent pan-sarbecovirus neutralizing monoclonal antibodies isolated from a BNT162b2-vaccinated SARS-CoV-1 survivor
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-07-2023
Abstract: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron h ered efforts in controlling the ongoing coronavirus disease 2019 pandemic due to their ability to escape neutralizing antibodies induced by vaccination or prior infection, highlighting the need to develop broad-spectrum vaccines and therapeutics. Most human monoclonal antibodies (mAbs) reported to date have not demonstrated true pan-sarbecovirus neutralizing breadth especially against animal sarbecoviruses. Here, we report the isolation and characterization of highly potent mAbs targeting the receptor binding domain (RBD) of huACE2-dependent sarbecovirus from a SARS-CoV survivor vaccinated with BNT162b2. Among the six mAbs identified, one (E7) showed better huACE2-dependent sarbecovirus neutralizing potency and breadth than any other mAbs reported to date. Mutagenesis and cryo–electron microscopy studies indicate that these mAbs have a unique RBD contact footprint and that E7 binds to a quaternary structure–dependent epitope.
Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection
Publisher: Rockefeller University Press
Date: 03-2021
DOI: 10.1084/JEM.20202617
Abstract: The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between antiviral and inflammatory features. SARS-CoV-2–specific T cells in in iduals who clear SARS-CoV-2 without symptoms could reveal nonpathological yet protective characteristics. We longitudinally studied SARS-CoV-2–specific T cells in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. We quantified T cells reactive to structural proteins (M, NP, and Spike) using ELISpot and cytokine secretion in whole blood. Frequencies of SARS-CoV-2–specific T cells were similar between asymptomatic and symptomatic in iduals, but the former showed an increased IFN-γ and IL-2 production. This was associated with a proportional secretion of IL-10 and proinflammatory cytokines (IL-6, TNF-α, and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2–specific T cell activation in symptomatic in iduals. Thus, asymptomatic SARS-CoV-2–infected in iduals are not characterized by weak antiviral immunity on the contrary, they mount a highly functional virus-specific cellular immune response.
Safety and cost savings of reducing adult dengue hospitalization in a tertiary care hospital in Singapore
Publisher: Oxford University Press (OUP)
Date: 2013
Self-reported knowledge and awareness about blood pressure and hypertension: a cross-sectional study of a random sample of men and women aged 60–74 years
Publisher: Informa UK Limited
Date: 02-2014
DOI: 10.2147/CLEP.S53706
Hyperlipidemia, statin use and dengue severity
Publisher: Springer Science and Business Media LLC
Date: 21-11-2018
DOI: 10.1038/S41598-018-35334-2
Abstract: Multiple in vitro and mice model studies suggest statins may attenuate dengue severity. However, little is known about statin use and dengue severity in adult dengue patients with hyperlipidemia. We conducted a retrospective cohort study from 2004–2008 and 2012–2013 in Tan Tock Seng Hospital, Singapore on adult dengue patients with hyperlipidemia, comparing those with and without statin usage at hospitalization in terms of primary outcome of dengue hemorrhagic fever (DHF) or shock syndrome (DSS), and severe dengue (SD). Of 13,975 subjects screened, 257 dengue patients were included 191 (74.3%) were statin users and 66 (25.7%) were non-users. Compared with non-users, statin use was not associated with decreased risk of DHF/DSS (adjusted risk ratio [aRR] = 0.66, 95%confidence interval [CI]: 0.41–1.08, P = 0.10) and SD (aRR = 1.43, 95%CI: 0.84–2.43, P = 0.19). Therefore, statin usage had minimal effect on dengue severity in our study population in Singapore.
Heterologous booster vaccination with CoronaVac following prime vaccination with mRNA vaccine
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1403
Abstract: Despite the high vaccine efficacy of mRNA COVID‐19 vaccines, there are in iduals who developed excessive reactogenic and/or allergic responses after the first mRNA dose and were considered ineligible for further mRNA doses. CoronaVac, an inactivated SARS‐CoV‐2 vaccine, is recommended in Singapore as an alternative. In iduals, ineligible for further mRNA vaccines (BNT162b2 or mRNA‐1273) because of excessive reactive responses to prime mRNA vaccination, were recruited and offered two doses of CoronaVac as booster vaccination 38–224 days post their mRNA vaccine dose. In iduals who did not develop any excessive reactive responses after the prime mRNA vaccination were also recruited and given another mRNA vaccine as booster vaccination. Blood s les were collected at days 0, 21 and 90 post first CoronaVac dose and mRNA dose, respectively, for analysis. We showed that two CoronaVac booster doses induced specific immunity in these mRNA vaccine‐primed in iduals. Although the spike‐specific antibody response was lower, their memory B cell response against the receptor‐binding domain (RBD) of the spike protein was similar, compared with in iduals who received two BNT162b2 injections. The spike‐specific memory T cell response also increased following CoronaVac booster doses. However, specific immunity against the Omicron variant was low, similar to in iduals with two BNT162b2 doses. Our findings showed that while mRNA vaccine‐primed in iduals can opt for two subsequent doses of CoronaVac, an additional dose may be necessary to achieve protection, especially against newly emerging immune escape variants such as Omicron.
BNT162b2 vaccine protection against omicron and effect of previous infection variant and vaccination sequence among children and adolescents in Singapore: a population-based cohort study
Publisher: Elsevier BV
Date: 07-2023
Population Pharmacokinetics of Polymyxin B
Publisher: Wiley
Date: 08-01-2018
DOI: 10.1002/CPT.981
Abstract: Polymyxin B is used as a last treatment resort for multidrug-resistant Gram-negative bacterial infections. The objectives of this study were to examine the population pharmacokinetics of polymyxin B and investigate factor(s) influencing pharmacokinetic variability. Four serial blood s les each were collected from 35 adult patients at steady state. The concentrations of in idual polymyxin B components were analyzed using a validated liquid chromatography / tandem mass spectrometry assay and combined to derive total concentrations. A maximum likelihood expectation maximization approach was used to fit the data. Various demographic variables were investigated as potential covariates for clearance and volume of distribution (V
The Associations between Poor Antibiotic and Antimicrobial Resistance Knowledge and Inappropriate Antibiotic Use in the General Population Are Modified by Age
Publisher: MDPI AG
Date: 30-12-2021
DOI: 10.3390/ANTIBIOTICS11010047
Abstract: Objectives: Understanding factors influencing inappropriate antibiotic use can guide the design of interventions to improve antibiotic practices and reduce antimicrobial resistance (AMR). Methods: A nationally representative cross-sectional survey (N = 2004) was conducted between November 2020 and January 2021. Knowledge of antibiotic use and AMR using the World Health Organization’s Multi-Country AMR Survey questionnaire, and antibiotic practices were examined. Multivariable logistic regression was performed to identify factors associated with inappropriate antibiotic use and examine effect measure modifications. Results: After adjusting for potential confounding, poor knowledge of antibiotic use was associated with a 3x increased odds of inappropriate antibiotic use in adults aged ≥50 years (aOR 3.11, 95% CI [2.24–4.32]), 5× increased odds in those aged 35–49 years (aOR 4.88, 95% CI [3.32–7.16]), and 7× increased odds in those aged 21–34 years (aOR 6.58, 95% CI [4.19–10.33]). While there was no statistically significant association in adults aged ≥50 years, poor knowledge of AMR increased the odds of inappropriate antibiotic use by 4 times in adults aged 35–49 years (aOR 3.73, 95% CI [1.53–9.11]) and 5 times in those aged 21–34 years (aOR 4.90, 95% CI [1.84–13.02]). Conclusions: Targeted educational interventions for specific age groups are needed in conjunction with empowering the public with knowledge of antibiotic use and AMR.
The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the a
Publisher: Cold Spring Harbor Laboratory
Date: 26-10-2020
DOI: 10.1101/2020.10.26.355107
Abstract: SARS-CoV-2-neutralizing antibodies are promising therapeutics for COVID-19. However, little is known about the mechanisms of action of these antibodies or their effective dosing windows. We report the discovery and development of SC31, a potent SARS-CoV-2 neutralizing IgG1 antibody, originally isolated from a convalescent patient at day 27 after the onset of symptoms. Neutralization occurs via a binding epitope that maps within the ACE2 interface of the SARS-CoV-2 Spike protein, conserved across all common circulating SARS-CoV-2 mutants. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, SC31 demonstrated potent survival benefit by dramatically reducing viral load concomitant with attenuated pro-inflammatory responses linked to severe systemic disease, such as IL-6. Comparison with a Fc-null LALA variant of SC31 demonstrated that optimal therapeutic efficacy of SC31 requires intact Fc-mediated effector functions that can further induce an IFNγ-driven anti-viral immune response. Dose-dependent efficacy for SC31 was observed down to 5mg/kg when dosed before the activation of lung inflammatory responses. Importantly, despite FcγR binding, no evidence of antibody dependent enhancement was observed with the Fc-competent SC31 even at sub-therapeutic doses. Therapeutic efficacy was confirmed in SARS-CoV-2-infected hamsters, where SC31 again significantly reduced viral load, decreased lung lesions and inhibited progression to severe disease manifestations. This study underlines the potential for significant COVID-19 patient benefit for the SC31 antibody that justifies rapid advancement to the clinic, as well as highlighting the importance of appropriate mechanistic and functional studies during development. Anti-SARS-CoV-2 IgG1 antibody SC31 controls infection in vivo by blocking SP:ACE2 binding and triggering a Fc-mediated anti-viral response.
Changes in serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates from adult patients in Asia: Emergence of drug-resistant non-vaccine serotypes
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.VACCINE.2019.09.065
Abstract: This study was performed to investigate the serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae in Asian countries. A prospective surveillance study on S. pneumoniae collected from adult patients (≥50 years old) with invasive pneumococcal disease or community-acquired pneumonia was performed at 66 hospitals in Asian countries (Korea, China, Malaysia, Singapore, the Philippines, and Thailand) in 2012-2017. Serotyping and antimicrobial susceptibility tests of 850 pneumococcal isolates were performed. The proportions of isolates with serotypes covered by 13-valent pneumococcal conjugate vaccine (PCV13) were 37.0% in Korea, 53.4% in China, 77.2% in Malaysia, 35.9% in the Philippines, 68.7% in Singapore, and 60.2% in Thailand. Major serotypes were 19F (10.4%), 19A (10.1%), and 3 (8.5%) in 2012-2017, with different serotype distributions in each country. Macrolide resistance in pneumococci was high (66.8%) and prevalence of multidrug resistance (MDR) also remained high (50.8%). MDR non-PCV13 serotypes such as 11A, 15A, 35B, and 23A have emerged in Asian countries. This study showed the persistent prevalence of 19F and 19A with a noteworthy increase of certain non-PCV13 serotypes in Asian countries. High prevalence of macrolide resistance and MDR was also found in pneumococcal isolates. These data emphasize the need for continued surveillance of pneumococcal epidemiology in Asia in the post-pneumococcal vaccine era.
Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC β-Lactamase–Producing Enterobacter spp, Citrobacter freundii, Morganella mor
Publisher: Oxford University Press (OUP)
Date: 08-2021
DOI: 10.1093/OFID/OFAB387
Abstract: Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative. We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days. Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI}, –12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC β-lactamase genes identified were blaCMY-2, blaDHA-17, blaCMH-3, and blaACT-17. No ESBL, OXA, or other carbapenemase genes were identified. Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen. NCT02437045.
MRSA Transmission Dynamics Among Interconnected Acute, Intermediate-Term, and Long-Term Healthcare Facilities in Singapore
Publisher: Oxford University Press (OUP)
Date: 29-04-2017
DOI: 10.1093/CID/CIX072
Local transmission and global dissemination of New Delhi Metallo-Beta-Lactamase (NDM): a whole genome analysis
Publisher: Springer Science and Business Media LLC
Date: 13-06-2016
The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens
Publisher: Springer Science and Business Media LLC
Date: 30-06-2022
DOI: 10.1038/S41746-022-00627-4
Abstract: IDentif.AI-x, a clinically actionable artificial intelligence platform, was used to rapidly pinpoint and prioritize optimal combination therapies against COVID-19 by pairing a prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus and Vero E6 assay with a quadratic optimization workflow. A starting pool of 12 candidate drugs developed in collaboration with a community of infectious disease clinicians was first narrowed down to a six-drug pool and then interrogated in 50 combination regimens at three dosing levels per drug, representing 729 possible combinations. IDentif.AI-x revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived, and pinpointed a number of clinically actionable drug interactions, which were further reconfirmed in SARS-CoV-2 variants B.1.351 (Beta) and B.1.617.2 (Delta). IDentif.AI-x prioritized promising drug combinations for clinical translation and can be immediately adjusted and re-executed with a new pool of promising therapies in an actionable path towards rapidly optimizing combination therapy following pandemic emergence.
Linear B-Cell Epitopes in the Spike and Nucleocapsid Proteins as Markers of SARS-CoV-2 Exposure and Disease Severity
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3605114
Statin use is associated with lower disease severity in COVID-19 infection
Publisher: Springer Science and Business Media LLC
Date: 15-10-2020
DOI: 10.1038/S41598-020-74492-0
Abstract: We aim to study the association of hyperlipidemia and statin use with COVID-19 severity. We analysed a retrospective cohort of 717 patients admitted to a tertiary centre in Singapore for COVID-19 infection. Clinical outcomes of interest were oxygen saturation ≤ 94% requiring supplemental oxygen, intensive-care unit (ICU) admission, invasive mechanical-ventilation and death. Patients on long term dyslipidaemia medications (statins, fibrates or ezetimibe) were considered to have dyslipidaemia. Logistic regression models were used to study the association between dyslipidaemia and clinical outcomes adjusted for age, gender and ethnicity. Statin treatment effect was determined, in a nested case–control design, through logistic treatment models with 1:3 propensity matching for age, gender and ethnicity. All statistical tests were two-sided, and statistical significance was taken as p 0.05. One hundred fifty-six (21.8%) patients had dyslipidaemia and 97% of these were on statins. Logistic treatment models showed a lower chance of ICU admission for statin users when compared to non-statin users (ATET: Coeff (risk difference): − 0.12 (− 0.23, − 0.01) p = 0.028). There were no other significant differences in other outcomes. Statin use was independently associated with lower ICU admission. This supports current practice to continue prescription of statins in COVID-19 patients.
High Yield of HIV Testing in Dengue-Like Febrile Illness in Singapore
Publisher: Oxford University Press (OUP)
Date: 13-07-2018
DOI: 10.1093/OFID/OFY171
Abstract: Where dengue virus infections are endemic, acute febrile illness is often managed as dengue fever (DF) without diagnostic testing. In a prospective study of 140 patients with clinical features of DF, 3 (2.1%) had acute HIV infection (AHI). We recommend testing for AHI in dengue-like febrile illness.
Influenza in the tropics
Publisher: Elsevier BV
Date: 08-2009
Antibiotic Therapy in the Treatment of COVID-19 Pneumonia: Who and When?
Publisher: MDPI AG
Date: 31-01-2022
DOI: 10.3390/ANTIBIOTICS11020184
Abstract: Background: COVID-19 imposes challenges in antibiotic decision-making due to similarities between bacterial pneumonia and moderate to severe COVID-19. We evaluated the effects of antibiotic therapy on the clinical outcomes of COVID-19 pneumonia patients and diagnostic accuracy of key inflammatory markers to inform antibiotic decision-making. Methods: An observational cohort study was conducted in patients hospitalised with COVID-19 at the National Centre for Infectious Diseases and Tan Tock Seng Hospital, Singapore, from January to April 2020. Patients were defined as receiving empiric antibiotic treatment for COVID-19 if started within 3 days of diagnosis. Results: Of 717 patients included, 86 (12.0%) were treated with antibiotics and 26 (3.6%) had documented bacterial infections. Among 278 patients with COVID-19 pneumonia, those treated with antibiotics had more diarrhoea (26, 34.7% vs. 24, 11.8%, p 0.01), while subsequent admissions to the intensive care unit were not lower (6, 8.0% vs. 10, 4.9% p = 0.384). Antibiotic treatment was not independently associated with lower 30-day (adjusted odds ratio, aOR 19.528, 95% confidence interval, CI 1.039–367.021) or in-hospital mortality (aOR 3.870, 95% CI 0.433–34.625) rates after adjusting for age, co-morbidities and severity of COVID-19 illness. Compared to white cell count and procalcitonin level, the C-reactive protein level had the best diagnostic accuracy for documented bacterial infections (area under the curve, AUC of 0.822). However, the sensitivity and specificity were less than 90%. Conclusion: Empiric antibiotic use in those presenting with COVID-19 pneumonia did not prevent deterioration or mortality. More studies are needed to evaluate strategies to diagnose bacterial co-infections in these patients.
Differential Cytokine Responses in Hospitalized COVID-19 Patients Limit Efficacy of Remdesivir
Publisher: Frontiers Media SA
Date: 28-06-2021
DOI: 10.3389/FIMMU.2021.680188
Abstract: A significant proportion of COVID-19 patients will progress to critical illness requiring invasive mechanical ventilation. This accentuates the need for a therapy that can reduce the severity of COVID-19. Clinical trials have shown the effectiveness of remdesivir in shortening recovery time and decreasing progression to respiratory failure and mechanical ventilation. However, some studies have highlighted its lack of efficacy in patients on high-flow oxygen and mechanical ventilation. This study uncovers some underlying immune response differences between responders and non-responders to remdesivir treatment. Immunological analyses revealed an upregulation of tissue repair factors BDNF, PDGF-BB and PIGF-1, as well as an increase in ratio of Th2-associated cytokine IL-4 to Th1-associated cytokine IFN-γ. Serological profiling of IgG subclasses corroborated this observation, with significantly higher magnitude of increase in Th2-associated IgG2 and IgG4 responses. These findings help to identify the mechanisms of immune regulation accompanying successful remdesivir treatment in severe COVID-19 patients.
Simple Clinical and Laboratory Predictors of Chikungunya versus Dengue Infections in Adults
Publisher: Public Library of Science (PLoS)
Date: 27-09-2012
Metformin Use and Severe Dengue in Diabetic Adults
Publisher: Springer Science and Business Media LLC
Date: 20-02-2018
DOI: 10.1038/S41598-018-21612-6
Abstract: Diabetes mellitus is a risk factor for severe dengue in adults, but few studies have examined the association between metformin use and disease severity in dengue. In addition to its effect on glucose control, metformin has been associated with pleiotropic properties in preclinical studies. Using a cohort of laboratory-confirmed adult (≥21 years) dengue patients with diabetes mellitus admitted to Tan Tock Seng Hospital, we conducted a retrospective cohort study involving 131 (58.7%) metformin users and 92 (41.3%) non-users. Dengue severity was categorized as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) in World Health Organization (WHO) 1997 criteria and severe dengue (SD) in WHO 2009 criteria. Multivariable Poisson regression with robust error variance was used to estimate risk ratio (RR). Compared with non-use, metformin use was associated with a decreased risk of developing severe dengue (adjusted risk ratio [aRR] = 0.60, 95% confidence interval [CI]: 0.37–0.98, P = 0.04). Additionally, there was an inverse dose-response relationship (aRR = 0.69, 95% CI: 0.49–0.98, P = 0.04) with dengue severity as classified by WHO 2009 criteria. Use of metformin, however, was not associated with dengue severity based on WHO 1997 criteria and no dose-response relationship was noted. Our results suggest metformin use could attenuate disease severity in dengue-infected diabetes mellitus in iduals.
Comparison of Diabetic and Non-diabetic Human Leukocytic Responses to Different Capsule Types of Klebsiella pneumoniae Responsible for Causing Pyogenic Liver Abscess.
Publisher: Frontiers Media SA
Date: 07-09-2017
Predictors for development of critical illness amongst older adults with COVID-19: Beyond age to age-associated factors
Publisher: Elsevier BV
Date: 05-2021
FromSARS toCOVID ‐19: the Singapore journey
Publisher: Wiley
Date: 31-05-2020
DOI: 10.5694/MJA2.50623
Pregnancy Outcomes in COVID-19: A Prospective Cohort Study in Singapore
Publisher: Academy of Medicine, Singapore
Date: 30-11-2020
DOI: 10.47102/ANNALS-ACADMEDSG.2020437
Abstract: Introduction: Pregnant women are reported to be at increased risk of severe coronavirus disease 2019 (COVID-19) due to underlying immunosuppression during pregnancy. However, the clinical course of COVID-19 in pregnancy and risk of vertical and horizontal transmission remain relatively unknown. We aim to describe and evaluate outcomes in pregnant women with COVID-19 in Singapore. Methods: Prospective observational study of 16 pregnant patients admitted for COVID-19 to 4 tertiary hospitals in Singapore. Outcomes included severe disease, pregnancy loss, and vertical and horizontal transmission. Results: Of the 16 patients, 37.5%, 43.8% and 18.7% were infected in the first, second and third trimesters, respectively. Two gravidas aged ≥35 years (12.5%) developed severe pneumonia one patient (body mass index 32.9kg/m2) required transfer to intensive care. The median duration of acute infection was 19 days one patient remained reverse transcription polymerase chain reaction (RT-PCR) positive weeks from diagnosis. There were no maternal mortalities. Five pregnancies produced term live-births while 2 spontaneous miscarriages occurred at 11 and 23 weeks. RT-PCR of breast milk and maternal and neonatal s les taken at birth were negative placenta and cord histology showed non-specific inflammation and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulins were elevated in paired maternal and umbilical cord blood (n=5). Conclusion: The majority of COVID-19 infected pregnant women had mild disease and only 2 women with risk factors (obesity, older age) had severe infection this represents a slightly higher incidence than observed in age-matched non-pregnant women. Among the women who delivered, there was no definitive evidence of mother-to-child transmission via breast milk or placenta. Keywords: Pregnancy outcomes, maternal morbidity, mother-child transmission, SARS-CoV-2, transferred immunity
Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients
Publisher: Elsevier BV
Date: 02-2021
Hot topics in the diagnosis and management of skin and soft-tissue infections
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.IJANTIMICAG.2016.04.011
Abstract: Eighteen hot topics regarding the diagnosis and management of skin and soft-tissue infections (SSTIs) were selected and reviewed by members of the SSTI Working Group of the International Society of Chemotherapy (ISC). Despite the large amount of literature available on the issue selected, there are still many unknowns with regard to many of them and further studies are required to answer these challenging issues that face clinicians on a daily basis.
Economic Impact of Dengue Illness and the Cost-Effectiveness of Future Vaccination Programs in Singapore
Publisher: Public Library of Science (PLoS)
Date: 20-12-2011
Oral versus intravenous antibiotics for patients with Klebsiella pneumoniae liver abscess: study protocol for a randomized controlled trial
Publisher: Springer Science and Business Media LLC
Date: 31-10-2013
Abstract: Klebsiella pneumoniae liver abscess is the most common etiology of liver abscess in Singapore and much of Asia, and its incidence is increasing. Current management includes prolonged intravenous antibiotic therapy, but there is limited evidence to guide oral conversion. The implicated K1/K2 capsule strain of Klebsiella pneumoniae is almost universally susceptible to ciprofloxacin, an antibiotic with high oral bioavailability. Our primary aim is to compare the efficacy of early ( one week) step-down to oral antibiotics, to continuing four weeks of intravenous antibiotics, in patients with Klebsiella liver abscess. The study is designed as a multi-center randomized open-label active comparator-controlled non-inferiority trial, with a non-inferiority margin of 12%. Eligible participants will be inpatients over the age of 21 with a CT or ultrasound scan suggestive of a liver abscess, and Klebsiella pneumoniae isolated from abscess fluid or blood. Randomization into intervention or active control arms will be performed with a 1:1 allocation ratio. Participants randomized to active control will receive IV ceftriaxone 2 grams daily to complete a total of four weeks of IV antibiotics. Participants randomized to intervention will be immediately converted to oral ciprofloxacin 750 mg twice daily. At Week four, all participants will undergo abdominal imaging and be assessed for clinical response (CRP 20 mg/l, absence of fever, plus scan showing that the maximal diameter of the abscess has reduced). If criteria are met, antibiotics are stopped if not, oral antibiotics are continued, with reassessment for clinical response fortnightly. If criteria for clinical response are met by Week 12, the primary endpoint of clinical cure is met. A cost analysis will be performed to assess the cost saving of early conversion to oral antibiotics, and a quality of life analysis will be performed to assess whether treatment with oral antibiotics is less burdensome than prolonged IV antibiotics. Our results would help inform local and international practice guidelines regarding the optimal antibiotic management of Klebsiella liver abscess. A finding of non-inferiority may translate to the wider adoption of a more cost-effective strategy that reduces hospital length of stay and improves patient-centered outcomes and satisfaction. Clinical trials gov NCT01723150
Measles Ring Vaccination in Dormitories: An Outbreak Containment Measure and Simulation Study
Publisher: Elsevier BV
Date: 2019
DOI: 10.2139/SSRN.3502369
Association of SARS-CoV-2 clades with clinical, inflammatory and virologic outcomes: An observational study
Publisher: Elsevier BV
Date: 04-2021
Critical care for dengue in adult patients: an overview of current knowledge and future challenges
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2016
Effects of Early Oseltamivir Therapy on Viral Shedding in 2009 Pandemic Influenza A (H1N1) Virus Infection
Publisher: Oxford University Press (OUP)
Date: 04-2010
DOI: 10.1086/651083
Abstract: Pandemic influenza (H1N1) 2009 is susceptible to oseltamivir. There are few reports on its clinical and virologic response to oseltamivir. During the pandemic containment response in Singapore, all patients with positive polymerase chain reaction (PCR) results for pandemic influenza (H1N1) 2009 were hospitalized, given oseltamivir for 5 days, and discharged when daily PCR results for combined nasal and throat swab s les became negative. Six patients had concurrent positive viral culture and PCR results. The median age of the first 70 consecutive patients was 26 years (interquartile range, 21-38 years) 60% were men, and 29% had comorbidity. The mean time (+/-SD) from illness onset to hospital admission was 3+/-2 days. Influenza-like illness was noted in 63% of patients. Fever occurred in 91%, cough in 88%, sore throat in 66%, and rhinorrhea in 53% of patients. The mean duration (+/-SD) of viral shedding from illness onset was day 6+/-2 days. Viral shedding persisted beyond 7 days in 37% of patients. Clinical features and viral shedding were similar between those with and without comorbidity, except the former had more cough and lower oxygen saturation. Patients receiving oseltamivir on days 1 to 3 of illness had significantly shorter viral shedding duration, compared with those treated from day 4 onwards (P < .05). The mean durations (+/-SD) of positive PCR and viral culture results were 5+/-8 and 4+/-18 days, respectively, for 6 patients with concurrent positive viral culture and PCR results. Prolonged viral shedding was noted in young immunocompetent adults with mild pandemic influenza (H1N1) 2009 despite receipt of oseltamivir. When prescribed during the first 3 days of illness, oseltamivir shortened the duration of viral shedding.
Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-blind, randomised, placebo-controlled, phase 3 trial
Publisher: Elsevier BV
Date: 12-2021
Remdesivir Versus Standard-of-Care for Severe Coronavirus Disease 2019 Infection: An Analysis of 28-Day Mortality
Publisher: Oxford University Press (OUP)
Date: 26-05-2021
DOI: 10.1093/OFID/OFAB278
Abstract: Remdesivir is approved by the US Food and Drug Administration for the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19) and has been shown to shorten time to recovery and improve clinical outcomes in randomized trials. This was the final day 28 comparative analysis of data from a phase 3, randomized, open-label study comparing 2 remdesivir regimens (5 vs 10 days, combined for this analysis [remdesivir cohort]) and a real-world retrospective longitudinal cohort study of patients receiving standard-of-care treatment (nonremdesivir cohort). Eligible patients, aged ≥18 years, had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), oxygen saturation ≤94% on room air or required supplemental oxygen, with pulmonary infiltrates. Propensity score matching (up to 1:10 ratio) was used to ensure comparable populations. We assessed day 14 clinical recovery (determined using a 7-point ordinal scale) and day 28 all-cause mortality (coprimary endpoints). A total of 368 (remdesivir) and 1399 (nonremdesivir) patients were included in the matched analysis. The day 14 clinical recovery rate was significantly higher among the remdesivir versus the nonremdesivir cohort (65.2% vs 57.1% odds ratio [OR], 1.49 95% confidence interval [CI], 1.16–1.90 P = 0.002). The day 28 mortality rate was significantly lower in the remdesivir cohort versus the nonremdesivir cohort (12.0% vs 16.2% OR, 0.67 95% CI, 0.47–.95 P = .03). Remdesivir was associated with significantly higher rates of day 14 clinical recovery, and lower day 28 mortality, compared with standard-of-care treatment in hospitalized patients with COVID-19. These data, taken together, support the use of remdesivir to improve clinical recovery and decrease mortality from SARS-CoV-2 infection.
Patient and physician predictors of patient receipt of therapies recommended by a computerized decision support system when initially prescribed broad-spectrum antibiotics: a cohort study
Publisher: Oxford University Press (OUP)
Date: 05-09-2015
DOI: 10.1093/JAMIA/OCV120
Abstract: Objective Antibiotic computerized decision support systems (CDSSs) were developed to guide antibiotic decisions, yet prescriptions of CDSS-recommended antibiotics have remained low. Our aim was to identify predictors of patients' receipt of empiric antibiotic therapies recommended by a CDSS when the prescribing physician had an initial preference for using broad-spectrum antibiotics. Methods We conducted a prospective cohort study in a 1 500-bed tertiary-care hospital in Singapore. We included all patients admitted from October 1, 2011 through September 30, 2012, who were prescribed piperacillin-tazobactam or carbapenem for empiric therapy and auto-triggered to receive antibiotic recommendations by the in-house antibiotic CDSS. Relevant data on the patient, prescribing and attending physicians were collected via electronic linkages of medical records and administrative databases. To account for clustering, we used multilevel logistic regression models to explore factors associated with receipt of CDSS-recommended antibiotic therapy. Results One-quarter of the 1 886 patients received CDSS-recommended antibiotics. More patients treated for pneumonia (33.2%) than sepsis (12.1%) and urinary tract infections (7.1%) received CDSS-recommended antibiotic therapies. The prescribing physician – but not the attending physician or clinical specialty – accounted for some (13.3%) of the variation. Prior hospitalization (odds ratio [OR] 1.32, 95% CI, 1.01-1.71), presumed pneumonia (OR 6.77, 95% CI, 3.28-13.99), intensive care unit (ICU) admission (OR 0.38, 95% CI, 0.21-0.66), and renal impairment (OR 0.70, 95% CI, 0.52-0.93) were factors associated with patients’ receipt of CDSS-recommended antibiotic therapies. Conclusions We observed that ICU admission and renal impairment were negative predictors of patients’ receipt of CDSS-recommended antibiotic therapies. Patients admitted to ICU and those with renal impairment might have more complex clinical conditions that require a physician's assessment in addition to antibiotic CDSS.
Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study
Publisher: Oxford University Press (OUP)
Date: 27-10-2020
DOI: 10.1093/CID/CIAA1479
Abstract: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC & mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8–87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%–15%) and 8% (95% CI 2%–15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI −1% to 10%) after excluding strains with piperacillin/tazobactam MIC values & mg/L. Isolates coharboring extended spectrum β-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%–28%). After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.
Self-Reported Pain Intensity with the Numeric Reporting Scale in Adult Dengue
Publisher: Public Library of Science (PLoS)
Date: 05-2014
Effectiveness of BNT162b2 Vaccine against Omicron in Children 5 to 11 Years of Age
Publisher: Massachusetts Medical Society
Date: 11-08-2022
Prolonged inflammation in patients hospitalized for coronavirus disease 2019 (COVID‐19) resolves 2 years after infection
Publisher: Wiley
Date: 05-2023
DOI: 10.1002/JMV.28774
Abstract: Long‐term complications from coronavirus disease 2019 (COVID‐19) are concerning, as survivors can develop subclinical multiorgan dysfunction. It is unknown if such complications are due to prolonged inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination may reduce sequela. We conducted a prospective longitudinal study on hospitalized patients over 24 months. Clinical symptoms were collected by self‐reporting during follow‐up, along with blood s les for quantification of inflammatory markers and immune cell frequencies. All patients were given one dose of mRNA vaccine at 12−16 months. Their immune profiles at 12 and 24 months were compared. Approximately 37% and 39% of our patients reported post‐COVID‐19 symptoms at 12 and 24 months, respectively. The proportion of symptomatic patients with more than one symptom decreased from 69% at 12 months to 56% at 24 months. Longitudinal cytokine profiling revealed a cluster of in iduals with persistently high inflammatory cytokine levels 12 months after infection. Patients with prolonged inflammation showed elevated terminally differentiated memory T cells in their blood 54% had symptoms at 12 months. The majority of inflammatory markers and dysregulated immune cells in vaccinated patients recovered to a healthy baseline at 24 months, even though symptoms persisted. Post‐COVID‐19 symptoms can linger for 2 years after the initial infection and are associated with prolonged inflammation. Prolonged inflammation in hospitalized patients resolves after 2 years. We define a set of analytes associated with persistent inflammation and presence of symptoms, which could be useful biomarkers for identifying and monitoring high‐risk survivors.
Increased Serum Hyaluronic Acid and Heparan Sulfate in Dengue Fever: Association with Plasma Leakage and Disease Severity
Publisher: Springer Science and Business Media LLC
Date: 10-04-2017
DOI: 10.1038/SREP46191
Abstract: Plasma leakage is a major pathogenic mechanism of severe dengue, but the etiology remains unclear. The association between endothelial glycocalyx integrity and vascular permeability in older adults with dengue has not been evaluated. A prospective cohort study of adults with undifferentiated fever screened for dengue by RT-PCR or NS1 antigen testing was performed. Patients were assessed daily while symptomatic and at convalescence. Serum hyaluronic acid (HA), heparan sulfate (HS) and selected cytokines (TNF-α, IL-6, IL-10) were measured on enrollment and convalescence. Patients were diagnosed as dengue fever (DF, n = 30), dengue hemorrhagic fever (DHF, n = 20) and non-dengue (ND) febrile illness (n = 11). Acute HA and HS levels were significantly higher in all dengue patients compared to ND (p = 0.0033 and p = 0.0441 respectively), but not different between DF and DHF (p = 0.3426 and p = 0.9180 respectively). Enrolment HA inversely correlated with serum albumin, protein and platelets in all dengue and DHF (p 0.05). HA and HS in all dengue patients decreased significantly at convalescence. Serum IL-10 was significantly associated with HA in all dengue patients (p = 0.002). Serum HA and HS levels were increased in adult dengue and HA was associated with markers of disease severity. Endothelial glycocalyx damage may have a role in vascular leakage in dengue.
Large-Scale HLA Tetramer Tracking of T Cells during Dengue Infection Reveals Broad Acute Activation and Differentiation into Two Memory Cell Fates
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.IMMUNI.2019.10.007
Abstract: T cells play important multifaceted roles during dengue infection, and understanding their responses is important for defining correlates of protective immunity and identifying effective vaccine antigens. Using mass cytometry and a highly multiplexed peptide-HLA (human leukocyte antigen) tetramer staining strategy, we probed T cells from dengue patients-a total of 430 dengue and control candidate epitopes-together with key markers of activation, trafficking, and differentiation. During acute disease, dengue-specific CD8
Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19
Publisher: Cold Spring Harbor Laboratory
Date: 12-06-2020
DOI: 10.1101/2020.06.11.147389
Abstract: SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood s les from 54 COVID-19 patients revealed a dramatic increase in the number of immature neutrophils. This increase strongly correlated with disease severity and was associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts was observed for CD8 T-cells and VD2 γδ T-cells, which both exhibited increased differentiation and activation. ROC analysis revealed that the count ratio of immature neutrophils to CD8 or VD2 T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.
Coronavirus Disease 2019 (COVID-19): The Singapore Experience. A Review of the First Eight Months
Publisher: Academy of Medicine, Singapore
Date: 18-11-2020
DOI: 10.47102/ANNALS-ACADMEDSG.2020306
Abstract: As of 27 October 2020, there have been 57,980 confirmed cases of COVID-19 in Singapore, with 28 fatalities. To summarise the Singapore experience in managing and containing COVID-19 based on available published data and from relevant sources, a review of literature using research databases such as PubMed and OVID Medline, along with non-peer-reviewed articles and other sources, was conducted with the search terms ‘COVID-19’ and ‘Singapore’. Research conducted in Singapore has provided insight into the clinical manifestations and period of infectivity of COVID-19, demonstrated evidence of pre-symptomatic transmission, linked infection clusters using serological tools, and highlighted aspects of hospital-based environmental contamination. It has also provided guidance for diagnostic testing and has described immune and virologic correlates with disease severity. Evidence of effectiveness of containment measures such as early border control, rigorous contact training, and calibrated social distancing measures have also been demonstrated. Singapore’s multipronged strategy has been largely successful at containing COVID-19 and minimising fatalities, but the risk of re-emergence is high. Keywords: Epidemiology, management, prevention, transmission
Evaluation of the Effectiveness of Surveillance and Containment Measures for the First 100 Patients with COVID-19 in Singapore — January 2–February 29, 2020
Publisher: Centers for Disease Control MMWR Office
Date: 20-03-2020
Multidrug-Resistant Gram-Negative Bloodstream Infections among Residents of Long-Term Care Facilities
Publisher: Cambridge University Press (CUP)
Date: 05-2014
DOI: 10.1086/675823
Abstract: Prevalence of multidrug-resistant (MDR) gram-negative (GN) bacteria is increasing globally and is complicated by patient movement between acute and long-term care facilities (LTCFs). In Asia, the contribution of LTCFs as a source of MDR GN infections is poorly described. We aimed to define the association between residence in LTCFs and MDR GN bloodstream infections (BSIs). Secondary analysis of data from an observational cohort. Two tertiary referral hospitals in Singapore, including the 1,400-bed Tan Tock Seng Hospital and the 1,600-bed Singapore General Hospital. Adult patients with healthcare-onset (HCO) or hospital-onset (HO) GN BSI. Patients were identified from hospital databases using standard definitions. Risk factors for both MDR GN HCO and HO BSI were analyzed using a multivariable logistic regression model. A total of 675 episodes of GN BSI occurred over a 31-month period. Residence in a LTCF was an independent risk factor for developing MDR GN BSI (odds ratio [OR], 5.1 [95% confidence interval (CI), 2.2–11.9] P .01) when antibiotics were not used within the preceding 30 days. This risk persisted beyond the first 48 hours of hospitalization (OR, 3.4 [95% CI, 1.3–9.0] P = .01). Previous culture growing an MDR organism (OR, 1.8 [95% CI, 1.3–2.7] P .01), previous antibiotic use (OR, 1.8 [95% CI, 1.2–2.6] P .01), and intensive care unit stay (OR, 2.2 [95% CI, 1.2–3.9] P = .01), increased the risk of MDR GN BSI. Residence in a LTCF is an independent risk factor for MDR GN BSI. Attempts to contain MDR GN bacteria in large Asian cities, where the proportion of the population that is elderly is projected to increase, should include infection prevention strategies that engage LTCFs.
Outcomes of Appropriate Empiric Combination versus Monotherapy for Pseudomonas aeruginosa Bacteremia
Publisher: American Society for Microbiology
Date: 03-2013
DOI: 10.1128/AAC.02235-12
Abstract: Pseudomonas aeruginosa bacteremia is associated with high hospital mortality. Empirical combination therapy is commonly used to increase the likelihood of appropriate therapy, but the benefits of employing active agent have yet to be established. The purpose of this study was to compare outcomes of patients receiving appropriate empirical combination versus monotherapy for P. aeruginosa bacteremia. This was a retrospective, multicenter, cohort study of hospitalized adult patients with P. aeruginosa bacteremia from 2002 to 2011. The primary endpoint (30-day mortality) was assessed using multivariate logistic regression, adjusting for underlying confounding variables. Secondary endpoints of hospital mortality and time to mortality were assessed by Fisher's exact test and the Cox proportional hazards model, respectively. A total of 384 patients were analyzed. Thirty-day mortality was higher for patients receiving inappropriate therapy than for those receiving appropriate empirical therapy (43.8% versus 21.5% P = 0.03). However, there were no statistical differences in 30-day mortality following appropriate empirical combination versus monotherapy after adjusting for baseline APACHE II scores and lengths of hospital stay prior to the onset of bacteremia ( P = 0.55). Observed hospital mortality was 36.6% for patients administered combination therapy, compared with 28.7% for monotherapy patients ( P = 0.17). After adjusting for baseline APACHE II scores, the relationship between time to mortality and combination therapy was not statistically significant ( P = 0.59). Overall, no significant differences were observed for 30-day mortality, hospital mortality, and time to mortality between combination and monotherapy for P. aeruginosa bacteremia. Empirical combination therapy did not appear to offer an additional benefit, as long as the isolate was susceptible to at least one antimicrobial agent.
An outcomes analysis of outpatient parenteral antibiotic therapy (OPAT) in a large Asian cohort
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.IJANTIMICAG.2013.01.015
Abstract: Outpatient parenteral antibiotic therapy (OPAT) facilitates early discharge, easing demands on inpatient resources and allowing patients the opportunity to restore home life. In Singapore, two large hospitals established a common prospective database in 2006. This study presents an analysis of all enrolled cases over 6 years to consider factors potentially causing adverse outcomes. In this prospective observational study, patients' first OPAT episodes, from initiation to completion, re-admission or early cessation, were recorded and analysed using Cox regression to identify factors associated with clinical deterioration leading to unplanned hospital re-admission. Of 2229 first episodes, 1874 (84.1%) completed treatment in OPAT as planned 201 episodes (9.0%) were complicated by clinical deterioration and re-admitted. Other patients who failed to complete treatment were either re-admitted for elective procedures, experienced adverse drug reactions or peripherally inserted central catheter-related complications, or had other reasons for not completing treatment. Increased risk of clinical deterioration was associated with homecare OPAT (aHR=2.5, 95% CI 1.7-3.8 P 70 years (aHR=1.6, 95% CI 1.1-2.2 P=0.008) and non-private care (aHR=1.8, 95% CI 1.0-3.0 P=0.033). Diagnosis and type of antibiotic treatment were not significant risk factors for re-admission. OPAT provides intravenous antibiotics to those who would otherwise remain as hospital inpatients. In this large Asian cohort, clinical factors did not relate to the ability of patients to complete their treatment in OPAT. Criteria identified as significant warrant ongoing consideration as patients are assessed for acceptance into OPAT programmes.
Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study
Publisher: Elsevier BV
Date: 06-2021
Differentiating coronavirus disease 2019 (COVID-19) from influenza and dengue
Publisher: Research Square Platform LLC
Date: 18-06-2020
DOI: 10.21203/RS.3.RS-36343/V1
Abstract: Background: The novel coronavirus disease 2019 (COVID-19) presents with non-specific clinical features. This may result in misdiagnosis or delayed diagnosis, and lead to further transmission in the community. We aimed to derive early predictors to differentiate COVID-19 from influenza and dengue. Methods: The study comprised 126 patients with COVID-19, 171 with influenza and 180 with dengue, who presented within 5 days of symptom onset. All cases were confirmed by reverse transcriptase polymerase chain reaction tests. We used logistic regression models to identify clinical characteristics and laboratory markers in classifying COVID-19 versus influenza, and COVID-19 versus dengue. The performance of the models were evaluated using receiver operating characteristic curves (ROC). Results: Shortness of breath was the strongest predictor in the models for differentiating between COVID-19 and influenza, followed by diarrhoea. Higher lymphocyte count was predictive of COVID-19 versus influenza and versus dengue. In the model for differentiating between COVID-19 and dengue, patients with cough and higher platelet count were at increased odds of COVID-19, while headache, joint pain, skin rash and vomiting/nausea were indicative of dengue. The area under the ROC was 0.92 for flu model and 0.99 for dengue model. Conclusion: Models based on clinical features and simple laboratory markers for differentiating COVID-19 from influenza and dengue, which possess good predictive performance, can serve as a useful tool for primary care physicians to determine if further investigations or referrals would be required.
Monkeypox: disease epidemiology, host immunity and clinical interventions
Publisher: Springer Science and Business Media LLC
Date: 05-09-2022
Effectiveness of primary series and booster vaccination against SARS-CoV-2 infection and hospitalisation among adolescents aged 12–17 years in Singapore: a national cohort study
Publisher: Elsevier BV
Date: 02-2023
Immune Landscape of 382-Nt Deleted SARS-CoV-2 Reveals Heightened Adaptive Response Indicating Prophylactic Potential Against COVID-19
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3707283
Immunological and Viral Correlates of COVID-19 Disease Severity: A Prospective Cohort Study of the First 100 Patients in Singapore
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3576846
Serological response to trivalent inactivated influenza vaccine in HIV-infected adults in Singapore
Publisher: Informa UK Limited
Date: 17-02-2017
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19
Publisher: Massachusetts Medical Society
Date: 05-11-2020
Anxiety and depression among healthcare workers during the COVID-19 pandemic: a systematic umbrella review of the global evidence
Publisher: BMJ
Date: 09-2021
DOI: 10.1136/BMJOPEN-2021-054528
Abstract: To summarise the evidence relating to the prevalence of anxiety and depression among healthcare workers (HCWs) during the COVID-19 pandemic. An umbrella review of systematic reviews was undertaken using the Joanna Briggs Institute (JBI) methods. The Cochrane database of systematic reviews, JBI Evidence Synthesis, MEDLINE, Web of Science, PsycINFO, Embase and CINAHL were searched in March 2021 for reviews published in English. Systematic reviews reporting the prevalence of anxiety and depression among HCWs during the COVID-19 pandemic. Two researchers screened each abstract and independently reviewed full text articles. Study quality was assessed using the JBI critical appraisal tool for systematic reviews, and the degree of overlap in primary studies was calculated. Ten systematic reviews (100 unique studies), including 169 157 HCWs from 35 countries were included. The prevalence of anxiety among all HCWs ranged from 22.2% (95% CI 21.3% to 23.1%) to 33.0% (95% CI 31.9% to 34.1%). The prevalence of anxiety among physicians (n=5820) was reported to be between 17% and 19.8% and for nurses (n=14 938) between 22.8% and 27%. The prevalence of depression among all HCWs ranged from 17.9% (95% CI 17.1% to 18.8%) to 36% (95% CI 34.9% to 37.1%). The prevalence of depression among physicians (n=643) and nurses (n=8063) was reported to be 40.4% and 28%, respectively. There is wide variation evident in the presence of anxiety and depression among HCWs. In particular, the prevalence of depression among physicians was high. Strategies to reduce the incidence of anxiety and depression are urgently required. CRD42021238960.
Safety and clinical outcomes of carbapenem de-escalation as part of an antimicrobial stewardship programme in an ESBL-endemic setting
Publisher: Oxford University Press (OUP)
Date: 03-12-2014
DOI: 10.1093/JAC/DKU479
Abstract: To evaluate the safety and clinical outcomes of patients who received carbapenem de-escalation as guided by an antimicrobial stewardship programme (ASP) in a setting where ESBL-producing Enterobacteriaceae are endemic. Patients receiving meropenem or imipenem underwent a prospective ASP review for eligibility for de-escalation according to defined institutional guidelines. Patients in whom carbapenem was de-escalated or not de-escalated, representing the acceptance and rejection of the ASP recommendation, respectively, were compared. The primary outcome was the clinical success rate secondary outcomes included the 30 day readmission and mortality rates, the duration of carbapenem therapy, the incidence of adverse drug reactions due to antimicrobials, the acquisition of carbapenem-resistant Gram-negative bacteria and the occurrence of Clostridium difficile-associated diarrhoea (CDAD). The de-escalation recommendations for 300 patients were evaluated 204 (68.0%) were accepted. The patient demographics and disease severity were similar. The clinical success rates were similar [de-escalated versus not de-escalated, 183/204 (89.7%) versus 85/96 (88.5%), P = 0.84], as was the survival at hospital discharge [173/204 (84.8%) versus 79/96 (82.3%), P = 0.58]. In the de-escalated group, the duration of carbapenem therapy was shorter (6 versus 8 days, P & 0.001), the rate of adverse drug reactions was lower [11/204 (5.4%) versus 12/96 (12.5%), P = 0.037], there was less diarrhoea [9/204 (4.4%) versus 12/96 (12.5%), P = 0.015], there was a lower incidence of carbapenem-resistant Acinetobacter baumannii acquisition [4/204 (2.0%) versus 7/96 (7.3%), P = 0.042] and there was a lower incidence of CDAD [2/204 (1.0%) versus 4/96 (4.2%), P = 0.081]. This study suggests that the ASP-guided de-escalation of carbapenems led to comparable clinical success, fewer adverse effects and a lower incidence of the development of resistance. This approach is safe and practicable, and should be a key component of an ASP.
Detection of air and surface contamination by SARS-CoV-2 in hospital rooms of infected patients
Publisher: Springer Science and Business Media LLC
Date: 29-05-2020
DOI: 10.1038/S41467-020-16670-2
Abstract: Understanding the particle size distribution in the air and patterns of environmental contamination of SARS-CoV-2 is essential for infection prevention policies. Here we screen surface and air s les from hospital rooms of COVID-19 patients for SARS-CoV-2 RNA. Environmental s ling is conducted in three airborne infection isolation rooms (AIIRs) in the ICU and 27 AIIRs in the general ward. 245 surface s les are collected. 56.7% of rooms have at least one environmental surface contaminated. High touch surface contamination is shown in ten (66.7%) out of 15 patients in the first week of illness, and three (20%) beyond the first week of illness ( p = 0.01, χ 2 test). Air s ling is performed in three of the 27 AIIRs in the general ward, and detects SARS-CoV-2 PCR-positive particles of sizes µm and 1–4 µm in two rooms, despite these rooms having 12 air changes per hour. This warrants further study of the airborne transmission potential of SARS-CoV-2.
Comparative neutralisation profile of SARS-CoV-2 omicron subvariants BA.2.75 and BA.5
Publisher: Elsevier BV
Date: 12-2022
A vaccination update for rheumatologists—SARS‐CoV‐2, influenza and herpes zoster
Publisher: Wiley
Date: 08-2021
Utility of warning signs in guiding admission and predicting severe disease in adult dengue
Publisher: Springer Science and Business Media LLC
Date: 24-10-2013
Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.CMI.2016.10.023
Abstract: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.
Performance of Population Pharmacokinetic Models in Predicting Polymyxin B Exposures
Publisher: MDPI AG
Date: 18-11-2020
DOI: 10.3390/MICROORGANISMS8111814
Abstract: Polymyxin B is the last line of defense in treating multidrug-resistant gram-negative bacterial infections. Dosing of polymyxin B is currently based on total body weight, and a substantial intersubject variability has been reported. We evaluated the performance of different population pharmacokinetic models to predict polymyxin B exposures observed in in idual patients. In a prospective observational study, standard dosing (mean 2.5 mg/kg daily) was administered in 13 adult patients. Serial blood s les were obtained at steady state, and plasma polymyxin B concentrations were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The best-fit estimates of clearance and daily doses were used to derive the observed area under the curve (AUC) in concentration–time profiles. For comparison, 5 different population pharmacokinetic models of polymyxin B were conditioned using patient-specific dosing and demographic (if applicable) variables to predict polymyxin B AUC of the same patient. The predictive performance of the models was assessed by the coefficient of correlation, bias, and precision. The correlations between observed and predicted AUC in all 5 models examined were poor (r2 0.2). Nonetheless, the models were reasonable in capturing AUC variability in the patient population. Therapeutic drug monitoring currently remains the only viable approach to in idualized dosing.
Early oral stepdown antibiotic therapy versus continuing intravenous therapy for uncomplicated Gram-negative bacteraemia (the INVEST trial): study protocol for a multicentre, randomised controlled, open-label, phase III, non-inferiority trial.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2022
DOI: 10.1186/S13063-022-06495-3
Abstract: The incidence of Gram-negative bacteraemia is rising globally and remains a major cause of morbidity and mortality. The majority of patients with Gram-negative bacteraemia initially receive intravenous (IV) antibiotic therapy. However, it remains unclear whether patients can step down to oral antibiotics after appropriate clinical response has been observed without compromising outcomes. Compared with IV therapy, oral therapy eliminates the risk of catheter-associated adverse events, enhances patient quality of life and reduces healthcare costs. As current management of Gram-negative bacteraemia entails a duration of IV therapy with limited evidence to guide oral conversion, we aim to evaluate the clinical efficacy and economic impact of early stepdown to oral antibiotics. This is an international, multicentre, randomised controlled, open-label, phase III, non-inferiority trial. To be eligible, adult participants must be clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia. Randomisation to the intervention or standard arms will be performed with 1:1 allocation ratio. Participants randomised to the intervention arm (within 72 h from index blood culture collection) will be immediately switched to an oral fluoroquinolone or trimethoprim-sulfamethoxazole. Participants randomised to the standard arm will continue to receive IV therapy for at least 24 h post-randomisation before clinical re-assessment and decision-making by the treating doctor. The recommended treatment duration is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Primary outcome is 30-day all-cause mortality, and the key secondary outcome is health economic evaluation, including estimation of total healthcare cost as well as assessment of patient quality of life and number of quality-adjusted life years saved. Assuming a 30-day mortality of 8% in the standard and intervention arms, with 6% non-inferiority margin, the target s le size is 720 participants which provides 80% power with a one-sided 0.025 α-level after adjustment for 5% drop-out. A finding of non-inferiority in efficacy of oral fluoroquinolones or trimethoprim-sulfamethoxazole versus IV standard of care antibiotics may hypothetically translate to wider adoption of a more cost-effective treatment strategy with better quality of life outcomes. ClinicalTrials.gov NCT05199324. Registered 20 January 2022.
Dengue and travellers: implications for doctors in Australia
Publisher: AMPCo
Date: 04-2017
DOI: 10.5694/MJA16.01450
Decision tree algorithm in deciding hospitalization for adult patients with dengue haemorrhagic fever in Singapore
Publisher: Wiley
Date: 24-08-2009
DOI: 10.1111/J.1365-3156.2009.02337.X
Abstract: To develop a simple decision tree for clinicians to decide between hospitalization and outpatient monitoring of adult dengue patients. Retrospective cohort study on all laboratory-diagnosed dengue patients admitted in 2004 to Tan Tock Seng Hospital, Singapore. Demographic, clinical, laboratory and radiological data were collected, and cases classified as dengue fever (DF) or dengue haemorrhagic fever (DHF) using World Health Organization criteria. To develop the decision tree, we used chi-squared automatic interaction detector (CHAID) with bi-way and multi-way splitting. The resulting trees were pruned to achieve the highest sensitivity with the shortest tree. In 2004, 1973 probable and confirmed adult dengue patients were admitted DF comprised 1855 (94.0%) and DHF 118 (6.0%) of the cases. The best decision tree prediction had three branches, consisting of a history of clinical bleeding, serum urea, and serum total protein. This decision tree had a sensitivity of 1.00, specificity of 0.46, positive predictive value of 7.5%, and negative predictive value of 100%. The overall accuracy of the decision tree was 48.1%. The test sensitivity and specificity compared favourably with other predictive probability equations and sophisticated laboratory tests, and would prevent 43.9% of mild DF cases from hospitalization. A simple decision tree is effective in predicting DHF in the clinical setting for adult dengue infection.
SARS-CoV-2 Infection among Travelers Returning from Wuhan, China
Publisher: Massachusetts Medical Society
Date: 09-04-2020
DOI: 10.1056/NEJMC2003100
Longitudinal Study of Cellular and Systemic Cytokine Signatures to Define the Dynamics of a Balanced Immune Environment During Disease Manifestation in Zika Virus–Infected Patients
Publisher: Oxford University Press (OUP)
Date: 16-04-2018
Neutralizing Anti-Interferon-Gamma Autoantibody Levels May Not Correlate With Clinical Course of Disease
Publisher: Oxford University Press (OUP)
Date: 25-05-2016
DOI: 10.1093/CID/CIW351
Combination strategies for pandemic influenza response - a systematic review of mathematical modeling studies
Publisher: Springer Science and Business Media LLC
Date: 12-2009
Medical and psychosocial factors associated with antibiotic prescribing in primary care: survey questionnaire and factor analysis
Publisher: Royal College of General Practitioners
Date: 16-01-2017
Abstract: Acute upper respiratory infections (AURI) are the leading causes of antibiotic prescribing in primary care although antibiotics are often not indicated. To gain an understanding of the knowledge, attitudes, and practices (KAP) of GPs in Singapore and the associated latent factors to guide the implementation of an effective programme to reduce antibiotic use in primary care. An anonymous survey on the KAP of antibiotic use in AURI of GPs in Singapore. KAP survey questionnaires were posted to all GPs from a database. To ascertain the latent factors affecting prescribing patterns, exploratory factor analysis was performed. Among 427 responses, 351 (82.2%) were from GPs working in private practice. It was found that 58.4% of GPs in the private versus 72.4% of those in the public sector recognised that % of AURIs were caused by viruses ( P = 0.02). The majority of GPs (353/427 82.7%) felt that antibiotics were overprescribed in primary care. Significant factors associated with low antibiotic prescribing were good medical knowledge and clinical competency (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI] = 2.4 to 4.3), good clinical practice (aOR 2.7 [95% CI = 2.0 to 3.6]), availability of diagnostic tests (aOR 1.4 [95% CI = 1.1 to 1.8]), and desire to improve clinical practice (aOR 1.5 [95% CI = 1.2 to 1.9]). The conservative practice of giving antibiotics ‘to be on the safe side’ is significantly less likely to be associated with low antibiotic prescribing (aOR 0.7 [95% CI = 0.5 to 0.9]). This is the first KAP survey on antibiotic prescribing for AURI among GPs in Singapore. With the latent factors identified, future interventions should be directed at addressing these factors to reduce inappropriate antibiotic prescribing.
Differentiating coronavirus disease 2019 (COVID-19) from influenza and dengue
Publisher: Springer Science and Business Media LLC
Date: 05-10-2021
DOI: 10.1038/S41598-021-99027-Z
Abstract: The novel coronavirus disease 2019 (COVID-19) presents with non-specific clinical features. This may result in misdiagnosis or delayed diagnosis, and lead to further transmission in the community. We aimed to derive early predictors to differentiate COVID-19 from influenza and dengue. The study comprised 126 patients with COVID-19, 171 with influenza and 180 with dengue, who presented within 5 days of symptom onset. All cases were confirmed by reverse transcriptase polymerase chain reaction tests. We used logistic regression models to identify demographics, clinical characteristics and laboratory markers in classifying COVID-19 versus influenza, and COVID-19 versus dengue. The performance of each model was evaluated using receiver operating characteristic (ROC) curves. Shortness of breath was the strongest predictor in the models for differentiating between COVID-19 and influenza, followed by diarrhoea. Higher lymphocyte count was predictive of COVID-19 versus influenza and versus dengue. In the model for differentiating between COVID-19 and dengue, patients with cough and higher platelet count were at increased odds of COVID-19, while headache, joint pain, skin rash and vomiting/nausea were indicative of dengue. The cross-validated area under the ROC curve for all four models was above 0.85. Clinical features and simple laboratory markers for differentiating COVID-19 from influenza and dengue are identified in this study which can be used by primary care physicians in resource limited settings to determine if further investigations or referrals would be required.
Discovery and Genomic Characterization of a 382-Nucleotide Deletion in ORF7b and ORF8 during the Early Evolution of SARS-CoV-2
Publisher: American Society for Microbiology
Date: 25-08-2020
Abstract: During the SARS epidemic in 2003/2004, a number of deletions were observed in ORF8 of SARS-CoV, and eventually deletion variants became predominant, leading to the hypothesis that ORF8 was an evolutionary hot spot for adaptation of SARS-CoV to humans. However, due to the successful control of the SARS epidemic, the importance of these deletions for the epidemiological fitness of SARS-CoV in humans could not be established. The emergence of multiple SARS-CoV-2 strains with ORF8 deletions, combined with evidence of a robust immune response to ORF8, suggests that the lack of ORF8 may assist with host immune evasion. In addition to providing a key insight into the evolutionary behavior of SARS-CoV-2 as the virus adapts to its new human hosts, the emergence of ORF8 deletion variants may also impact vaccination strategies.
Risk prediction models to guide antibiotic prescribing: a study on adult patients with uncomplicated upper respiratory tract infections in an emergency department
Publisher: Springer Science and Business Media LLC
Date: 02-11-2020
DOI: 10.1186/S13756-020-00825-3
Abstract: Appropriate antibiotic prescribing is key to combating antimicrobial resistance. Upper respiratory tract infections (URTIs) are common reasons for emergency department (ED) visits and antibiotic use. Differentiating between bacterial and viral infections is not straightforward. We aim to provide an evidence-based clinical decision support tool for antibiotic prescribing using prediction models developed from local data. Seven hundred-fifteen patients with uncomplicated URTI were recruited and analysed from Singapore’s busiest ED, Tan Tock Seng Hospital, from June 2016 to November 2018. Confirmatory tests were performed using the multiplex polymerase chain reaction (PCR) test for respiratory viruses and point-of-care test for C-reactive protein. Demographic, clinical and laboratory data were extracted from the hospital electronic medical records. Seventy percent of the data was used for training and the remaining 30% was used for validation. Decision trees, LASSO and logistic regression models were built to predict when antibiotics were not needed. The median age of the cohort was 36 years old, with 61.2% being male. Temperature and pulse rate were significant factors in all 3 models. The area under the receiver operating curve (AUC) on the validation set for the models were similar. (LASSO: 0.70 [95% CI: 0.62–0.77], logistic regression: 0.72 [95% CI: 0.65–0.79], decision tree: 0.67 [95% CI: 0.59–0.74]). Combining the results from all models, 58.3% of study participants would not need antibiotics. The models can be easily deployed as a decision support tool to guide antibiotic prescribing in busy EDs.
Pandemic (H1N1) 2009 Surveillance and Prevalence of Seasonal Influenza, Singapore
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 2010
Lack of detail in population-level data impedes analysis of SARS-CoV-2 variants of concern and clinical outcomes
Publisher: Elsevier BV
Date: 09-2021
Nonconcordance with surgical site infection prevention guidelines and rates of surgical site infections for general surgical, neurological, and orthopedic procedures
Publisher: American Society for Microbiology
Date: 10-2011
DOI: 10.1128/AAC.00562-11
Abstract: Surgical site infection (SSI) is a common and preventable complication of surgery, but the relative importance of in idual measures recommended by guidelines has not been determined. Elective general surgical, neurological, and orthopedic procedures requiring antibiotic prophylaxis from a 3-month period were retrospectively studied to determine concordance with SSI prevention guidelines and to identify factors which predicted the development of SSIs. A total of 216 surgeries were reviewed, with 18 SSIs (8.3%). A mean of 1.4 antibiotic prophylaxis errors per surgery were identified, with correct antibiotic type identified for 64%, antibiotic timing for 83%, supplemental antibiotic dosing for 34%, and antibiotic duration of less than 24 h for 44%. Normothermia was present in 79% of surgeries, and normoglycemia was present in 17%. Univariate analysis of the SSI rate identified four significant factors. Antibiotic prophylaxis for less than 24 h postoperatively (odds ratio [OR], 0.213 95% confidence interval [95% CI]0.060 to 0.757) and neurosurgery (OR, 0.118 95% CI, 0.15 to 0.903) correlated with a reduced risk of SSI. The mean number of prophylaxis errors (OR, 1.6 95% CI, 1.02 to 2.4) and a duration of surgical drainage for more than 3 days (OR, 2.679 95% CI, 1.009 to 7.113) predicted SSI. By multivariate analysis, errors in in idual antibiotic prophylaxis measures were not significantly associated with SSI however, the presence of more than two errors was significant (OR, 4.030 95% CI, 1.018 to 15.96). A strong correlation was identified between the degree of concordance to SSI prevention guidelines and the SSI rate ( P = 0.001, Mantel-Haenszel linear-by-linear association chi-square test).
Heterologous booster vaccination with CoronaVac following prime vaccination with mRNA vaccine
Publisher: Wiley
Date: 2023
DOI: 10.1002/CTI2.1449
In vitro vaccine challenge of PBMCs from BNT162b2 anaphylaxis patients reveals HSP90α‐NOD2‐NLRP3 nexus
Publisher: Wiley
Date: 10-09-2022
DOI: 10.1111/ALL.15503
Hot topics on vertebral osteomyelitis from the International Society of Antimicrobial Chemotherapy
Publisher: Elsevier BV
Date: 08-2019
Imported chloroquine-resistant plasmodium vivax in Singapore: Case report and literature review
Publisher: Oxford University Press (OUP)
Date: 2010
DOI: 10.1111/J.1708-8305.2009.00376.X
Abstract: Chloroquine-resistant Plasmodium vivax (CRPV) infection is emerging as a clinically significant problem. Detailed travel history is crucial to the management of imported malarial cases. We report a 58-year-old business traveler who returned from Indonesia and experienced relapse due to CRPV. The epidemiology and diagnostic challenges of CRPV for travel medicine clinicians are reviewed.
Altered properties and structures of root exudate polysaccharides in a root hairless mutant of barley
Publisher: Oxford University Press (OUP)
Date: 25-07-2022
Abstract: Root exudates and rhizosheaths of attached soil are important features of growing roots. To elucidate factors involved in rhizosheath formation, wild-type (WT) barley (Hordeum vulgare L. cv. Pallas) and a root hairless mutant, bald root barley (brb), were investigated with a combination of physiological, biochemical, and immunochemical assays. When grown in soil, WT barley roots bound ∼5-fold more soil than brb per unit root length. High molecular weight (HMW) polysaccharide exudates of brb roots had less soil-binding capacity than those of WT root exudates. Carbohydrate and glycan monoclonal antibody analyses of HMW polysaccharide exudates indicated differing glycan profiles. Relative to WT plants, root exudates of brb had reduced signals for arabinogalactan-protein (AGP), extensin, and heteroxylan epitopes. In contrast, the root exudate of 2-week-old brb plants contained ∼25-fold more detectable xyloglucan epitope relative to WT. Root system immunoprints confirmed the higher levels of release of the xyloglucan epitope from brb root apices and root axes relative to WT. Epitope detection with anion-exchange chromatography indicated that the increased detection of xyloglucan in brb exudates was due to enhanced abundance of a neutral polymer. Conversely, brb root exudates contained decreased amounts of an acidic polymer, with soil-binding properties, containing the xyloglucan epitope and glycoprotein and heteroxylan epitopes relative to WT. We, therefore, propose that, in addition to physically structuring soil particles, root hairs facilitate rhizosheath formation by releasing a soil-binding polysaccharide complex.
Standardized outpatient management of Klebsiella pneumoniae liver abscesses
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.IJID.2012.10.002
Abstract: Community-acquired Klebsiella pneumoniae has emerged as a major cause of liver abscess in Asia. Using a standardized protocol, we conducted a prospective cohort study of all cases of K. pneumoniae liver abscess treated from 2005 to 2011 at two outpatient parenteral antimicrobial therapy (OPAT) centers in Singapore, to assess the safety and efficacy of treatment. We included all OPAT eligible patients with radiologically confirmed (computed tomography or ultrasound) liver abscesses and K. pneumoniae-positive microbiological cultures obtained from abscess fluid and/or blood at two university teaching hospitals. The endpoints investigated were cure, clinical response, readmission, and mortality. All 109 patients enrolled in the study successfully completed treatment in OPAT. Nine patients required a short-term readmission due to clinical deterioration. There were no deaths or relapses at 30 days post cessation of antibiotics. Abscess size greater than 5 cm was associated with a delayed clinical response (odds ratio 5.34, 95% confidence interval 1.25-22.91, p = 0.02). The management of K. pneumoniae liver abscesses via OPAT using a standardized protocol is a safe and effective alternative to inpatient intravenous antibiotics.
Outbreak of Measles in a Residential Home for the Intellectually Disabled in Singapore in 2019
Publisher: American Public Health Association
Date: 10-2020
Abstract: A measles outbreak involving 19 adults in a home for the intellectually disabled occurred in Singapore in 2019. Further investigation, including a serological survey, was conducted. Mass vaccination and infection control measures were implemented, terminating further secondary transmission. Seropositivity among residents aged 40 to 49 years (90.7% 95% confidence interval = 78.4%, 96.3%) was lower than among the Singapore adult population (P .001). This sheltered population, like others previously reported in the literature, had lower measles immunity than the general community, possibly because of limited social interaction. Targeted catch-up vaccination for similarly vulnerable populations should be considered.
Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection
Publisher: Cold Spring Harbor Laboratory
Date: 27-11-2020
DOI: 10.1101/2020.11.25.399139
Abstract: The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between their antiviral and inflammatory features. SARS-CoV-2-specific T cells in in iduals who clear SARS-CoV-2 infection without symptoms or disease could reveal non-pathological yet protective characteristics. We therefore compared the quantity and function of SARS-CoV-2-specific T cells in a cohort of asymptomatic in iduals (n=85) with that of symptomatic COVID-19 patients (n=76), at different time points after antibody seroconversion. We quantified T cells reactive to structural proteins (M, NP and Spike) using ELISpot assays, and measured the magnitude of cytokine secretion (IL-2, IFN-γ, IL-4, IL-6, IL-1β, TNF-α and IL-10) in whole blood following T cell activation with SARS-CoV-2 peptide pools as a functional readout. Frequencies of T cells specific for the different SARS-CoV-2 proteins in the early phases of recovery were similar between asymptomatic and symptomatic in iduals. However, we detected an increased IFN-γ and IL-2 production in asymptomatic compared to symptomatic in iduals after activation of SARS-CoV-2-specific T cells in blood. This was associated with a proportional secretion of IL-10 and pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic in iduals. Thus, asymptomatic SARS-CoV-2 infected in iduals are not characterized by a weak antiviral immunity on the contrary, they mount a robust and highly functional virus-specific cellular immune response. Their ability to induce a proportionate production of IL-10 might help to reduce inflammatory events during viral clearance.
Risk factors for concurrent bacteremia in adult patients with dengue
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.JMII.2015.06.008
Abstract: Bacteremia in dengue may occur with common exposure to pathogens in association with severe organ impairment or severe dengue, which may result in death. Cohort studies identifying risk factors for concurrent bacteremia among patients with dengue are rare. We conducted a retrospective case-control study of adult patients with dengue who were admitted to the Department of Infectious Diseases at Tan Tock Seng Hospital, Singapore from 2004 to 2008. For each case of dengue with concurrent bacteremia (within the first 72 hours of admission), we selected four controls without bacteremia, who were matched on year of infection and dengue confirmation method. Conditional logistic regression was performed to identify risk factors for concurrent bacteremia. Among 9,553 patients with dengue, 29 (0.3%) had bacteremia. Eighteen of these patients (62.1%) had concurrent bacteremia. The predominant bacteria were Staphylococcus aureus, one of which was a methicillin-resistant strain. Dengue shock syndrome occurred more frequently and hospital stay was longer among cases than among controls. Three cases did not survive, whereas none of the controls died. In multivariate analysis, being critically ill at hospital presentation was independently associated with 15 times the likelihood of a patient with dengue having concurrent bacteremia. Concurrent bacteremia in adult patients with dengue is uncommon but presents atypically and results in more deaths and longer hospital stay. Given the associated mortality, collection of blood cultures and empiric antibiotic therapy may be considered in patients who are critically ill.
Predictive performance of pharmacokinetic models for outpatients receiving vancomycin continuous infusion
Publisher: Elsevier BV
Date: 02-2014
Risk factors and treatment outcome of ertapenem non-susceptible enterobacteriaceae bacteraemia
Publisher: Elsevier BV
Date: 03-2013
Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial
Publisher: Elsevier BV
Date: 09-2022
Predictors and Clinical Outcomes of Poor Platelet Recovery in Adult Dengue With Thrombocytopenia: A Multicenter, Prospective Study
Publisher: Oxford University Press (OUP)
Date: 18-10-2019
DOI: 10.1093/CID/CIZ850
Abstract: Platelet transfusion is common in dengue patients with thrombocytopenia. We previously showed in a randomized clinical trial that prophylactic platelet transfusion did not reduce clinical bleeding. In this study, we aimed to characterize the predictors and clinical outcomes of poor platelet recovery in transfused and nontransfused participants. We analyzed patients from the Adult Dengue Platelet Study with laboratory-confirmed dengue with ≤20 000 platelets/μL and without persistent mild bleeding or any severe bleeding in a post hoc analysis. Poor platelet recovery was defined as a platelet count of ≤20 000/μL on Day 2. We recruited 372 participants from 5 acute care hospitals located in Singapore and Malaysia between 29 April 2010 and 9 December 2014. Of these, 188 were randomly assigned to the transfusion group and 184 to the control group. Of 360 patients, 158 had poor platelet recovery. Age, white cell count, and day of illness at study enrollment were significant predictors of poor platelet recovery after adjustment for baseline characteristics and platelet transfusion. Patients with poor platelet recovery had longer hospitalizations but no significant difference in other clinical outcomes, regardless of transfusion. We found a significant interaction between platelet recovery and transfusion patients with poor platelet recovery were more likely to bleed if given a prophylactic platelet transfusion (odds ratio 2.34, 95% confidence interval 1.18–4.63). Dengue patients with thrombocytopenia who were older or presented earlier and with lower white cell counts were more likely to have poor platelet recovery. In patients with poor platelet recovery, platelet transfusion does not improve outcomes and may actually increase the risk of bleeding. The mechanisms of poor platelet recovery need to be determined. NCT01030211.
Neurology of COVID-19 in Singapore
Publisher: Elsevier BV
Date: 11-2020
Role of outpatient parenteral antibiotic therapy in the treatment of community acquired skin and soft tissue infections in Singapore
Publisher: Springer Science and Business Media LLC
Date: 06-07-2017
Mortality Benefits of Antibiotic Computerised Decision Support System: Modifying Effects of Age
Publisher: Springer Science and Business Media LLC
Date: 30-11-2015
DOI: 10.1038/SREP17346
Abstract: Antibiotic computerised decision support systems (CDSSs) are shown to improve antibiotic prescribing, but evidence of beneficial patient outcomes is limited. We conducted a prospective cohort study in a 1500-bed tertiary-care hospital in Singapore, to evaluate the effectiveness of the hospital’s antibiotic CDSS on patients’ clinical outcomes and the modification of these effects by patient factors. To account for clustering, we used multilevel logistic regression models. One-quarter of 1886 eligible inpatients received CDSS-recommended antibiotics. Receipt of antibiotics according to CDSS’s recommendations seemed to halve mortality risk of patients (OR 0.54, 95% CI 0.26–1.10, P = 0.09). Patients aged ≤65 years had greater mortality benefit (OR 0.45, 95% CI 0.20–1.00, P = 0.05) than patients that were older than 65 (OR 1.28, 95% CI 0.91–1.82, P = 0.16). No effect was observed on incidence of Clostridium difficile (OR 1.02, 95% CI 0.34–3.01) and multidrug-resistant organism (OR 1.06, 95% CI 0.42–2.71) infections. No increase in infection-related readmission (OR 1.16, 95% CI 0.48–2.79) was found in survivors. Receipt of CDSS-recommended antibiotics reduced mortality risk in patients aged 65 years or younger and did not increase the risk in older patients. Physicians should be informed of the benefits to increase their acceptance of CDSS recommendations.
Nephrotoxicity of continuous versus intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.IJANTIMICAG.2009.07.011
Abstract: Intravenous (i.v.) vancomycin is increasingly used as outpatient parenteral antimicrobial therapy (OPAT). Despite the potential advantages of administration by continuous infusion (CI) compared with intermittent infusion (II), the relative nephrotoxicity of these two modes of delivery has not been well established. We compared the rate of nephrotoxicity of vancomycin given by CI and II. A retrospective cohort study of OPAT patients receiving i.v. vancomycin between January 2004 to June 2008 was performed. All patients had a normal baseline serum creatinine concentration. Propensity scoring analysis was used to adjust for risk factors of CI. The primary outcomes examined were the prevalence and rate of onset of nephrotoxicity. A total of 167 patients receiving vancomycin were identified, 112 by CI and 55 by II. The overall cumulative prevalence of nephrotoxicity was 15.6%. There were significant differences in baseline characteristics between the two groups. Matching based on propensity scores was undertaken, leaving 80 patients available for the analysis. Both in unadjusted and adjusted analyses, vancomycin CI was associated with a slower onset of nephrotoxicity but not a lower prevalence of nephrotoxicity. Both groups received a similar cumulative vancomycin dose. In adult OPAT patients with normal renal function, vancomycin CI was associated with a slower onset of nephrotoxicity.
Potential Harm of Prophylactic Platelet Transfusion in Adult Dengue Patients
Publisher: Public Library of Science (PLoS)
Date: 25-03-2016
Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-08-2020
Real-World Use of Sotrovimab for Pre-Emptive Treatment in High-Risk Hospitalized COVID-19 Patients: An Observational Cross-Sectional Study
Publisher: MDPI AG
Date: 05-03-2022
DOI: 10.3390/ANTIBIOTICS11030345
Abstract: Data on use of monoclonal antibodies (mAbs) in hospitalized patients are limited. In this cross-sectional study, we evaluated the use of mAbs for early treatment of unvaccinated hospitalized patients with mild-to-moderate COVID-19. All inpatients at our center were screened on 27 October 2021. Primary outcome was in-hospital deterioration as defined by a composite of oxygen requirement, intensive care unit (ICU) admission, or mortality within 28 days of admission. Ninety-four out of 410 COVID-19 inpatients were included in the final analysis, of whom 19 (20.2%) received early treatment with sotrovimab. The median age was 73 years (IQR 61–83), and 35 (37.2%) were female. Although the treatment group was significantly older and had more comorbidities, there was a lower proportion of progression to oxygen requirement (31.6% vs. 54.7%), ICU admission (10.5% vs. 24.0%), or mortality (5.3% vs. 13.3%). Kaplan–Meier curves showed a significant difference in time to in-hospital deterioration (log-rank test, p = 0.043). Cox proportional hazards model for in-hospital deterioration showed that sotrovimab treatment was protective (hazard ratio, 0.41 95% CI, 0.17–0.99 p = 0.047) after adjustment for baseline ISARIC deterioration score. Our findings support the use of sotrovimab for early treatment in hospitalized patients with mild-to-moderate COVID-19 at a high risk of disease progression.
Robust Virus-Specific Adaptive Immunity in COVID-19 Patients with SARS-CoV-2 Δ382 Variant Infection
Publisher: Springer Science and Business Media LLC
Date: 30-10-2021
DOI: 10.1007/S10875-021-01142-Z
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that have become dominant as the pandemic progresses bear the ORF8 mutation together with multiple spike mutations. A 382-nucleotide deletion (Δ382) in the ORF7b and ORF8 regions has been associated with milder disease phenotype and less systemic inflammation in COVID-19 patients. However, its impact on host immunity against SARS-CoV-2 remains undefined. Here, RNA-sequencing was performed to elucidate whole blood transcriptomic profiles and identify contrasting immune signatures between patients infected with either wildtype or Δ382 SARS-CoV-2 variant. Interestingly, the immune landscape of Δ382 SARS-CoV-2 infected patients featured an increased adaptive immune response, evidenced by enrichment of genes related to T cell functionality, a more robust SARS-CoV-2-specific T cell immunity, as well as a more rapid antibody response. At the molecular level, eukaryotic initiation factor 2 signaling was found to be upregulated in patients bearing Δ382, and its associated genes were correlated with systemic levels of T cell-associated and pro-inflammatory cytokines. This study provides more in-depth insight into the host–pathogen interactions of ORF8 with great promise as a therapeutic target to combat SARS-CoV-2 infection.
Author Correction: Increased Serum Hyaluronic Acid and Heparan Sulfate in Dengue Fever: Association with Plasma Leakage and Disease Severity
Publisher: Springer Science and Business Media LLC
Date: 21-06-2021
DOI: 10.1038/S41598-021-92487-3
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Diagnostic Accuracy of Parameters for Zika and Dengue Virus Infections, Singapore
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 12-2017
Diagnosing Dengue at the Point-of-Care: Utility of a Rapid Combined Diagnostic Kit in Singapore
Publisher: Public Library of Science (PLoS)
Date: 19-03-2014
Serological differentiation between COVID-19 and SARS infections
Publisher: Informa UK Limited
Date: 2020
Predictive Value of Proteinuria in Adult Dengue Severity
Publisher: Public Library of Science (PLoS)
Date: 20-02-2014
Analysis of the complete genome of a virus associated with twisted leaf disease of cherry reveals evidence of a close relationship to unassigned viruses in the family Betaflexiviridae.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2014
DOI: 10.1007/S00705-014-2075-6
Abstract: The genome of a virus associated with cherry twisted leaf disease (CTLaV, isolate ZH) was sequenced and consists of 8431 nucleotides, excluding a poly(A) tail at the 3' end. Genome analysis shows that CTLaV-ZH represents a new and distinct species and has a genome organization similar to those of unassigned viruses in the family Betaflexiviridae. The CTLaV-ZH genome has five open reading frames (ORFs), with putative ORFs within ORF2 and ORF5, identified as ORF2a and ORF5a, respectively. The AUG start codons of ORF2a and ORF5a are in contexts suitable for efficient translation, with appropriate stop codons in frame.
Validation of Probability Equation and Decision Tree in Predicting Subsequent Dengue Hemorrhagic Fever in Adult Dengue Inpatients in Singapore
Publisher: American Society of Tropical Medicine and Hygiene
Date: 11-2011
Higher Risk of Infection with Dengue at the Weekend among Male Singaporeans
Publisher: American Society of Tropical Medicine and Hygiene
Date: 05-12-2012
Outcomes of Fosfomycin Use in Ceftriaxone-Resistant Enterobacteriaceae Urinary Tract Infection in the Elderly
Publisher: Elsevier BV
Date: 02-2019
Association of SARS-CoV-2 Clades with Clinical, Inflammatory and Virologic Outcomes: An Observational Study
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3741264
Progress and Challenges towards Point-of-Care Diagnostic Development for Dengue
Publisher: American Society for Microbiology
Date: 12-2017
DOI: 10.1128/JCM.00707-17
Abstract: Dengue detection strategies involve viral RNA, antigen, and/or antibody detection. Each strategy has its advantages and disadvantages. Optimal, user-friendly, rapid diagnostic tests based on immunochromatographic assays are pragmatic point-of-care tests (POCTs) in regions where dengue is endemic where there are limited laboratory capabilities and optimal storage conditions. Increasingly, there is a greater public health significance for a multiplexing assay that differentiates dengue from Zika or pathogens with similar clinical presentations. Although there have been many assay latform developments toward POCTs, independent validation and implementation remain very limited. This review highlights the current key progress and challenges toward the development of a dengue POCT.
Care of the pregnant woman with coronavirus disease 2019 in labor and delivery: anesthesia, emergency cesarean delivery, differential diagnosis in the acutely ill parturient, care of the newborn, and
Publisher: Elsevier BV
Date: 07-2020
Radiographic features of COVID-19 based on an initial cohort of 96 patients in Singapore
Publisher: Medknow
Date: 28-10-2021
Abstract: INTRODUCTION Chest radiographs (CXRs) are widely used for the screening and management of COVID-19. This article describes the radiographic features of COVID-19 based on an initial national cohort of patients. METHODS This is a retrospective review of swab-positive patients with COVID-19 who were admitted to four different hospitals in Singapore between 22 January and 9 March 2020. Initial and follow-up CXRs were reviewed by three experienced radiologists to identify the predominant pattern and distribution of lung parenchymal abnormalities. RESULTS In total, 347 CXRs of 96 patients were reviewed. Initial CXRs were abnormal in 41 (42.7%) out of 96 patients. The mean time from onset of symptoms to CXR abnormality was 5.3 ± 4.7 days. The predominant pattern of lung abnormality was ground-glass opacity on initial CXRs (51.2%) and consolidation on follow-up CXRs (51.0%). Multifocal bilateral abnormalities in mixed central and peripheral distribution were observed in 63.4% and 59.2% of abnormal initial and follow-up CXRs, respectively. The lower zones were involved in 90.2% of initial CXRs and 93.9% of follow-up CXRs. CONCLUSION In a cohort of swab-positive patients, including those identified from contact tracing, we found a lower incidence of CXR abnormalities than was previously reported. The most common pattern was ground-glass opacity or consolidation, but mixed central and peripheral involvement was more common than peripheral involvement alone.
A Sensitive Method for Detecting Zika Virus Antigen in Patients’ Whole-Blood Specimens as an Alternative Diagnostic Approach
Publisher: Oxford University Press (OUP)
Date: 06-06-2017
Household transmission of carbapenemase-producing Enterobacteriaceae: a prospective cohort study
Publisher: Oxford University Press (OUP)
Date: 08-01-2021
DOI: 10.1093/JAC/DKAA561
Abstract: To estimate the transmission rate of carbapenemase-producing Enterobacteriaceae (CPE) in households with recently hospitalized CPE carriers. We conducted a prospective case-ascertained cohort study. We identified the presence of CPE in stool s les from index subjects, household contacts and companion animals and environmental s les at regular intervals. Linked transmissions were identified by WGS. A Markov model was constructed to estimate the household transmission potential of CPE. Ten recently hospitalized index patients and 14 household contacts were included. There were seven households with one contact, two households with two contacts, and one household with three contacts. Index patients were colonized with blaOXA-48-like (n = 4), blaKPC-2 (n = 3), blaIMP (n = 2), and blaNDM-1 (n = 1), distributed among ergent species of Enterobacteriaceae. After a cumulative follow-up time of 9.0 years, three family members (21.4%, 3/14) acquired four different types of CPE in the community (hazard rate of 0.22/year). The probability of CPE transmission from an index patient to a household contact was 10% (95% CI 4%–26%). We observed limited transmission of CPE from an index patient to household contacts. Larger studies are needed to understand the factors associated with household transmission of CPE and identify preventive strategies.
Vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations: study protocol for a ph
Publisher: Springer Science and Business Media LLC
Date: 19-06-2014
A prospective observational study of the prevalence and risk factors for colonization by antibiotic resistant bacteria in patients at admission to hospital in singapore
Publisher: Springer Science and Business Media LLC
Date: 02-06-2014
Lack of Efficacy of Prophylactic Platelet Transfusion for Severe Thrombocytopenia in Adults with Acute Uncomplicated Dengue Infection
Publisher: Oxford University Press (OUP)
Date: 05-2009
DOI: 10.1086/597773
Abstract: Thrombocytopenia in dengue infection raises concerns about bleeding risk. Of 256 patients with dengue infection who developed thrombocytopenia (platelet count, < 20 x 10(3) platelets/microL) without prior bleeding, 188 were given platelet transfusion. Subsequent bleeding, platelet increment, and platelet recovery were similar between patients given transfusion and patients not given transfusion. Prophylactic platelet transfusion was ineffective in preventing bleeding in adult patients with dengue infection.
Corrigendum to ‘Neurology of COVID-19 in Singapore’ [Journal of the Neurological Sciences Volume 418, 15 November 2020, 117118]
Publisher: Elsevier BV
Date: 05-2021
Cross-Reactivity and Anti-viral Function of Dengue Capsid and NS3-Specific Memory T Cells Toward Zika Virus
Publisher: Frontiers Media SA
Date: 10-2018
Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors
Publisher: Massachusetts Medical Society
Date: 07-10-2021
Utilities and Limitations of the World Health Organization 2009 Warning Signs for Adult Dengue Severity
Publisher: Public Library of Science (PLoS)
Date: 17-01-2013
Comparative Effectiveness of mRNA and Inactivated Whole-Virus Vaccines Against Coronavirus Disease 2019 Infection and Severe Disease in Singapore
Publisher: Oxford University Press (OUP)
Date: 06-06-2022
DOI: 10.1093/CID/CIAC288
Abstract: Compared with in iduals vaccinated with Pfizer-BioNTech/Comirnaty, recipients of Sinovac-CoronaVac and Sinopharm were 2.37 (95% CI, 2.29–2.46) and 1.62 (95% CI, 1.43–1.85) times more likely to be infected with coronavirus disease 19, respectively, while in iduals vaccinated with Moderna were 0.42 (95% CI, 0.25–0.70) times less likely to develop severe disease.
Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections
Publisher: Frontiers Media SA
Date: 22-11-2022
DOI: 10.3389/FMICB.2022.1043049
Abstract: COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Plasma s les were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected in iduals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.
First-in-Human Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Rapidly Developed SARS-CoV-2 Therapeutic Antibody, AOD01, in Healthy Adults
Publisher: Springer Science and Business Media LLC
Date: 04-09-2022
Rapid measurement of SARS-CoV-2 spike T cells in whole blood from vaccinated and naturally infected individuals
Publisher: American Society for Clinical Investigation
Date: 30-03-2022
DOI: 10.1172/JCI152379
Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia
Publisher: Rockefeller University Press
Date: 16-06-2022
DOI: 10.1084/JEM.20220131
Abstract: Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (& yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5–13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10−11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.
The Significance of Prolonged and Saddleback Fever in Hospitalised Adult Dengue
Publisher: Public Library of Science (PLoS)
Date: 09-12-2016
Efficacy of voriconazole for Scedosporium apiospermum skull base osteomyelitis: case report and literature review
Publisher: Elsevier BV
Date: 02-2008
Differential host susceptibility and bacterial virulence factors driving Klebsiella liver abscess in an ethnically diverse population
Publisher: Springer Science and Business Media LLC
Date: 13-07-2016
DOI: 10.1038/SREP29316
Abstract: Hypervirulent Klebsiella pneumoniae is an emerging cause of community-acquired pyogenic liver abscess. First described in Asia, it is now increasingly recognized in Western countries, commonly afflicting those with Asian descent. This raises the question of genetic predisposition versus geospecific strain acquisition. We leveraged on the Antibiotics for Klebsiella Liver Abscess Syndrome Study (A-KLASS) clinical trial ongoing in ethnically erse Singapore, to prospectively examine the profiles of 70 patients together with their isolates’ genotypic and phenotypic characteristics. The majority of isolates belonged to capsule type K1, a genetically homogenous group corresponding to sequence-type 23. The remaining K2, K5, K16, K28, K57 and K63 isolates as well as two novel cps isolates were genetically heterogeneous. K1 isolates carried higher frequencies of virulence-associated genes including rmpA (regulator of mucoid phenotype A), kfu (Klebsiella ferric uptake transporter), iuc (aerobactin), iro (salmochelin) and irp (yersiniabactin) than non-K1 isolates. The Chinese in our patient cohort, mostly non-diabetic, had higher prevalence of K1 infection than the predominantly diabetic non-Chinese (Malays, Indian and Caucasian). This differential susceptibility to different capsule types among the various ethnic groups suggests patterns of transmission (e.g. environmental source, familial transmission) and/or genetic predisposition unique to each race despite being in the same geographical location.
High specificity of OraQuick® rapid HIV-1/2 antibody testing during dengue infection
Publisher: Elsevier BV
Date: 10-2020
Linear B-cell epitopes in the spike and nucleocapsid proteins as markers of SARS-CoV-2 exposure and disease severity
Publisher: Elsevier BV
Date: 08-2020
Hot topics in diabetic foot infection
Publisher: Elsevier BV
Date: 06-2020
Myeloperoxidase inhibition may protect against endothelial glycocalyx shedding induced by COVID-19 plasma
Publisher: Springer Science and Business Media LLC
Date: 05-05-2023
DOI: 10.1038/S43856-023-00293-X
Abstract: SARS-CoV-2, the causative agent of COVID-19, is a threat to public health. Evidence suggests increased neutrophil activation and endothelial glycocalyx (EG) damage are independently associated with severe COVID-19. Here, we hypothesised that an increased level of blood neutrophil myeloperoxidase (MPO) is associated with soluble EG breakdown, and inhibiting MPO activity may reduce EG damage. Analysing a subset of acute and convalescent COVID-19 plasma, 10 from severe and 15 from non-severe COVID-19 cases, and 9 from pre-COVID-19 controls, we determined MPO levels, MPO activity and soluble EG proteins (syndecan-1 and glypican-1) levels by enzyme-linked immunosorbent assay. In vitro primary human aortic endothelial cells were cultured with plasma untreated or treated with specific MPO inhibitors (MPO-IN-28, AZD5904) to determine EG shedding. We then investigated whether inhibiting MPO activity decreased EG degradation. In COVID-19 plasma, MPO levels, MPO activity and levels of soluble EG proteins are significantly raised compared to controls, and concentrations increase in proportion to disease severity. Despite clinical recovery, protein concentrations remain significantly elevated. Interestingly, there is a trend of increasing MPO activity in convalescent plasma in both severe and non-severe groups. MPO levels and MPO activity correlate significantly with soluble EG levels and inhibiting MPO activity leads to reduced syndecan-1 shedding, in vitro. Neutrophil MPO may increase EG shedding in COVID-19, and inhibiting MPO activity may protect against EG degradation. Further research is needed to evaluate the utility of MPO inhibitors as potential therapeutics against severe COVID-19.
A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentr
Publisher: Springer Science and Business Media LLC
Date: 06-2018
Outcomes of treating AmpC-producing Enterobacterales bacteraemia with carbapenems vs. non-carbapenems
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.IJANTIMICAG.2019.105860
Abstract: AmpC β-lactamases are found in Enterobacter species, Serratia species, Citrobacter freundii, Providencia species and Morganella morganii ('ESCPM'). Carbapenems are commonly used to treat severe 'ESCPM' infections. Carbapenem-sparing agents are needed because of increasing carbapenem resistance worldwide. Use of cefepime and piperacillin-tazobactam has limited supportive clinical data. We evaluated the efficacy of non-carbapenems vs. carbapenems in 'ESCPM' bacteraemia. A retrospective cohort study was conducted on patients with 'ESCPM' bacteraemia. Primary outcome was 30-day mortality. Analyses were performed on patients who received carbapenems vs. piperacillin-tazobactam or cefepime monotherapy as empirical and definitive therapy. Propensity score for carbapenem therapy was adjusted for in multivariate analyses for 30-day mortality. A total of 241 patients were included. The most common bacterium isolated was Enterobacter species (58.1%). Common sources were urinary (22.8%) and vascular lines (22.0%). Carbapenems (28.6%) and piperacillin-tazobactam (28.6%) were the commonest empirical antibiotics. Carbapenems (54.8%) and cefepime (23.7%) were the most common definitive antibiotics. Median Pitt bacteraemia score was 1 (interquartile range [IQR], 0-2). Overall, 30-day mortality was 12.9%. Adjusted multivariate analyses for empirical and definitive antibiotic treatment models yielded risk factors for 30-day mortality, including higher Pitt bacteraemia score (empirical: adjusted OR [aOR] 1.21 for each point increase, 95% confidence interval [CI]:1.01-1.45 definitive: aOR 1.33 for each point increase, 95% CI:1.06-1.69) and age (empirical: aOR 1.04 for each year increase, 95% CI:1.01-1.08). Empirical piperacillin-tazobactam (aOR 0.29, 95% CI:0.07-1.27) and definitive cefepime (aOR 0.65, 95% CI:0.12-3.55) were not associated with 30-day mortality. Compared with carbapenem therapy, empirical piperacillin-tazobactam and definitive cefepime were not associated with 30-day mortality in 'ESCPM' bacteraemia.
Predictive value of simple clinical and laboratory variables for dengue hemorrhagic fever in adults
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.JCV.2007.12.017
Abstract: Singapore experienced its worst dengue outbreak in 30 years in 2004, with 9459 notified cases, of which 83% were hospitalized. To determine predictors of dengue hemorrhagic fever (DHF) upon first presentation to hospital to aid clinicians in determining need for admission. We conducted a retrospective cohort study on dengue patients in Tan Tock Seng Hospital, Singapore in 2004, with patients categorized into dengue fever (DF) and DHF. Demographic, clinical, and laboratory variables upon first presentation were compared to determine the likelihood of developing DHF. There were 1973 dengue patients-118 (6.0%) were DHF, of which 82 (4.2%) developed DHF during hospitalization. From the multivariate analysis, patients with bleeding had an odds of developing DHF 237.6 times that of DF, a unit decrease in total protein (g/L) had an odds of 1.28 times, a unit increase in blood urea (mmol/L) had an odds of 1.31 times, and a unit decrease in lymphocyte proportion had an odds of 1.08 times. The model had a sensitivity of 97.6%, specificity of 60.2%, and may reduce 1118 (56.7%) dengue admissions. A few easily available clinical and laboratory results may assist clinicians in determining dengue admissions.
Viral Dynamics and Immune Correlates of Coronavirus Disease 2019 (COVID-19) Severity
Publisher: Oxford University Press (OUP)
Date: 28-08-2020
DOI: 10.1093/CID/CIAA1280
Abstract: Key knowledge gaps remain in the understanding of viral dynamics and immune response of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We evaluated these characteristics and established their association with clinical severity in a prospective observational cohort study of 100 patients with PCR-confirmed SARS-CoV-2 infection (mean age, 46 years 56% male 38% with comorbidities). Respiratory s les (n = 74) were collected for viral culture, serum s les for measurement of IgM/IgG levels (n = 30), and plasma s les for levels of inflammatory cytokines and chemokines (n = 81). Disease severity was correlated with results from viral culture, serologic testing, and immune markers. Fifty-seven (57%) patients developed viral pneumonia, of whom 20 (20%) required supplemental oxygen, including 12 (12%) with invasive mechanical ventilation. Viral culture from respiratory s les was positive for 19 of 74 patients (26%). No virus was isolated when the PCR cycle threshold (Ct) value was & or & days after symptom onset. Seroconversion occurred at a median (IQR) of 12.5 (9–18) days for IgM and 15.0 (12–20) days for IgG 54/62 patients (87.1%) s led at day 14 or later seroconverted. Severe infections were associated with earlier seroconversion and higher peak IgM and IgG levels. Levels of IP-10, HGF, IL-6, MCP-1, MIP-1α, IL-12p70, IL-18, VEGF-A, PDGF-BB, and IL-1RA significantly correlated with disease severity. We found virus viability was associated with lower PCR Ct value in early illness. A stronger antibody response was associated with disease severity. The overactive proinflammatory immune signatures offer targets for host-directed immunotherapy, which should be evaluated in randomized controlled trials.
Data-Driven Analysis of COVID-19 Reveals Persistent Immune Abnormalities in Convalescent Severe Individuals
Publisher: Frontiers Media SA
Date: 19-11-2021
DOI: 10.3389/FIMMU.2021.710217
Abstract: Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of “long COVID-19”, and defines key cells and cytokines that delineate true and quasi-convalescent states.
Estimated Health Outcomes and Costs Associated With Use of Monoclonal Antibodies for Prevention or Mitigation of SARS-CoV-2 Infections
Publisher: American Medical Association (AMA)
Date: 05-04-2022
Continuous versus intermittent infusion of polymyxin B in the treatment of infections caused by multidrug-resistant Gram-negative bacteria
Publisher: Elsevier BV
Date: 2008
Effectiveness of a Fourth Dose of COVID-19 mRNA Vaccine Against Omicron Variant Among Elderly People in Singapore
Publisher: American College of Physicians
Date: 11-2022
DOI: 10.7326/M22-2042
Correction Due to Nonthermally Coupled Emission Bands and Its Implications on the Performance of Y2O3:Yb3+ /Er3+ Single-Particle Thermometers
Publisher: American Chemical Society (ACS)
Date: 16-05-2023
Epidemiology and Transmission of Carbapenemase-Producing Enterobacteriaceae in a Health Care Network of an Acute-Care Hospital and Its Affiliated Intermediate- and Long-
Publisher: American Society for Microbiology
Date: 16-07-2021
DOI: 10.1128/AAC.02584-20
Abstract: Movement of patients in a health care network poses challenges for the control of carbapenemase-producing Enterobacteriaceae (CPE). We aimed to identify intra- and interfacility transmission events and facility type-specific risk factors of CPE in an acute-care hospital (ACH) and its intermediate-term and long-term-care facilities (ILTCFs).
Distinguishing Zika and Dengue Viruses through Simple Clinical Assessment, Singapore
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 08-2018
Related Organisations
Royal College Of Physicians Of Edinburgh
Location: United Kingdom of Great Britain and Northern Ireland
National University Singapore Yong Loo Lin School Of Medicine
Location: Singapore
Related Funding Activities
No related grants have been discovered for David Lye.