ORCID Profile
0000-0002-2158-846X
Current Organisation
University of Oxford
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Publisher: Public Library of Science (PLoS)
Date: 29-03-2021
DOI: 10.1371/JOURNAL.PNTD.0009302
Abstract: Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs). For this updated systematic review, we searched the following databases from 1 st Jan 2016 through 2 nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from in idual treatment arms were combined in a meta-analysis using random effects Poisson regression. We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal hotericin B (L-AmB) in 52 (15.0%), hotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), hotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041–0.114 I 2 = 81.4% 95% prediction interval (PI): 0.001–2.779] per 1,000 person-days at risk the rate was 0.628 [95% CI: 0.368–1.021 I 2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021–0.081 I 2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244–1.355 I 2 = 91.9%] compared to 0.043 [95% CI: 0.020–0.090 I 2 = 62.5%] in 160 arms which excluded HIV co-infections. Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble in idual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.
Publisher: Springer Science and Business Media LLC
Date: 26-10-2017
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.IJID.2022.07.018
Abstract: In this study, we aimed to conduct a systematic review to characterize antimicrobial resistance (AMR) patterns for bacterial causes of febrile illness in Africa and Asia. We included published literature from 1980-2015 based on data extracted from two recent systematic reviews of nonmalarial febrile illness from Africa, South Asia, and Southeast Asia. Selection criteria included articles with full bacterial identification and antimicrobial susceptibility testing (AST) results for key normally sterile site pathogen-drug combinations. Pooled proportions of resistant isolates were combined using random effects meta-analysis. Study data quality was graded using the Microbiology Investigation Criteria for Reporting Objectively (MICRO) framework. Of 3475 unique articles included in the previous reviews, 371 included the target pathogen-drug combinations. Salmonella enterica tested against ceftriaxone and ciprofloxacin were the two highest reported combinations (30,509 and 22,056 isolates, respectively). Pooled proportions of resistant isolates were high for third-generation cephalosporins for Klebsiella pneumoniae and Escherichia coli in all regions. The MICRO grading showed an overall lack of standardization. This review highlights a general increase in AMR reporting and in resistance over time. However, there were substantial problems with diagnostic microbiological data quality. Urgent strengthening of laboratory capacity, standardized testing, and reporting of AST results is required to improve AMR surveillance.
Publisher: Public Library of Science (PLoS)
Date: 10-01-2017
Publisher: Springer Science and Business Media LLC
Date: 05-07-2019
Publisher: Springer Science and Business Media LLC
Date: 27-11-2019
DOI: 10.1186/S12874-019-0856-Z
Abstract: Antimalarial clinical efficacy studies for uncomplicated Plasmodium falciparum malaria frequently encounter situations in which molecular genotyping is unable to discriminate between parasitic recurrence, either new infection or recrudescence. The current WHO guideline recommends excluding these in iduals with indeterminate outcomes in a complete case (CC) analysis. Data from the four artemisinin-based combination (4ABC) trial was used to compare the performance of multiple imputation (MI) and inverse probability weighting (IPW) against the standard CC analysis for dealing with indeterminate recurrences. 3369 study participants from the multicentre study (4ABC trial) with molecularly defined parasitic recurrence treated with three artemisinin-based combination therapies were used to represent a complete dataset. A set proportion of recurrent infections (10, 30 and 45%) were reclassified as missing using two mechanisms: a completely random selection (mechanism 1) missingness weakly dependent (mechanism 2a) and strongly dependent (mechanism 2b) on treatment and transmission intensity. The performance of MI, IPW and CC approaches in estimating the Kaplan-Meier (K-M) probability of parasitic recrudescence at day 28 was then compared. In addition, the maximum likelihood estimate of the cured proportion was presented for further comparison (analytical solution). Performance measures (bias, relative bias, standard error and coverage) were reported as an average from 1000 simulation runs. The CC analyses resulted in absolute underestimation of K-M probability of day 28 recrudescence by up to 1.7% and were associated with reduced precision and poor coverage across all the scenarios studied. Both MI and IPW method performed better (greater consistency and greater efficiency) compared to CC analysis. In the absence of censoring, the analytical solution provided the most consistent and accurate estimate of cured proportion compared to the CC analyses. The widely used CC approach underestimates antimalarial failure IPW and MI procedures provided efficient and consistent estimates and should be considered when reporting the results of antimalarial clinical trials, especially in areas of high transmission, where the proportion of indeterminate outcomes could be large. The analytical solution estimating the cured proportion could provide an alternative approach, in scenarios with minimal censoring due to loss to follow-up or new infections.
Publisher: Elsevier BV
Date: 06-2015
Publisher: Springer Science and Business Media LLC
Date: 18-09-2015
Publisher: Springer Science and Business Media LLC
Date: 24-03-2022
DOI: 10.1186/S12936-021-03980-Z
Abstract: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria. In idual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up. Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47–74%] of recrudescences in African children and 32% [95% CI 15–45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19–90%] in children under 5 years old treated with 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0–22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution. Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.
Publisher: Public Library of Science (PLoS)
Date: 10-08-2021
DOI: 10.1371/JOURNAL.PNTD.0009650
Abstract: Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not systematically captured and cases are rarely followed-up to detect consequences of infection and treatment on the pregnant women and foetus. A review of all published literature was undertaken to identify cases of VL infections among pregnant women by searching the following database: Ovid MEDLINE Ovid Embase Cochrane Database of Systematic Reviews Cochrane Central Register of Controlled Trials World Health Organization Global Index Medicus: LILACS (Americas) IMSEAR (South-East Asia) IMEMR (Eastern Mediterranean) WPRIM (Western Pacific) ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Selection criteria included any clinical reports describing the disease in pregnancy or vertical transmission of the disease in humans. Articles meeting pre-specified inclusion criteria and non-primary research articles such as textbook, chapters, letters, retrospective case description, or reports of accidental inclusion in trials were also considered. The systematic literature search identified 272 unique articles of which 54 records were included in this review a further 18 records were identified from additional search of the references of the included studies or from personal communication leading to a total of 72 records (71 case reports/case series 1 retrospective cohort study 1926–2020) describing 451 cases of VL in pregnant women. The disease was detected during pregnancy in 398 (88.2%), retrospectively confirmed after giving birth in 52 (11.5%), and the time of identification was not clear in 1 (0.2%). Of the 398 pregnant women whose infection was identified during pregnancy, 346 (86.9%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 49 (12.3%). Of 346 pregnant women, Liposomal hotericin B (L-AmB) was administered in 202 (58.4%) and pentavalent antimony (PA) in 93 (26.9%). Outcomes were reported in 176 pregnant women treated with L-AmB with 4 (2.3%) reports of maternal deaths, 5 (2.8%) miscarriages, and 2 (1.1%) foetal death/stillbirth. For PA, outcomes were reported in 88 of whom 4 (4.5%) died, 24 (27.3%) had spontaneous abortion, 2 (2.3%) had miscarriages. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified with a median detection time of 6 months (range: 0–18 months). Outcomes of VL treatment during pregnancy is rarely reported and under-researched. The reported articles were mainly case reports and case series and the reported information was often incomplete. From the studies identified, it is difficult to derive a generalisable information on outcomes for pregnant women and babies, although reported data favours the usage of liposomal hotericin B for the treatment of VL in pregnant women.
Publisher: Blue Eyes Intelligence Engineering and Sciences Engineering and Sciences Publication - BEIESP
Date: 30-11-2019
DOI: 10.35940/IJRTE.B2530.118419
Abstract: recently, a rapidly increasing type of education that is mostly adopted by higher education in developed countries is known as E-learning. The aim of the research was to evaluating students’ satisfaction of e-Learning. In the current research, both the theory of technology acceptance model (TAM) and the method of employed structural equation modelling (SEM) with Smart PLS were used to examine the process of students' adoption. It has been found that the learning satisfaction was positively influenced by the perceived ease of use (PEOU), perceived usefulness (PU) and intention to use (IU) as witnessed among university students. Significant and positive perceptions towards e-learning and intend to practice it by university students in Malaysia have been observed by this research.
Publisher: Public Library of Science (PLoS)
Date: 16-08-2021
DOI: 10.1371/JOURNAL.PNTD.0009697
Abstract: Chagas disease (CD), caused by the parasite Trypanosoma cruzi , affects ~6–7 million people worldwide. Significant limitations still exist in our understanding of CD. Harnessing in idual participant data (IPD) from studies could support more in-depth analyses to address the many outstanding research questions. This systematic review aims to describe the characteristics and treatment practices of clinical studies in CD and assess the breadth and availability of research data for the potential establishment of a data-sharing platform. This review includes prospective CD clinical studies published after 1997 with patients receiving a trypanocidal treatment. The following electronic databases and clinical trial registry platforms were searched: Cochrane Library, PubMed, Embase, LILACS, Scielo, Clintrials.gov, and WHO ICTRP. Of the 11,966 unique citations screened, 109 (0.9%) studies (31 observational and 78 interventional) representing 23,116 patients were included. Diagnosis for patient enrolment required 1 positive test result in 5 (4.6%) studies (2 used molecular method, 1 used molecular and serology, 2 used serology and parasitological methods), 2 in 60 (55.0%), 3 in 14 (12.8%) and 4 or more in 4 (3.7%) studies. A description of treatment regimen was available for 19,199 (83.1%) patients, of whom 14,605 (76.1%) received an active treatment and 4,594 (23.9%) were assigned to a placebo/no-treatment. Of the 14,605 patients who received an active treatment, benznidazole was administered in 12,467 (85.4%), nifurtimox in 825 (5.6%), itraconazole in 284 (1.9%), allopurinol in 251 (1.7%) and other drugs in 286 (1.9%). Assessment of efficacy varied largely and was based primarily on biological outcome parasitological efficacy relied on serology in 67/85 (78.8%) studies, molecular methods in 52/85 (61.2%), parasitological in 34/85 (40.0%), microscopy in 3/85 (3.5%) and immunohistochemistry in 1/85 (1.2%). The median time at which parasitological assessment was carried out was 79 days [interquartile range (IQR): 30–180] for the first assessment, 180 days [IQR: 60–500] for second, and 270 days [IQR: 18–545] for the third assessment. This review demonstrates the heterogeneity of clinical practice in CD treatment and in the conduct of clinical studies. The sheer volume of potential IPD identified demonstrates the potential for development of an IPD platform for CD and that such efforts would enable in-depth analyses to optimise the limited pharmacopoeia of CD and inform prospective data collection.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2019
Publisher: F1000 Research Ltd
Date: 02-06-2020
DOI: 10.12688/WELLCOMEOPENRES.15933.1
Abstract: Background: Since the coronavirus disease 2019 (COVID-19) outbreak was first reported in December 2019, many independent trials have been planned that aim to answer similar questions. Tools allowing researchers to review studies already underway can facilitate collaboration, cooperation and harmonisation. The Infectious Diseases Data Observatory (IDDO) has undertaken a living systematic review (LSR) to provide an open, accessible and frequently updated resource summarising characteristics of COVID-19 study registrations. Methods: Review of all eligible trial records identified by systematic searches as of 3 April 2020 and initial synthesis of clinical study characteristics were conducted. In partnership with Exaptive , an open access, cloud-based knowledge graph has been created using the results. Results: There were 728 study registrations which met eligibility criteria and were still active. Median (25 th , 75 th percentile) s le size was 130 (60, 400) for all studies and 134 (70, 300) for RCTs. Eight lower middle and low income countries were represented among the planned recruitment sites. Overall 109 pharmacological interventions or advanced therapy medicinal products covering 23 drug categories were studied. Majority (57%, 62/109) of them were planned only in one study arm, either alone or in combination with other interventions. There were 49 distinct combinations studied with 90% (44/49) of them administered in only one or two study arms. The data and interactive platform are available at iddo.cognitive.city/ . Conclusions: Baseline review highlighted that the majority of investigations in the first three months of the outbreak were small studies with unique treatment arms, likely to be unpowered to provide solid evidence. The continued work of this LSR will allow a more dependable overview of interventions tested, predict the likely strength of evidence generated, allow fast and informative filtering of relevant trials for specific user groups and provide the rapid guidance needed by investigators and funders to avoid duplication of efforts.
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: American Society of Tropical Medicine and Hygiene
Date: 10-2014
Publisher: Elsevier BV
Date: 09-2018
Publisher: F1000 Research Ltd
Date: 18-05-2022
DOI: 10.12688/WELLCOMEOPENRES.17739.1
Abstract: Introduction: Visceral leishmaniasis (VL) is a vector-borne disease caused by protozoan parasites of the genus Leishmania. The disease is endemic in parts of South Asia, East Africa, South America and the Mediterranean region, with an estimated 50,000 to 90,000 cases occurring annually. A living systematic review of existing scientific literature is proposed to identify clinical drug efficacy studies against VL, conducted following the Preferred Reporting Items for Systematic-Reviews and Meta-Analyses (PRISMA) guidelines. Methods and analysis: The proposed living systematic review builds on a previous systematic review first carried out in 2016, and the current protocol is designed to capture any published or registered VL clinical study from Nov-2021 onwards. The following databases will be searched by a medical librarian: PubMed, Ovid Embase, Scopus, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, clinicaltrials.gov, WHO ICTRP, as well as IMEMR, IMSEAR, and LILACS from the WHO Global Index Medicus. The systematic review will consider both randomised and non-randomised interventional studies, including single-armed studies. Ethics and dissemination: A database of eligible studies, including study characteristics, is openly available ( ool/vl-surveyor ) and will be continually updated every six months. All findings will be published in a peer-reviewed journal. PROSPERO registration: CRD42021284622 (29/11/2021)
Publisher: Public Library of Science (PLoS)
Date: 04-10-2019
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Prabin Dahal.