ORCID Profile
0000-0003-4309-9162
Current Organisations
NHS Blood and Transplant
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University of Oxford
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Publisher: John Wiley & Sons, Ltd
Date: 19-03-2014
Publisher: American Medical Association (AMA)
Date: 05-04-2022
Publisher: Wiley
Date: 24-03-2023
DOI: 10.1111/TRF.17315
Abstract: Managing critical bleeding with massive transfusion (MT) requires a multidisciplinary team, often physically separated, to perform several simultaneous tasks at short notice. This places a significant cognitive load on team members, who must maintain situational awareness in rapidly changing scenarios. Similar resuscitation scenarios have benefited from the use of clinical decision support (CDS) tools. A multicenter, multidisciplinary, user‐centered design (UCD) study was conducted to design a computerized CDS for MT. This study included analysis of the problem context with a cognitive walkthrough, development of a user requirement statement, and co‐design with users of prototypes for testing. The final prototype was evaluated using qualitative assessment and the System Usability Scale (SUS). Eighteen participants were recruited across four institutions. The first UCD cycle resulted in the development of four prototype interfaces that addressed the user requirements and context of implementation. Of these, the preferred interface was further developed in the second UCD cycle to create a high‐fidelity web‐based CDS for MT. This prototype was evaluated by 15 participants using a simulated bleeding scenario and demonstrated an average SUS of 69.3 (above average, SD 16) and a clear interface with easy‐to‐follow blood product tracking. We used a UCD process to explore a highly complex clinical scenario and develop a prototype CDS for MT that incorporates distributive situational awareness, supports multiple user roles, and allows simulated MT training. Evaluation of the impact of this prototype on the efficacy and efficiency of managing MT is currently underway.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2021
DOI: 10.1186/S12879-021-06829-7
Abstract: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, 0.17605/OSF.IO/GEHFX ). In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92 1.02) with between-study heterogeneity not beyond chance (I 2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
Publisher: Georg Thieme Verlag KG
Date: 2017
DOI: 10.1160/TH17-01-0015
Abstract: Red cells play a key role in normal haemostasis in vitro but their importance clinically is less clear. The objective of this meta-analysis was to assess if correction of anaemia by transfusing red cells at a high haemoglobin threshold (liberal transfusion) is superior to transfusion at a lower haemoglobin threshold (restrictive transfusion) for reducing the risk of bleeding or thrombotic events. We searched for randomised controlled trials in any clinical setting that compared two red cell transfusion thresholds and investigated the risk of bleeding. We searched for studies published up to October 19, 2016 in The Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, and the Transfusion Evidence Library and ISI Web of Science. Relative risks (RR) or Peto Odds Ratios (pOR) were pooled using a random-effect model. Nineteen randomised trials with 9852 participants were eligible for inclusion in this review. Overall there was no difference in the risk of any bleeding between transfusion strategies (RR 0.91, 95 % confidence interval [CI] 0.74 to 1.12). The risk of severe or life-threatening bleeding was lower with a restrictive strategy (RR 0.75, 95 % CI 0.57 to 0.99). There was no difference in the risk of thrombotic events (RR 0.83, 95 % CI 0.61 to 1.13). The risk of any bleeding was not reduced with liberal transfusion and there was no overall difference in the risk of thrombotic events. Data from the included trials do not support aiming for a high haemoglobin threshold to improve haemostasis. PROSPERO registration number CRD42016035519. Supplementary Material to this article is available online at www.thrombosis-online.com.
Publisher: Massachusetts Medical Society
Date: 09-05-2013
Publisher: American Medical Association (AMA)
Date: 11-04-2023
Abstract: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor n = 10), or no RAS inhibitor (control n = 264) for up to 10 days. The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. ClinicalTrials.gov Identifier: NCT02735707
Publisher: American Medical Association (AMA)
Date: 06-10-2020
Publisher: Wiley
Date: 30-09-2015
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 20-03-2015
Publisher: American Society for Microbiology
Date: 20-04-2022
DOI: 10.1128/JCM.02283-21
Abstract: Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing s les with low viral loads or low RNA quality.
Publisher: Oxford University Press (OUP)
Date: 24-05-2021
Abstract: Convalescent plasma containing neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is under investigation for coronavirus disease 2019 (COVID-19) treatment. We report erse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomized controlled trial that potentially influence treatment outcomes. SARS-CoV-2 RNA in nasopharyngeal swabs collected pretreatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. Of 1274 subjects, 90% were PCR positive with viral loads 118–1.7 × 1011IU/mL. Median viral loads were 40-fold higher in those IgG seronegative (n = 354 28%) compared to seropositives (n = 939 72%). Frequencies of B.1.1.7 increased from & % in November 2020 to 82% of subjects in January 2021. Seronegative in iduals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8 × 106 and 2.0 × 105 IU/mL, respectively P = 2 × 10−15). High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads, and antibody status define subgroups for analysis of treatment efficacy.
Publisher: Elsevier BV
Date: 05-2021
Publisher: SAGE Publications
Date: 05-2021
Abstract: Massive transfusions guided by massive transfusion protocols are commonly used to manage critical bleeding, when the patient is at significant risk of morbidity and mortality, and multiple timely decisions must be made by clinicians. Clinical decision support systems are increasingly used to provide patient-specific recommendations by comparing patient information to a knowledge base, and have been shown to improve patient outcomes. To investigate current massive transfusion practice and the experiences and attitudes of anaesthetists towards massive transfusion and clinical decision support systems, we anonymously surveyed 1000 anaesthetists and anaesthesia trainees across Australia and New Zealand. A total of 228 surveys (23.6%) were successfully completed and 227 were analysed for a 23.3% response rate. Most respondents were involved in massive transfusions infrequently (88.1% managed five or fewer massive transfusion protocols per year) and worked at hospitals which have massive transfusion protocols (89.4%). Massive transfusion management was predominantly limited by timely access to point-of-care coagulation assessment and by competition with other tasks, with trainees reporting more significant limitations compared to specialists. The majority of respondents reported that they were likely, or very likely, both to use (73.1%) and to trust (85%) a clinical decision support system for massive transfusions, with no significant difference between anaesthesia trainees and specialists ( P = 0.375 and P = 0.73, respectively). While the response rate to our survey was poor, there was still a wide range of massive transfusion experience among respondents, with multiple subjective factors identified limiting massive transfusion practice. We identified several potential design features and barriers to implementation to assist with the future development of a clinical decision support system for massive transfusion, and overall wide support for a clinical decision support system for massive transfusion among respondents.
Publisher: Springer Science and Business Media LLC
Date: 05-2023
DOI: 10.1038/S41591-023-02343-2
Abstract: Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated in iduals with severe obesity (BMI 40 kg/m 2 ) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 in iduals with severe obesity compared to 41 control in iduals with normal BMI (BMI 18.5–24.9 kg/m 2 ). We found that 55% of in iduals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of in iduals with normal BMI ( P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for in iduals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of in iduals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in in iduals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.
Publisher: Wiley
Date: 14-04-2014
DOI: 10.1111/TRF.12646
Abstract: A recent randomized trial compared a policy of no prophylaxis with a policy of prophylactic platelet (PLT) transfusions at counts of fewer than 10 × 10(9) /L in patients with hematologic malignancies. The results suggested the effectiveness of prophylactic PLT transfusions may vary according to patient diagnosis and treatment plan. This article presents full subgroup analyses and compares treatment effects between autologous hematopoietic stem cell transplantation (autoHSCT n = 421) and chemotherapy/allogeneic HSCT (chemo/alloHSCT n = 179) patients. Prespecified subgroup analysis found that the reduction in proportion of patients experiencing WHO Grade 2 to 4 bleeds (main trial outcome) seen in the prophylaxis arm was of greater magnitude in chemo/alloHSCT than autoHSCT patients (interaction p = 0.04). Analysis of secondary outcomes showed a shorter time to first bleeding episode with no prophylaxis in the chemo/alloHSCT group (hazard ratio, 1.84 95% confidence interval CI, 1.21-2.79 p = 0.004) compared to the autoHSCT group (hazard ratio, 1.12 95% CI, 0.85-1.48 p = 0.4 interaction p = 0.08). The increased number of days with Grade 2 to 4 bleeds with a no-prophylaxis policy was similar in chemo/alloHSCT (rate ratio, 1.89 95% CI, 1.10-3.26) and in autoHSCT patients (rate ratio, 1.43 95% CI, 1.04-1.97). Both subgroups showed significant reductions in PLT transfusions with a no-prophylaxis strategy. There is evidence that the effectiveness of prophylactic PLT transfusions may differ between subgroups, with chemo/alloHSCT patients receiving prophylactic PLT transfusions appearing to show a greater reduction in bleeding outcomes compared to patients following a no-prophylaxis policy.
Publisher: Wiley
Date: 20-04-2012
Publisher: Massachusetts Medical Society
Date: 22-04-2021
Publisher: Wiley
Date: 20-05-2021
DOI: 10.1111/VOX.13113
Publisher: Wiley
Date: 20-05-2021
DOI: 10.1111/VOX.13114
Publisher: American Medical Association (AMA)
Date: 02-11-2021
Publisher: Wiley
Date: 14-07-2021
DOI: 10.1111/VOX.13130
Publisher: Springer Science and Business Media LLC
Date: 12-07-2021
Publisher: American Medical Association (AMA)
Date: 03-01-2023
Abstract: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm) futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Among 4869 randomized patients (mean age, 59.3 years 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR & .83) was high for therapeutic anticoagulation (99.9% HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2% HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6% HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9% HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8% HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.
Publisher: Wiley
Date: 10-01-2013
DOI: 10.1111/TRF.12058
Abstract: Many platelet (PLT) transfusion trials now use bleeding as a primary outcome however, previous studies have shown a wide variation in the amount (5%-70%) and type of bleeding documented. Differences in the way bleeding has been identified, recorded, and graded may account for some of this variability. This study's aim was to compare trials' method to document and grade bleeding. Data were collected via three methods: a review of study publications, study case report forms, and a questionnaire sent to the authors. Authors of randomized controlled trials of PLT transfusion that used bleeding as an outcome measure were identified from the searches reported by two recent systematic reviews. Twenty-four authors were contacted, and 13 agreed to participate. Data submitted were reviewed and summarized. More recent studies with trained bleeding assessors, detailed documentation, and expanded grading systems have reported higher overall levels of bleeding. The World Health Organization grading system was widely used to grade bleeding, but there was no consistency in the bleeding grade definitions. For ex le, bleeding classified as Grade 2 in some studies (spreading petechiae) was classified as Grade 1 in other studies. This study has highlighted differences in the method of recording and grading bleeding, which may account for some of the variation in reported bleeding rates. To ensure that differences between studies can be attributed to trial interventions or types of participant included, this study group is developing consensus bleeding definitions, a standardized approach to record and grade bleeding, and guidance notes to educate and train bleeding assessors.
Publisher: SAGE Publications
Date: 12-05-2022
Publisher: Wiley
Date: 15-05-2014
DOI: 10.1111/TRF.12697
Abstract: This cost analysis uses data from a randomized trial comparing a no prophylaxis versus prophylactic platelet (PLT) transfusion policy (counts <10 × 10(9) /L) in adult patients with hematologic malignancies. Results are presented for all patients and separately for autologous hematopoietic stem cell transplantation (HSCT) (autoHSCT) and chemotherapy/allogeneic HSCT (chemo/alloHSCT) patients. Data were collected to 30 days on PLT and red blood cell (RBC) transfusions, major bleeds, serious adverse events, critical care, and hematology ward stay. Data were costed using 2011 to 2012 UK unit costs and converted into US$. Sensitivity analyses were performed on uncertain cost variables. Across the whole trial no prophylaxis saved costs compared to prophylaxis: -$1760 per patient (95% confidence interval [CI], -$3250 to -$249 p < 0.05). For autoHSCT patients there was no cost difference between arms: -$110 per patient (95% CI, -$1648 to $1565 p = 0.89). For chemo/alloHSCT patients no prophylaxis cost significantly less than prophylaxis: -$5686 per patient (95% CI, -$8580 to -$2853 p < 0.01). The cost impact of no prophylaxis differed significantly between subgroups. Sensitivity analyses varying daily treatment costs and ward stay for chemo/alloHSCT patients reduced cost differences to -$941 per patient (p = 0.21) across the whole trial and -$2927 per patient (p < 0.05) in chemo/alloHSCT subgroup. It is unclear whether a no-prophylaxis policy saves costs overall. In chemo/alloHSCT patients cost savings are apparent but their magnitude is sensitive to a number of variables and must be considered alongside clinical data showing increased bleeding rates. In autoHSCT patients savings generated through lower PLT use in no-prophylaxis arm were offset by cost increases elsewhere, for ex le, additional RBC transfusions. Cost-effectiveness analyses of alternative PLT transfusion policies simultaneously considering costs and patient-reported outcomes are warranted.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.HOC.2016.01.002
Abstract: Patients with hematologic malignancies frequently become thrombocytopenic as a result of their underlying malignancy or treatments, including cytotoxic chemotherapy and hematopoietic stem cell transplantation and are at increased risk of hemorrhage. Prophylactic platelet transfusions are aimed at preventing severe or life-threatening hemorrhage. This review summarizes recent evidence, including the need for prophylactic platelet transfusions, the optimal dose, platelet transfusion triggers, and risk factors for bleeding. It also discusses controversies surrounding platelet transfusions in this population.
Publisher: American Society of Hematology
Date: 25-03-2021
Abstract: Convalescent plasma (CP) from blood donors with antibodies to severe acute respiratory syndrome coronavirus 2 may benefit patients with COVID-19 by providing immediate passive immunity via transfusion or by being used to manufacture hyperimmune immunoglobulin preparations. Optimal product characteristics (including neutralizing antibody titers), transfusion volume, and administration timing remain to be determined. Preliminary COVID-19 CP safety data are encouraging, but establishing the clinical efficacy of CP requires an ongoing international collaborative effort. Preliminary results from large, high-quality randomized trials have recently started to be reported.
Publisher: Cold Spring Harbor Laboratory
Date: 05-03-2021
DOI: 10.1101/2021.02.24.21251989
Abstract: Treatment of COVID-19 patients with convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation as a means of reducing viral loads, ameliorating disease outcomes, and reducing mortality. However, its efficacy might be reduced in those infected with the emerging B.1.1.7 SARS-CoV-2 variant. Here, we report the erse virological characteristics of UK patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial. SARS-CoV-2 viral RNA was detected and quantified by real-time PCR in nasopharyngeal swabs obtained from study subjects within 48 hours of admission to intensive care unit. Antibody status was determined by spike-protein ELISA. B.1.1.7 strain was differentiated from other SARS-CoV-2 strains by two novel typing methods detecting the B.1.1.7-associated D1118H mutation with allele-specific probes and by restriction site polymorphism (SfcI). Of 1260 subjects, 90% were PCR-positive with viral loads in nasopharyngeal swabs ranging from 72 international units [IUs]/ml to 1.7×10 11 IU/ml. Median viral loads were 45-fold higher in those who were seronegative for IgG antibodies (n=314 28%) compared to seropositives (n=804 72%), reflecting in part the latter group’s possible later disease stage on enrolment. Frequencies of B.1.1.7 infection increased from early November ( %) to December 2020 ( %). Anti-SARS-CoV-2 seronegative in iduals infected with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians of 1.2×10 6 and 3.4 ×10 4 IU/ml respectively p=2×10 −9 ). However, viral load distributions were elevated in both seropositive and seronegative subjects infected with B.1.1.7 (13.4×10 6 and 7.6×10 6 IU/ml p=0.18). High viral loads in seropositive B.1.1.7-infected subjects are consistent with increased replication capacity and/or less effective clearance by innate or adaptive immune response of B.1.1.7 strain than wild-type. As viral genotype was associated with erse virological and immunological phenotypes, metrics of viral load, antibody status and infecting strain should be used to define subgroups for analysis of treatment efficacy.
Publisher: Cold Spring Harbor Laboratory
Date: 22-03-2022
DOI: 10.1101/2022.03.21.22272672
Abstract: A large number of studies have been carried out involving passive antibody administration for the treatment and prophylaxis of COVID-19 and have shown variable efficacy. However, the determinants of treatment effectiveness have not been identified. Here we aimed to aggregate all available data on randomised controlled trials of passive antibody treatment for COVID-19 to understand how the dose and timing affect treatment outcome. We analysed published studies of passive antibody treatment from inception to 7 January 2022 that were identified after searching various databases such as MEDLINE, Pubmed, ClinicalTrials.gov. We extracted data on treatment, dose, disease stage at treatment, and effectiveness for different clinical outcomes from these studies. To compare administered antibody levels between different treatments, we used data on in vitro neutralisation of pseudovirus to normalise the administered dose of antibody. We used a mixed-effects regression model to understand the relationship between disease stage at treatment and effectiveness. We used a logistic model to analyse the relationship between administered antibody dose (normalised to the mean convalescent titre) and outcome, and to predict efficacy of antibodies against different Omicron subvariants. We found that clinical stage at treatment was highly predictive of the effectiveness of both monoclonal antibodies and convalescent plasma therapy in preventing progression to subsequent stages (p .0001 and p=0.0089, respectively, chi-squared test). We also analysed the dose-response curve for passive antibody treatment of ambulant COVID-19 patients to prevent hospitalisation. Using this quantitative dose-response relationship, we predict that a number of existing monoclonal antibody treatment regimens should maintain clinical effectiveness in infection with currently circulating Omicron variants. Early administration of passive antibody therapy is crucial to achieving high efficacy in preventing clinical progression. A dose-response curve was derived for passive antibody therapy administered to ambulant symptomatic subjects to prevent hospitalisation. For many of the monoclonal antibody regimens analysed, the administered doses are estimated to be between 7 and fold higher than necessary to achieve 90% of the maximal efficacy against the ancestral (Wuhan-like) virus. This suggests that a number of current treatments should maintain high efficacy against Omicron subvariants despite reduction in in vitro neutralisation potency. This work provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. This work is supported by an Australian government Medical Research Future Fund awards GNT2002073 and MRF2005544 (to MPD, SJK), MRF2005760 (to MPD), an NHMRC program grant GNT1149990 (SJK and MPD), and the Victorian Government (SJK). SJK is supported by a NHMRC fellowship. DC, MPD, ZKM and EMW are supported by NHMRC Investigator grants and ZKM and EMW by an NHMRC Synergy grant (1189490). DSK is supported by a University of New South Wales fellowship. KLC is supported by PhD scholarships from Monash University, the Haematology Society of Australia and New Zealand and the Leukaemia Foundation. TT, HW and CB are members of the National COVID-19 Clinical Evidence Taskforce which is funded by the Australian Government Department of Health. We identified randomised controlled trials (RCTs) evaluating the effectiveness of SARS-CoV-2-specific neutralising monoclonal antibodies, hyperimmune immunoglobulin and convalescent plasma in the treatment of participants with a confirmed diagnosis of COVID-19 and in uninfected participants with or without potential exposure to SARS-CoV-2. The RCTs were identified from published searches conducted by the Cochrane Haematology living systematic review teams. A total of 37 randomised controlled trials (RCT) of passive antibody administration for COVID-19 were identified. This included 12 trials on monoclonal antibodies, 21 trials of convalescent plasma treatment, and 4 trials of hyperimmune globulin. These trials involved treatment of in iduals either prophylactically or at different stages of infection including post-exposure prophylaxis, symptomatic infection, and hospitalisation. The level of antibody administered ranged from a 250 ml volume of convalescent plasma through to 8 grams of monoclonal antibodies. Data for analysis was extracted from the original publications including dose and antibody levels of antibody administered, disease stage and timing of administration, primary outcome of study and whether they reported on our prespecified outcomes of interest, which include protection against symptomatic infection, hospitalisation, need for invasive mechanical ventilation (IMV) and death (all-cause mortality at 30 days). Our study included data across all 37 RCTs of passive antibody interventions for COVID-19 and aggregated the studies by the stage of infection at initiation of treatment. We found that prophylactic administration or treatment in earlier stages of infection had significantly higher effectiveness than later treatment. We also estimated the dose-response relationship between administered antibody dose and protection from progression from symptomatic ambulant COVID-19 to hospitalisation. We used this relationship to predict the efficacy of different monoclonal antibody treatment regimes against the Omicron subvariants BA.1, BA.2, and BA.4/5. We also used this dose-response relationship to estimate the maximal efficacy of monoclonal antibody therapy in the context of pre-existing endogenous neutralising antibodies. This work identifies that both prophylactic therapy and treatment in the early stages of symptomatic infection can achieve significant protection from infection or hospitalisation respectively. The dose-response relationship provides a quantitative means to predict the change in efficacy of different monoclonal antibodies against new variants and in semi-immune populations based on in vitro neutralisation data. We predict a number of existing monoclonal antibodies will be effective for preventing severe outcomes when administered early in BA.4/5 infections. It is likely that these therapies will provide little protection in in iduals with high levels of endogenous neutralising antibodies, such as healthy in iduals who have recently received a third dose of an mRNA vaccine.
Publisher: American Medical Association (AMA)
Date: 12-03-2019
Abstract: Blood transfusion is one of the most frequently used therapies worldwide and is associated with benefits, risks, and costs. To develop a set of evidence-based recommendations for patient blood management (PBM) and for research. The scientific committee developed 17 Population/Intervention/Comparison/Outcome (PICO) questions for red blood cell (RBC) transfusion in adult patients in 3 areas: preoperative anemia (3 questions), RBC transfusion thresholds (11 questions), and implementation of PBM programs (3 questions). These questions guided the literature search in 4 biomedical databases (MEDLINE, EMBASE, Cochrane Library, Transfusion Evidence Library), searched from inception to January 2018. Meta-analyses were conducted with the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework by 3 panels including clinical and scientific experts, nurses, patient representatives, and methodologists, to develop clinical recommendations during a consensus conference in Frankfurt/Main, Germany, in April 2018. From 17 607 literature citations associated with the 17 PICO questions, 145 studies, including 63 randomized clinical trials with 23 143 patients and 82 observational studies with more than 4 million patients, were analyzed. For preoperative anemia, 4 clinical and 3 research recommendations were developed, including the strong recommendation to detect and manage anemia sufficiently early before major elective surgery. For RBC transfusion thresholds, 4 clinical and 6 research recommendations were developed, including 2 strong clinical recommendations for critically ill but clinically stable intensive care patients with or without septic shock (recommended threshold for RBC transfusion, hemoglobin concentration <7 g/dL) as well as for patients undergoing cardiac surgery (recommended threshold for RBC transfusion, hemoglobin concentration <7.5 g/dL). For implementation of PBM programs, 2 clinical and 3 research recommendations were developed, including recommendations to implement comprehensive PBM programs and to use electronic decision support systems (both conditional recommendations) to improve appropriate RBC utilization. The 2018 PBM International Consensus Conference defined the current status of the PBM evidence base for practice and research purposes and established 10 clinical recommendations and 12 research recommendations for preoperative anemia, RBC transfusion thresholds for adults, and implementation of PBM programs. The relative paucity of strong evidence to answer many of the PICO questions supports the need for additional research and an international consensus for accepted definitions and hemoglobin thresholds, as well as clinically meaningful end points for multicenter trials.
Publisher: Wiley
Date: 06-2016
DOI: 10.1111/VOXS.12264
Publisher: Springer Science and Business Media LLC
Date: 31-05-2023
Publisher: Massachusetts Medical Society
Date: 26-08-2021
Publisher: Wiley
Date: 14-07-2021
DOI: 10.1111/VOX.13129
Publisher: American Medical Association (AMA)
Date: 10-08-2021
Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2021
DOI: 10.1101/2021.11.01.21265384
Abstract: Tools to detect SARS-Coronavirus-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing s les with low viral loads or low RNA quality. An allele-specific probe polymerase chain reaction (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 s les from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. In idual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. Comparative advantage for ASP-PCR over NGS was most pronounced in s les with Ct values between 26-30 and in s les that showed evidence of degradation. Results for s les screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well-suited to augment but not replace NGS. The method can differentiate SARS-COV-2 lineages with high accuracy and would be best deployed to screen s les with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer:target base mismatch through altered oligonucleotide chemistry or chemical additives.
Publisher: Massachusetts Medical Society
Date: 26-08-2021
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
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 Lise Estcourt.