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On 4 June 2020, after a week of increasing scientific concern and scrutiny, first The Lancet, then the New England Journal of Medicine, retracted studies that were based on inaccessible data. The studies have been extremely damaging to chloroquine and hydroxychloroquine COVID-19 clinical trials around the globe. MORU researchers played a key role in bringing this scandal to light, whose consequences continue to play out.
Clinical characteristics of children and young people hospitalised with covid-19 in the United Kingdom: prospective multicentre observational cohort study
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>To characterise the clinical features of children and young people admitted to hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK, and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to covid-19 (MIS-C).</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Prospective observational cohort study with rapid data gathering and near real time analysis.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>260 acute care hospitals in England, Wales, and Scotland between 17th January and 5<jats:sup>th</jats:sup> June 2020, with a minimal follow-up time of two weeks (to 19<jats:sup>th</jats:sup> June 2020).</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>451 children and young people aged less than 19 years admitted to 116 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory-confirmed SARS-CoV-2.</jats:p></jats:sec><jats:sec><jats:title>Main Outcome Measures</jats:title><jats:p>Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Median age was 3.9 years [interquartile range (IQR) 0.3-12.9 years], 36% (162/451) were under 12 months old, and 57% (256/450) were male. 56% (224/401) were White, 12% (49/401) South Asian and 10% (40/401) Black. 43% (195/451) had at least one recorded comorbidity. A muco-enteric cluster of symptoms was identified, closely mirroring the WHO MIS-C criteria.</jats:p><jats:p>17% of children (72/431) were admitted to critical care. On multivariable analysis this was associated with age under one month odds ratio 5.05 (95% confidence interval 1.69 to 15.72, p=0.004), age 10 to 14 years OR 3.11 (1.21 to 8.55, p=0.022) and Black ethnicity OR 3.02 (1.30 to 6.84, p=0.008). Three young people died (0.7 %, 3/451) aged 16 to 19 years, all of whom had profound comorbidity.</jats:p><jats:p>Twelve percent of children (36/303) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Those meeting MIS-C criteria were older, (median age 10.8 years ([IQR 8.4-14.1] vs 2.0 [0.2-12.6]), p<0.001) and more likely to be of non-White ethnicity (70% (23/33) vs 43% (101/237), p=0.005). Children with MIS-C were four times more likely to be admitted to critical care (61% (22/36) vs 15% (40/267, p<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with headache (45% (13/29) vs 11% (19/171), p<0.001), myalgia (39% (11/28) vs 7% (12/170), p<0.001), sore throat (37% (10/27) vs (13% (24/183, p = 0.004) and fatigue (57% (17/30) vs 31% (60/192), p =0.012) than children who did not and to have a platelet count of less than 150 ×10<jats:sup>9</jats:sup>/L (30% (10/33) vs 10% (24/232), p=0.004).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our data confirms less severe covid-19 in children and young people than in adults and we provide additional evidence for refining the MIS-C case definition. The identification of a muco-enteric symptom cluster also raises the suggestion that MIS-C is the severe end of a spectrum of disease.</jats:p></jats:sec><jats:sec><jats:title>Study registration</jats:title><jats:p>ISRCTN66726260</jats:p></jats:sec>
Accessibility, inclusivity, and implementation of COVID-19 clinical management guidelines early in the pandemic: a global survey
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>With a rapidly changing evidence base, high-quality clinical management guidelines (CMGs) are key tools for aiding clinical decision making and increasing access to best available evidence-based care. A rapid review of COVID-19 CMGs found that most lacked methodological rigour, overlooked many at-risk populations, and had variations in treatment recommendations. Furthermore, social science literature highlights the complexity of implementing guidelines in local contexts where they were not developed and the resulting potential to compound health inequities. The aim of this study was to evaluate access to, inclusivity of, and implementation of Covid-19 CMGs in different settings.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A cross-sectional survey of clinicians worldwide from 15 June to 20 July 2020, to explore access to and implementation of Covid-19 CMGs and treatment and supportive care recommendations provided. Data on accessibility, inclusivity, and implementation of CMGs. were analyzed by geographic location.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Seventy-six clinicians, from 27 countries responded, 82% from high-income countries, 17% from low-middle income countries. Most respondents reported access to Covid-19 CMG and confidence in implementation of these. However, many respondents, particularly from LMICs reported barriers to implementation, including limited access to treatments and equipment. Only 20% of respondents reported having access to CMGs covering care for children, 25% for pregnant women and 50% for older adults (>65 years). Themes emerging were for CMGs to include recommendations for different at-risk populations, and settings, include supportive care guidance, be readily updated as evidence emerges, and CMG implementation supported by training, and access to treatments recommended.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings highlight important gaps in Covid-19 CMG development and implementation challenges during a pandemic, particularly affecting different at-risk populations and lower resourced settings., to improve access in evidence-based care recommendations during an emergency. The findings identifies an urgent need for an improved framework for CMG development, that is inclusive and adaptable to emerging evidence and considers contextual implementation support, to improve access to evidence-based care globally.</jats:p></jats:sec>
Development and validation of the 4C Deterioration model for adults hospitalised with COVID-19
<jats:title>Abstract</jats:title><jats:p>Prognostic models to predict the risk of clinical deterioration in acute COVID-19 are required to inform clinical management decisions. Among 75,016 consecutive adults across England, Scotland and Wales prospectively recruited to the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) study, we developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) using 11 routinely measured variables. We used internal-external cross-validation to show consistent measures of discrimination, calibration and clinical utility across eight geographical regions. We further validated the final model in held-out data from 8,252 individuals in London, with similarly consistent performance (C-statistic 0.77 (95% CI 0.75 to 0.78); calibration-in-the-large 0.01 (−0.04 to 0.06); calibration slope 0.96 (0.90 to 1.02)). Importantly, this model demonstrated higher net benefit than using other candidate scores to inform decision-making. Our 4C Deterioration model thus demonstrates unprecedented clinical utility and generalisability to predict clinical deterioration among adults hospitalised with COVID-19.</jats:p>
Antigenic cartography of immune responses to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1).
Naturally acquired clinical immunity to Plasmodium falciparum is partly mediated by antibodies directed at parasite-derived antigens expressed on the surface of red blood cells which mediate disease and are extremely diverse. Unlike children, adults recognize a broad range of variant surface antigens (VSAs) and are protected from severe disease. Though crucial to the design and feasibility of an effective malaria vaccine, it is not yet known whether immunity arises through cumulative exposure to each of many antigenic types, cross-reactivity between antigenic types, or some other mechanism. In this study, we measured plasma antibody responses of 36 children with symptomatic malaria to a diverse panel of 36 recombinant proteins comprising part of the DBLα domain (the 'DBLα-tag') of PfEMP1, a major class of VSAs. We found that although plasma antibody responses were highly specific to individual antigens, serological profiles of responses across antigens fell into one of just two distinct types. One type was found almost exclusively in children that succumbed to severe disease (19 out of 20) while the other occurred in all children with mild disease (16 out of 16). Moreover, children with severe malaria had serological profiles that were narrower in antigen specificity and shorter-lived than those in children with mild malaria. Borrowing a novel technique used in influenza-antigenic cartography-we mapped these dichotomous serological profiles to amino acid sequence variation within a small sub-region of the PfEMP1 DBLα domain. By applying our methodology on a larger scale, it should be possible to identify epitopes responsible for eliciting the protective version of serological profiles to PfEMP1 thereby accelerating development of a broadly effective anti-disease malaria vaccine.
Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine
<jats:p> Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in the treatment of rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and is being studied for the treatment and prevention of COVID-19. Here, we investigate through mathematical modelling the safety profile of HCQ, CQ and other QT-prolonging anti-infective agents to determine their risk categories for <jats:italic>Torsade de Pointes</jats:italic> (TdP) arrhythmia. We performed safety modelling with uncertainty quantification using a risk classifier based on the qNet <jats:italic>torsade metric score</jats:italic> , a measure of the net charge carried by major currents during the action potential under inhibition of multiple ion channels by a compound. Modelling results for HCQ at a maximum free therapeutic plasma concentration (free <jats:italic>C</jats:italic> <jats:sub>max</jats:sub> ) of approximately 1.2 µM (malaria dosing) indicated it is most likely to be in the high-intermediate-risk category for TdP, whereas CQ at a free <jats:italic>C</jats:italic> <jats:sub>max</jats:sub> of approximately 0.7 µM was predicted to most likely lie in the intermediate-risk category. Combining HCQ with the antibacterial moxifloxacin or the anti-malarial halofantrine (HAL) increased the degree of human ventricular action potential duration prolongation at some or all concentrations investigated, and was predicted to increase risk compared to HCQ alone. The combination of HCQ/HAL was predicted to be the riskiest for the free <jats:italic>C</jats:italic> <jats:sub>max</jats:sub> values investigated, whereas azithromycin administered individually was predicted to pose the lowest risk. Our simulation approach highlights that the torsadogenic potentials of HCQ, CQ and other QT-prolonging anti-infectives used in COVID-19 prevention and treatment increase with concentration and in combination with other QT-prolonging drugs. </jats:p>
The cardiotoxicity of antimalarials
The cardiotoxicity of antimalarial medicines has received renewed interest in recent years following the ‘Thorough QT’ assessment of the dihydroartemisinin-piperaquine formulation approved by the European Medicines Agency, which showed evidence of QT interval prolongation. Piperaquine is a bisquinoline antimalarial that is structurally related to chloroquine. Many drugs among the quinoline and structurally-related medicines affect myocardial depolarization and repolarization. WHO currently recommends the artemisinin-based combination treatment dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria. This treatment is being considered alongside other antimalarial medicines for preventive therapy and mass drug administration. To inform WHO recommendations, a group of experts met in October 2016 to review evidence on the cardiotoxicity risk of quinoline antimalarials and structurally-related medicines in people with and without clinical malaria. The following recommendations were proposed by the WHO Evidence Review Group for consideration by the WHO Malaria Policy Advisory Committee and the WHO Advisory Committee on Safety of Medicinal Products.
HIV - lessons from a late diagnosis.
Late HIV diagnosis is the most important predictor of HIV-related morbidity and mortality in the UK and often results from missed testing opportunities during earlier contact with health services. The HPA now recommends routine HIV testing be commissioned as a priority for all general medical admissions in high prevalence areas, such as Milton Keynes. We present the case of a patient admitted to our Medical Admissions Unit (MAU) managed initially for presumed septic complications of metastatic disease who was later found to have terminal HIV disease. In keeping with UK-wide experience which we review, a local audit following this case found MAU HIV test coverage increased after routine testing but not after staff education alone, and resulted in implementation of routine HIV testing in our MAU.
Smartphones for community health in rural Cambodia: A feasibility study
<ns4:p><ns4:bold>Background: </ns4:bold>Village Malaria Workers (VMWs) are lay people trained to provide a valuable role in frontline testing and treatment of malaria in rural villages in Cambodia. Emergence of artemisinin-resistant malaria highlights the essential role of such VMWs in surveillance and early treatment of malaria. Smartphone technology offers huge potential to support VMWs in isolated and resource-poor settings. </ns4:p><ns4:p> <ns4:bold>Methods: </ns4:bold>We investigated the feasibility of issuing established VMWs with a smartphone, bespoke Android application and solar charger to support their role. 27 VMWs in Kampong Cham and Kratie provinces participated. </ns4:p><ns4:p> <ns4:bold>Results: </ns4:bold>26/27 of the smartphones deployed were working well at study completion twelve months later. Interviews with VMWs using quantitative and qualitative methods revealed pride, ease of use and reports of faster communication with the smartphone. VMWs also expressed a strong wish to help people presenting with non-malarial fever, for which further potential supportive smartphone applications are increasingly available. </ns4:p><ns4:p> <ns4:bold>Conclusions: </ns4:bold>As a result of this pilot study, two smartphone based reporting systems for malaria have been developed at the Cambodian National Malaria Center, and the programme is now being extended nationwide. The full code for the smartphone application is made available to other researchers and healthcare providers with this article. Smartphones represent a feasible platform for developing the VMW role to include other health conditions, thus maintaining the relevance of these important community health workers.</ns4:p>
Smartphones for community health in rural Cambodia: A feasibility study.
Background: Village Malaria Workers (VMWs) are lay people trained to provide a valuable role in frontline testing and treatment of malaria in rural villages in Cambodia. Emergence of artemisinin-resistant malaria highlights the essential role of such VMWs in surveillance and early treatment of malaria. Smartphone technology offers huge potential to support VMWs in isolated and resource-poor settings. Methods: We investigated the feasibility of issuing established VMWs with a smartphone, bespoke Android application and solar charger to support their role. 27 VMWs in Kampong Cham and Kratie provinces participated. Results: 26/27 of the smartphones deployed were working well at study completion twelve months later. Interviews with VMWs using quantitative and qualitative methods revealed pride, ease of use and reports of faster communication with the smartphone. VMWs also expressed a strong wish to help people presenting with non-malarial fever, for which further potential supportive smartphone applications are increasingly available. Conclusions: As a result of this pilot study, two smartphone based reporting systems for malaria have been developed at the Cambodian National Malaria Center, and the programme is now being extended nationwide. The full code for the smartphone application is made available to other researchers and healthcare providers with this article. Smartphones represent a feasible platform for developing the VMW role to include other health conditions, thus maintaining the relevance of these important community health workers.