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Background: Proteins in the urine of women with preeclampsia (PE) bind Congo Red dye (urine congophilia). We sought to determine the diagnostic performance of a paper-based point-of-care test detecting urine congophilia for rapid triage and diagnosis of PE. Methods: Prospective cohort study conducted in 346 consecutive pregnant women evaluated for PE in the Labour and Delivery triage unit at our institution. The Congo Red Dot (CRD) Paper Test (index test) was performed on fresh urine samples. The CRD Paper Test results were compared to an expert adjudicated diagnosis in each case. The accuracy of the CRD Paper Test was also compared to urine and serum analytes (placental growth factor and soluble fms-like tyrosine kinase-1) previously proposed as diagnostic aids for PE. Findings: During the first triage visit, 32% (112/346) of women received a clinical diagnosis of PE. Yet, 63% (217/346) were admitted for in-patient diagnostic work-up or delivery. The CRD Paper Test was positive in 25% (86/346) of the cases. Adjudication confirmed PE in 28% (96/346) of all cases. The CRD Paper Test outperformed measured serum and urine markers (80·2% sensitivity, 89·2% specificity, 92·1% negative predictive value, 86·7% accuracy). The pre-test, positive and negative post-test probabilities were 27·7%, 74·0%, and 8·0%, respectively. Of women who were discharged undelivered, 38% (133/346) had at least one additional triage visit and the interval between the last negative and first positive CRD Paper Test was 12 (interquartile range, [5–34]) days. Interpretation: The CRD Paper Test is a simple, non-invasive, “sample-in/answer-out” point-of-care clinical tool for rapid identification of PE. Funding: Saving Lives at Birth Program and NICHD. Keywords: Preeclampsia, Cohort study, Congophilia, Misfolded proteins, Point-of-care

In this short note, we show that all results presented in Alderremy et al. (2018) are straightforward and can be obtained immediately as special cases by means of Laplace’s transform. Furthermore, we show that Elzaki’s transform is a special case of Laplace’s transform, and then cannot be a new transform. Also, we mention that the application of the recursion scheme of the new iterative method (NIM) is incorrect. Keywords: Elzaki transform, Laplace transform, Novel Elzaki iterative method

Background: Pertussis is a highly contagious respiratory disease caused by the bacterium Bordetella pertussis (B. pertussis). The infection is difficult to diagnose especially in underserved or resource-limited areas. We developed a low-cost and instrument-free diagnostic method for rapid and accurate detection of B. pertussis on a point-of-care (POC) testing device. Methods: We developed a paper/polymer hybrid microfluidic biochip integrated with loop-mediated isothermal amplification (LAMP) method for the rapid and accurate detection of B. pertussis. This microfluidic approach was validated by testing 100 de-identified remnant clinical nasopharyngeal swabs and aspirates, which were confirmed to be either positive or negative for B. pertussis by a validated real-time PCR assay at the Children's Hospital Los Angeles. Findings: The instrument-free detection results could be successfully read by the naked eye within 45 min with a limit of detection (LOD) of 5 DNA copies per well. Our optimized bacterial lysis protocol allowed the direct testing of clinical samples without any complicated sample processing/preparation (i.e. DNA extraction) or the use of any equipment (e.g. centrifuges). The validation of the microfluidic approach was accomplished by testing 100 clinical samples. High sensitivity (100%) and specificity (96%) with respect to real-time PCR were achieved. Interpretation: This microfluidic biochip shows great potential for point-of-care disease diagnosis in various venues including schools and physician's offices, especially in low-resource settings in developing nations. Funding: NIH/NIAID under award number R21AI107415, NIH RCMI Pilot Grant, the Philadelphia Foundation, the Medical Center of the Americas Foundation. Keywords: Pertussis diagnosis, Point-of-care detection, Microfluidic biochip, Whooping cough, Loop-mediated isothermal amplification (LAMP)

Background: Context-specific evidence of the spectrum of type 2 diabetes (T2D) burden is essential for setting priorities and designing interventions to reduce associated morbidity and mortality. However, there are currently limited data on the burden of T2D complications and comorbidity in sub-Saharan Africa (SSA). Here, we aimed to estimate the burden and risk factors for T2D complications and comorbidity in a large sample of sub-Saharan Africans. Methods: Using a standardized protocol, we documented and estimated the burden of T2D complications and comorbidities in 2,784 diabetes participants enrolled from tertiary health centers from Nigeria, Ghana and Kenya. T2D complications and comorbidities evaluated by study physicians and clinic staffs included cardiometabolic, ocular, neurological and renal characteristics. Using the same protocol, we contextualized the burden of these complications and comorbidities by evaluating them in a sample of 3,209 individuals without diabetes enrolled from the catchment communities where the cases originated. Logistic regression models were used to identify risk factors and to adjust estimates of risk. Results: The mean age of T2D participants was 56 (SD 11) years with a median duration of diabetes of 5 (interquartile range 2-10) years. The notable complications/comorbidities observed in this sample of T2D participants included hypertension (71%; 95% CI 69-73), obesity 27% (25-29) and hyperlipidemia 34% (32-36). Diabetic retinopathy was found in 15% (13-17) and cataracts in 32% (30-35). About 13% (12-15) had impaired renal function as assessed by eGFR, representing 1 in 8 participants. Erectile dysfunction was a complication in 35% (32-38) of men. Age, duration of T2D and body mass index were significant risk factors for most complications/comorbidities. Population-attributable fraction ranged between 6 and 64 percent for most comorbidities. Conclusion: We observed a substantial burden of diabetes complications and comorbidity in this sample of T2D participants from SSA. Given the reported association of these complications with increased burden of T2D morbidity and mortality we call for public health strategies that prioritise early detection, the maintenance of healthy blood pressure, weight and lipid levels, as well as strengthen health care system capacities to provide treatment and care for neurological and ophthalmological complications of diabetes. Funding Statement: The study was supported in part by the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362). Support for participant recruitment and initial genetic studies of the AADM study was provided by NIH grant No. 3T37TW00041-03S2 from the Office of Research on Minority Health. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study received ethical approval from the Institutional Review Board at each study site, Howard University and the United States National Institutes of Health.

Background: Total knee arthroplasty (TKA) is one the most common elective procedures in the world. Post-operative infection is one of its most devastating complications, often necessitating multiple additional surgeries. We aimed to describe the relationship between surgical duration and risk of deep infection following primary elective TKA. Methods: In this cohort study we analyses primary TKAs done between 2009 and 2016 in Ontario, Canada. We utilized restricted cubic splines to identify a threshold of surgical duration that was associated with an increased risk for infection requiring surgery. Patients with a ‘short’ duration of surgery were matched to those with a ‘long’ duration on patient age (±3 years), patient sex, severe obesity (BMI > 40), the primary surgeon, the hospital and the type of anesthetic. Findings: In 92,343 primary TKAs, the median surgical duration was 106 min. We identified a cut-point of 100 min that was associated with an increased risk for infection. Subsequently, 17,815 TKA recipients with a ‘long’ procedure length were matched to those with a ‘short’ procedure length. ‘Long’ procedures had a higher rate of deep infection (1.1% versus 0.6%, p

Background: Paclitaxel-coated balloons (DCB) are suitable to reduce the risk of restenosis after angioplasty of atherosclerotic femoropopliteal lesions. However, numerous types of DCBs are distinguished by drug density and coating. Conflicting evidence exists about the risk of all-cause death. Methods: Randomised trials published between Jan 1, 2005 and Feb 3, 2019 were identified by searching MEDLINE, CENTRAL, and Clinical.trials.gov. Studies on DCB versus plain old balloon angioplasty (POBA) for the treatment of femoropopliteal artery disease were included, and those focused on in-stent restenosis or critical limb ischemia were excluded. Random-effects meta-analysis was conducted to assess the main outcomes of freedom from target lesion revascularisation (FfTLR) and all-cause mortality. Findings: Of 552 identified records, 14 studies including 2504 patients were eligible. DCB significantly increased the probability of FfTLR with substantial heterogeneity (12-month: risk ratio [RR] 1·24 [95% CI 1·14- 2·27], I2 = 66%; 24-month RR 1·39 [95% CI 1·39-1·52], I2 = 21%). The risk of all-cause mortality was similar between groups at 12 months (RR 0·87 [95% CI 0·48-1·59]), and non-significantly increased after DCB angioplasty at 24 months (RR 1·53 [95% CI 0·94-2·50]). Interpretation: Efficacy of DCB for femoropopliteal angioplasty differs substantial across studies. Effect size depends on the type of DCB, treatment strategy, and lesion complexity. The risk of all-cause death at two years tended to be increased after DCB without evidence of causation. Trial Registration Number: This study is registered with ClinicalTrials.gov (NCT02927574). Funding Statement: The authors stated: "There was no funding source for this study." Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This systematic review and meta-analysis was conducted according to the Preferred Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Background: Hypoxaemia is a common complication of pneumonia and a major risk factor for death, but less is known about hypoxaemia in other common conditions. We evaluated the epidemiology of hypoxaemia and oxygen use in hospitalised neonates and children in Nigeria. Methods: We conducted a prospective cohort study among neonates and children (

Background: People released from incarceration have an increased risk of violence-related death. As deaths from violence are a rare event, meta-analysis is needed to calculate reliable estimates of this risk. We examined the crude mortality rates (CMRs), standardised mortality ratios (SMRs), and predictive factors for violence-related deaths among people released from incarceration. Methods: In this systematic review and meta-analysis, we searched MEDLINE, PubMed, PsycINFO, Scopus, Web of Science, CINCH, and Criminal Justice Abstracts from inception to 14 September 2020 for cohort studies published in English that examined violence-related deaths occurring in the community following release from adult or youth incarceration. We used the Methodological Standard for Epidemiological Research (MASTER) scale to assess the quality of included studies. We conducted a random-effects meta-analysis to calculate pooled estimates of the CMRs and SMRs. Heterogeneity was assessed using univariable meta-regression. This review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020209422). Findings: Our search identified 2,489 records, from which 11 studies met the eligibility criteria. The pooled CMR for violence-related deaths after release from incarceration was 78·7 per 100,000 person-years (95%CI 58·0-99·5). The pooled SMR was 7·6 (95%CI 2·4-12·8). The estimate of heterogeneity was high (I2≥99%) and the Cochran's Q test was significant (p

Background: Viral infections of the respiratory tract represent a major global health concern. Co-infection with bacteria may contribute to severe disease and increased mortality in patients. Nevertheless, viral-bacterial co-infection patterns and their clinical outcomes have not been well characterized to date. This study aimed to evaluate the clinical features and outcomes of patients with viral-bacterial respiratory tract co-infections.Methods: We included 19,361 patients with respiratory infection due to respiratory viruses [influenza A and B, respiratory syncytial virus (RSV), parainfluenza] and/or bacteria in four tertiary hospitals in Hong Kong from 2013 to 2017 using a large territory-wide healthcare database. All microbiological tests were conducted within 48 h of hospital admission. Four etiological groups were included: (1) viral infection alone; (2) bacterial infection alone; (3) laboratory-confirmed viral-bacterial co-infection and (4) clinically suspected viral-bacterial co-infection who were tested positive for respiratory virus and negative for bacteria but had received at least four days of antibiotics. Clinical features and outcomes were recorded for laboratory-confirmed viral-bacterial co-infection patients compared to other three groups as control. The primary outcome was 30-day mortality. Secondary outcomes were intensive care unit (ICU) admission and length of hospital stay. Propensity score matching estimated by binary logistic regression was used to adjust for the potential bias that may affect the association between outcomes and covariates.Findings: Among 15,906 patients with respiratory viral infection, there were 8451 (53.1%) clinically suspected and 1,087 (6.8%) laboratory-confirmed viral-bacterial co-infection. Among all the bacterial species, Haemophilus influenzae (226/1,087, 20.8%), Pseudomonas aeruginosa (180/1087, 16.6%) and Streptococcus pneumoniae (123/1087, 11.3%) were the three most common bacterial pathogens in the laboratory-confirmed co-infection group. Respiratory viruses co-infected with non-pneumococcal streptococci or methicillin-resistant Staphylococcus aureus was associated with the highest death rate [9/30 (30%) and 13/48 (27.1%), respectively] in this cohort. Compared with other infection groups, patients with laboratory-confirmed co-infection had higher ICU admission rate (p < 0.001) and mortality rate at 30 days (p = 0.028), and these results persisted after adjustment for potential confounders using propensity score matching. Furthermore, patients with laboratory-confirmed co-infection had significantly higher mortality compared to patients with bacterial infection alone.Interpretation: In our cohort, bacterial co-infection is common in hospitalized patients with viral respiratory tract infection and is associated with higher ICU admission rate and mortality. Therefore, active surveillance for bacterial co-infection and early antibiotic treatment may be required to improve outcomes in patients with respiratory viral infection.

Background: The disease course of inflammatory bowel disease (IBD) following treatment with glucagon-like peptide (GLP)-1 based therapies is unclear. Objectives: To examine clinical outcomes of IBD in patients with IBD and type 2 diabetes treated with GLP-1 based therapies compared with treatment with other antidiabetics. Methods: Using nationwide Danish registries, we identified patients with IBD and type 2 diabetes who received antidiabetic treatment between 1 January 2007 and 31 March 2019. The primary outcome was a composite of the need for oral corticosteroids, tumour necrosis factor-α inhibitors, IBD-related hospitalisation, or IBD-related surgery. In the setting of a new-user active comparator design, we used Poisson regression to estimate incidence rate ratios (IRRs) comparing treatment with GLP-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors with other antidiabetic therapies. The analyses were adjusted for age, sex, calendar year, IBD severity, and metformin use. Results: We identified 3751 patients with a diagnosis of IBD and type 2 diabetes and with a prescription of an antidiabetic drug (GLP-1 receptor agonists/DPP-4 inhibitors: 982 patients; other antidiabetic treatment: 2769 patients). The adjusted IRR of the composite outcome was 0.52 (95% CI: 0.42-0.65) for patients exposed to GLP-1 receptor agonists/DPP-4 inhibitors compared with patients exposed to other antidiabetics. Conclusion: In patients with IBD and type 2 diabetes, treatment with GLP-1 receptor agonists/DPP-4 inhibitors are associated with a lower risk of adverse clinical events compared with treatment with other antidiabetics. Funding Information: The study was funded by the Novo Nordisk Foundation [grant number NNF16OC0022586 and NNF17OC0029768]. Declaration of Interests: None of the authors have any conflicts of interest to disclose. Ethics Approval Statement: The study was approved by the Danish Data Protection Agency, and data were analysed on a secure research server at the Danish Health Data Authority. In Denmark, ethical approval is not required for research using pre-existing, routinely collected data.

Background There are growing concerns about the impact of the COVID-19 pandemic on mental health. With government-imposed restrictions as well as a general burden on healthcare systems, the pandemic has the potential to disrupt the access to, and delivery of, mental healthcare. Methods Electronic healthcare records from primary care psychological therapy services (Improving Access to Psychological Therapy) in England were used to examine changes in access to mental health services and service delivery during early stages of the COVID-19 pandemic. A descriptive time series was conducted using data from five NHS trusts to examine patterns in referrals to services (1st January 2019 to 24th May 2020) and appointments (1st January 2020 to 24th May 2020) taking place. Findings The number of patients accessing mental health services dropped by an average of 55% in the early weeks after the March 2020 lockdown was announced, reaching a maximum reduction of 74% in the initial 3 weeks after lockdown in the UK, which gradually recovered to a 28% reduction by May. We found some evidence suggesting changes in the sociodemographic and clinical characteristics of referrals. Despite a reduction in access, the impact on appointments appeared limited with service providers shifting to remote delivery of care. Interpretation Services appeared to adapt to provide continuity of care in mental healthcare. However, patients accessing services reduced, potentially placing a future burden on service. Despite the observational nature of the data, the present study can inform the planning of service provision and policy. Funding AD and TS were funded by Innovate UK (KTP #11,105).

Background The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease. Methods This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to 1:1 losartan (25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily) versus placebo for 10 days, and all patients and outcome assesors were blinded. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. (clinicatrials.gov, NCT04311177, closed to new participants) Findings From April to November 2020, 117 participants were randomized 58 to losartan and 59 to placebo, and all were analyzed under intent to treat principles. The primary outcome did not differ significantly between the two arms based on Barnard's test [losartan arm: 3 events (5.2% 95% CI 1.1, 14.4%) versus placebo arm: 1 event (1.7%; 95% CI 0.0, 9.1%)]; proportion difference -3.5% (95% CI -13.2, 4.8%); p = 0.32]. Viral loads were not statistically different between treatment groups at any time point. Adverse events per 10 patient days did not differ signifcantly [0.33 (95% CI 0.22–0.49) for losartan vs. 0.37 (95% CI 0.25–0.55) for placebo]. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early. Interpretation In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalizations, though assessment was limited by low event rate. Importantly, viral load was not statistically affected by treatment. This study does not support initiation of losartan for low-risk outpatients. Funding This study was supported by Minnesota Partnership for Biotechnology and Medical Genomics (CON000000076883).

Background: Migrants globally, including refugees and asylum seekers, have experienced adverse clinical and socioeconomic impacts of the COVID-19 pandemic. For approximately 56,000 refugees and asylum seekers in Reception and Identification Centers (RICs) and Reception Sites (RS) in Greece, living in severely substandard living conditions, prevention measures have been impossible with limited provision in terms of routine testing, surveillance, and access to healthcare. These migrant populations have experienced prolonged lockdowns and restricted movement since the pandemic began. We aimed to assess the impact of COVID-19 on refugees and asylum seekers in reception facilities in Greece and explore implications for policy and practice. Methods: A retrospective analysis of policy documents and national surveillance data was conducted to identify COVID-19 outbreaks and estimate incidence among asylum seekers and refugees residing in these camps during the first 9 months of the epidemic in Greece (26th February – 15th November 2020). Incidence proportion (IP) of COVID-19 confirmed cases was calculated for three population groups (refugees and asylum seekers in RICs, refugees and asylum seekers in RSs, and the general population in Greece) during three time periods (first wave, second wave, and overall across the 9-month period). Findings: Twenty-five COVID-19 outbreaks were identified in refugee and asylum seeker reception facilities, with 6 (85.7%) of 7 RICs and 18 (56.3%) of 32 RSs reporting at least one outbreak during the study period. The overall 9-month COVID-19 IP among refugee and asylum seeker populations residing in RSs on the Greek mainland was 1758 cases per 100,000 population; in RICs the incidence was 2052 cases per 100,000 population. Compared to the general population the risk of COVID-19 infection among refugees and asylum seekers in reception facilities was 2.5 to 3 times higher (p-value

Background: The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates’ drugs. Nitazoxanide (NTZ) has a broad antiviral effect. Methods: This was a randomized, double-blind pilot clinical trial comparing NTZ 600 mg BID versus Placebo for seven days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency from May 20th, 2020, to September 21st, 2020 (ClinicalTrials.gov NCT04348409). Clinical and virologic endpoints and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used. Findings: Two patients died in the NTZ arm compared to 6 in the placebo arm (p = 0.564). NTZ was superior to placebo when considering SSD (p < 0001), the mean time for hospital discharge (6.6 vs. 14 days, p = 0.021), and negative PCR at day 21 (p = 0.035), whereas the placebo group presented more adverse events (p = 0.04). Among adverse events likely related to the study drug, 14 were detected in the NTZ group and 22 in placebo (p = 0.24). Among the 30 adverse events unlikely related, 21 occurred in the placebo group (p = 0.04). A decrease from baseline was higher in the NTZ group for D-Dimer (p = 0.001), US-RCP (p < 0.002), TNF (p < 0.038), IL-6 (p < 0.001), IL-8 (p = 0.014), HLA DR. on CD4+ T lymphocytes (p < 0.05), CD38 in CD4+ and CD8+ T (both p < 0.05), and CD38 and HLA-DR. on CD4+ (p < 0.01) Interpretation: Compared to placebo in clinical and virologic outcomes and improvement of inflammatory out comes, the superiority of NTZ warrants further investigation of this drug for moderate COVID-19 in larger clinical trials. A higher incidence of adverse events in the placebo arm might be attributed to COVID-19 related symptoms. Funding: This study was supported by Farmoquimica (FQM), Brazil. Laboratory testing was partially sup ported by a grant from CNPq, Brazil (RD).

Background Amyloid positron emission tomography (PET) can measure in-vivo demyelination in patients with multiple sclerosis (MS). However, the value of 18F-labeled amyloid PET tracer, 18F-florbetapir in the longitudinal study for monitoring myelin loss and recovery has not been confirmed. Methods From March 2019 to September 2020, twenty-three patients with MS and nine healthy controls (HCs) underwent a hybrid PET/MRI at baseline and expanded disability status scale (EDSS) assessment, and eight of 23 patients further underwent follow-up PET/MRI. The distribution volume ratio (DVR) and standard uptake value ratio (SUVR) of 18F-florbetapir in damaged white matter (DWM) and normal-appearance white matter (NAWM) were obtained from dynamic and static PET acquisition. Diffusion tensor imaging-derived parameters were also calculated. Data were expressed as mean ± standard deviation with 99% confidence interval (99%CI). Finding The mean DVR (1.08 ± 0.12, 99%CI [1.02 ~ 1.14]) but not the mean SUVR of DWM lesions was lower than that of NAWM in patients with MS (1.25 ± 0.10, 99%CI [1.20 ~ 1.31]) and HCs (1.29 ± 0.08, 99%CI [1.23 ~ 1.36]). A trend toward lower mean fractional anisotropy (374.95 ± 45.30 vs. 419.07 ± 4.83) and higher mean radial diffusivity (0.45 ± 0.05 vs. 0.40 ± 0.01) of NAWM in patients with MS than those in HCs was found. DVR decreased in DWM lesions with higher MD (rho = -0.261, 99%CI [-0.362 ~ -0.144]), higher AD (rho = -0.200, 99%CI [-0.318 ~ -0.070]) and higher RD (rho = -0.198, 99%CI [-0.313 ~ -0.075]). Patients’ EDSS scores were reduced (B = 0.04, 99%CI [-0.005 ~ 0.084]) with decreased index of global demyelination in the longitudinal study. Interpretation Our exploratory study suggests that dynamic 18F-florbetapir PET/MRI may be a very promising tool for quantitatively monitoring myelin loss and recovery in patients with MS. Funding Shanghai Pujiang Program, Shanghai Municipal Key Clinical Specialty, Shanghai Shuguang Plan Project, Shanghai Health and Family Planning Commission Research Project, Clinical Research Plan of SHDC, French-Chinese program "Xu Guangqi".

Background While the effects of prolonged sleep deprivation (≥24 h) on seizure occurrence has been thoroughly explored, little is known about the effects of day-to-day variations in the duration and quality of sleep on seizure probability. A better understanding of the interaction between sleep and seizures may help to improve seizure management. Methods To explore how sleep and epileptic seizures are associated, we analysed continuous intracranial electroencephalography (EEG) recordings collected from 10 patients with refractory focal epilepsy undergoing ordinary life activities between 2010 and 2012 from three clinical centres (Austin Health, The Royal Melbourne Hospital, and St Vincent's Hospital of the Melbourne University Epilepsy Group). A total of 4340 days of sleep-wake data were analysed (average 434 days per patient). EEG data were sleep scored using a semi-automated machine learning approach into wake, stages one, two, and three non-rapid eye movement sleep, and rapid eye movement sleep categories. Findings Seizure probability changes with day-to-day variations in sleep duration. Logistic regression models revealed that an increase in sleep duration, by 1·66 ± 0·52 h, lowered the odds of seizure by 27% in the following 48 h. Following a seizure, patients slept for longer durations and if a seizure occurred during sleep, then sleep quality was also reduced with increased time spent aroused from sleep and reduced rapid eye movement sleep. Interpretation Our results suggest that day-to-day deviations from regular sleep duration correlates with changes in seizure probability. Sleeping longer, by 1·66 ± 0·52 h, may offer protective effects for patients with refractory focal epilepsy, reducing seizure risk. Furthermore, the occurrence of a seizure may disrupt sleep patterns by elongating sleep and, if the seizure occurs during sleep, reducing its quality.

Background: Despite a significant shortage of kidneys for transplantation in the US, kidneys from older deceased donors are infrequently transplanted. This is primarily over concern of graft quality and transplant durability. Methods: The US national transplant database (2000–2018) was assessed for deceased donor kidney transplant patient and graft survival, graft durability and stratified by donor age (), Kidney Donor Profile Index (KDPI) and estimated glomerual filtration rate (GFR) one year post-transplantation (eGFR-1) were calculated. Findings: Recipients of kidneys transplanted from deceased donors >65 years had a lower eGFR-1, (median 39 ml/min) than recipients of younger donor kidneys (median 54 ml/min). However, death-censored graft survival, stratified by eGFR-1, demonstrated similar survival, irrespective of donor age or KDPI. The durability of kidney survival decreases as the achieved eGFR-1 declines. KDPI has a poor association with eGFR-1 and lesser for graft durability. While recipients of kidneys > 65 years had a higher one year mortality than younger kidney recipients, recipients of kidneys > 65 years and an eGFR-1

Background Chlorhexidine gluconate (CHG) body washes and emollient application may modulate bacterial pathogen colonization and prevent neonatal hospital-acquired infections. Methods This pilot, non-randomized, open-label trial, enrolled preterm neonates (1000-1500g; day 1-3 of life) at a tertiary hospital in Cape Town, South Africa. Participants were sequentially allocated to 4 trial arms (n=20 each): 1% aqueous CHG (CHG), 1% CHG plus emollient (CHG+EM), emollient only (EM) and standard of care (SOC: no antiseptic/emollient). Trial treatment/s were applied daily for 10 days (d) post-enrolment, documenting neonatal skin condition score. Anterior nose, neck, umbilical and perianal swabs for bacterial culture were collected at d1, d3, d10 and d16 post-enrolment, (±1 day), reporting pathogen acquisition rates and semi-quantitative bacterial colony counts. (ClinicalTrials.gov identifier: NCT03896893; trial status: closed). Findings Eighty preterm neonates (mean gestational age 30 weeks [SD 2]) were enrolled between 4 March and 26 August 2019. The bacterial pathogen acquisition rate (comparing d1 and d16 swabs) varied from 33·9% [95%CI 22·9-47·0] at the umbilicus, 39·3% [95%CI 27·6-52·4] at the neck, to 71·4% [95%CI 58·5-81·7] at both the nose and perianal region. At d10, CHG babies had reduced bacterial density detected from neck, umbilicus, and perianal swabs compared to other groups (see Table 3). Following intervention cessation, colonization density was similar across all trial arms, but S. aureus colonization was more prevalent among EM and CHG+EM babies. Neonatal skin condition score improved in babies receiving emollient application (EM: -0·87 [95%CI 0·69-1·06] and CHG+EM: -0·73 [0·45-0·99]), compared to the SOC and CHG arms (Table 2); no CHG-related skin reactions occurred. Interpretation Bacterial colonization density was significantly reduced in babies receiving 1% CHG washes but colonization levels rebounded rapidly post-intervention. Emollient application improved skin condition but was associated with higher rates of S. aureus colonization. Funding South African Medical Research Council; National Institutes of Health (TW010682).

Background: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability. Methods: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (LA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment. Findings: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 LA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for LA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade ≥2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (Ctrough) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of CTrough through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV Ctrough was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future. Interpretation: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents. Keyword: RPV LA as Pre exposure prophylaxis

Background: The Glivec International Patient Assistance Program (GIPAP) is a unique direct-to-patient program that provides imatinib (Glivec) at no cost to eligible patients in low- and middle-income countries (LMICs) with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumor (GIST). This paper analyses the output, outcome and impact of the program between 2001 and 2014 using the data collected by the Max Foundation. Method: We extracted data on GIPAP patients’ country of residence, sex, diagnosis, date of enrollment in GIPAP, age at enrollment, case closure date, and reason for closure from The Max Foundation database covering the period 2001 to 2014. We used Kaplan-Meier method to assess the survival rate of patients in GIPAP and used the proportional hazard regression model to estimate the effect of different variables on patients’ survival. Findings: About 63,000 GIPAP patients in 93 countries received over 71 million defined daily doses (DDD) of imatinib between 2001 and 2014. Our analysis showed that GIPAP patients had a 5-year survival rate of 89% which compares favorably to survival in high income countries despite the challenges of delivering cancer care in LMICs. Age at enrollment into the program, sex, duration between diagnosis and enrollment into program, year of enrollment, and patients’ diagnosis (CML vs non-CML) were factors that influenced survival. Interpretation: The GIPAP program has improved the survival of CML and GIST patients in LMICs, most of whom would not have had access to imatinib in the absence of the donation and therapeutic support of the program. Funding: This work was funded as part of Access Accelerated case studies. Access Accelerated is an initiative of more than 20 global biopharmaceutical companies in partnership with the World Bank and Union of International Cancer Control that seeks to reduce barriers to prevention, treatment and care for non-communicable diseases in LMICs. Keywords: Glivec International Patient Assistance Program, GIPAP, Chronic myeloid leukemia, Access observatory, CML survival rate, Max foundation, Novartis

BACKGROUND: Early life exposures impact immune system development and therefore the risk of immune-mediated diseases, including inflammatory bowel disease (IBD). We systematically reviewed the impact of pre-, peri‑, and postnatal exposures up to the age of five years on subsequent IBD diagnosis. METHODS: We identified case-control and cohort studies reporting on the association between early life environmental factors and Crohn's disease (CD), ulcerative colitis (UC), or IBD overall. Databases were search from their inception until May 24th, 2019 until July 14th, 2020. We conducted meta-analyses for quantitative review of relevant risk factors that were comparable across studies and qualitative synthesis of the literature for a wide range of early life exposures, including maternal health and exposures during pregnancy, perinatal factors, birth month and related-factors, breastfeeding, hygiene-related factors and social factors, immigration, antibiotics, offspring health, including infections, and passive smoking. PROSPERO registration: CRD42019134980. FINDINGS: Prenatal exposure to antibiotics (OR 1.8; 95% CI 1.2-2.5) and tobacco smoke (OR 1.5; 95% CI 1.2-1.9), and early life otitis media (OR 2.1; 95% CI 1.2-3.6) were associated with IBD. There was a trend towards an association between exposure to antibiotics in infancy and IBD (OR: 1.7, 95% CI 0.97, 2.9), supported by positive data on population-based data. Breastfeeding was protective against IBD. Other early life risk factors had no association with IBD, but data were limited and heterogenous. INTERPRETATION: Early life is an important period of susceptibility for IBD development later in life. Tobacco smoke, infections and antibiotics were associated positively, and breastfeeding was associated negatively with IBD. Our findings offer an opportunity to develop primary prevention strategies. FUNDING: This study did not receive any funding. ispartof: ECLINICALMEDICINE vol:36 ispartof: location:England status: published

Background A significant proportion of individuals experience lingering and debilitating symptoms following acute COVID-19 infection. The National Institute for Health and Care Excellence (NICE) have coined the persistent cluster of symptoms as post-COVID syndrome. This has been further sub-categorised into acute post-COVID syndrome for symptoms persisting three weeks beyond initial infection and chronic post-COVID syndrome for symptoms persisting beyond twelve weeks. The aim of this review was to detail the prevalence of clinical features and identify potential predictors for acute and chronic post-COVID syndrome. Methods A systematic literature search, with no language restrictions, was performed to identify studies detailing characteristics and outcomes related to survivorship of post-COVID syndrome. The last search was performed on 6 March 2021 and all pre-dating published articles included. A means of proportion meta-analysis was performed to quantify characteristics of acute and chronic post-COVID syndrome. Study quality was assessed with a specific risk of bias tool. PROSPERO Registration: CRD42020222855 Findings A total of 43 studies met the eligibility criteria; of which, 38 allowed for meta-analysis. Fatigue and dyspnoea were the most prevalent symptoms in acute post-COVID (0·37 and 0·35) and fatigue and sleep disturbance in chronic post-COVID syndrome (0·48 and 0·44), respectively. The available evidence is generally of poor quality, with considerable risk of bias, and are of observational design. Interpretation In conclusion, this review highlights that flaws in data capture and interpretation, noted in the uncertainty within our meta-analysis, affect the applicability of current knowledge. Policy makers and researchers must focus on understanding the impact of this condition on individuals and society with appropriate funding initiatives and global collaborative research. Funding As stated in the Acknowledgements.

Background Guidelines to encourage responsible reporting of suicide in news media are a key component of suicide prevention strategies. Recent guidelines have been developed on portrayal of suicide in entertainment media although the relationship between these portrayals and subsequent suicidal behaviour has received considerably less attention in research. Methods We conducted a systematic review and meta-analysis to examine the association between portrayals of suicide and suicide attempt in entertainment media and suicidal behaviour in the population. We searched PubMed, Scopus, Embase, PsycInfo, Web of Science and Google Scholar until April 20, 2021. We included studies adopting interrupted time series or single/multiple arm pre-post designs. Separate analyses were undertaken for studies of suicide and suicide attempts. We synthesized studies at moderate risk of bias and included studies at serious risk in a sensitivity analysis. Using a random-effects meta-analysis, we synthesized studies at moderate risk of bias and included studies at serious risk in a sensitivity analysis. Study registration: PROSPERO (CRD42020221333). Findings Twelve studies met our inclusion criteria. Six studies were about suicide. Two of these were at moderate risk of bias and both examined the effects of the Netflix series 13 Reasons Why. The pooled rate ratio (RR) for these studies was 1·18 (95% CI 1·09 to 1·27, p

Background Fatal police violence in the United States disproportionately affects Black, Native American, and Hispanic people, and for these groups it is a racially oppressive population-level stressor that we hypothesize increases the risk of pregnancy loss. Focusing on core based statical areas (CBSAs) surrounding small and large urban centers, we accordingly tested whether gestational exposure to fatal police violence decreased the number of live births, which is reflective of a rise in lost pregnancies. Methods Our observational study linked microdata for all births (N = 7,709,300) in 520 CBSAs with at least one incident of fatal police violence in 2013–2015 to Fatal Encounters, a database that prospectively identified 2594 police-related fatalities using online media reports and public records. We estimated the association between month-to-month fatal police violence and conceptions resulting in live births using distributed lag quasi-Poisson models with CBSA-level fixed effects, adjusted for seasonality and stratified by maternal race/ethnicity. Findings For each additional police-related fatality that occurred in the first through sixth months of gestation, we observed a 0.14% decrease (95% confidence interval: 0.05%, 0.23%) in the total number of live births within CBSAs, and a 0.29% decrease in births to Black women (95% CI: 0.11%, 0.48%). The association was null for births to White women. Interpretation Our findings suggest fatal police violence may have population-level consequences for pregnancy loss and adds to the evidence regarding the importance of preventing these fatalities. Funding This study was supported in part by NIH grant P30ES00002 to MGW.

BACKGROUND: COVID-19 prediction models based on clinical characteristics, routine biochemistry and imaging, have been developed, but little is known on proteomic markers reflecting the molecular pathophysiology of disease progression. METHODS: The multicentre (six European study sites) Prospective Validation of a Proteomic Urine Test for Early and Accurate Prognosis of Critical Course Complications in Patients with SARS-CoV-2 Infection Study (Crit-COV-U) is recruiting consecutive patients (≥ 18 years) with PCR-confirmed SARS-CoV-2 infection. A urinary proteomic biomarker (COV50) developed by capillary-electrophoresis-mass spectrometry (CE-MS) technology, comprising 50 sequenced peptides and identifying the parental proteins, was evaluated in 228 patients (derivation cohort) with replication in 99 patients (validation cohort). Death and progression along the World Health Organization (WHO) Clinical Progression Scale were assessed up to 21 days after the initial PCR test. Statistical methods included logistic regression, receiver operating curve (ROC) analysis and comparison of the area under the curve (AUC). FINDINGS: In the derivation cohort, 23 patients died, and 48 developed worse WHO scores. The odds ratios (OR) for death per 1 standard deviation (SD) increment in COV50 were 3·52 (95% CI, 2·02-6·13, p

Background Angiotensin receptor blockers (ARBs), such as telmisartan, have been postulated to treat Covid-19-induced lung inflammation. Methods This is a parallel-group, randomized, two-arm, open-label, adaptive, multicenter superiority trial with 1:1 allocation ratio. Participants included patients from 18 years of age hospitalized with Covid-19 with 4 or fewer days since symptom onset enrolled at a university and a community hospital in Buenos Aires, Argentina. Exclusion criteria included prior intensive care unit (ICU) admission and use of ARBs/angiotensin converting enzyme inhibitors at randomization. Control arm received standard care alone and treatment arm telmisartan 80 mg twice daily for 14 days. Primary outcomes were C-reactive protein (CRP) plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge within 15 days, admission to ICU and death at 15- and 30-days. NCT04355936 (Completed). Findings A pragmatic decision to end the study before the third interim analysis was made on Oct. 30th due to sharp reduction in recruitment. A total of 162 patients were randomized. 158 patients enrolled between May 14 and October 30 2020, were included in the analysis, 80 in the standard care and 78 in the telmisartan added to standard care group. Baseline absolute CRP serum levels were 5.53 ± 6.19 mg/dL (95% CI 6.91 to 4.15, n = 80) and 9.04 ± 7.69 (95% CI 9.04 to 10.82, n = 74) in the standard care and telmisartan added to standard care groups, respectively. Day 5 control-group CRP levels were 6.06 ± 6.95 mg/dL (95% CI 7.79–4.35, n = 66) while telmisartan group were 3.83 ± 5.08 mg/dL (95% CI 5.08–2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 ± 8.19 mg/dL (95% CI 8.79–3.81, n = 44) and 2.37 ± 3.47 mg/dL (95% CI 3.44–1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean ± SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%, 16/71; telmisartan 4.29%, 3/70 participants; p = 0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30. No adverse events were reported. Interpretation Our study suggests that the ARB telmisartan, a widely used antihypertensive drug, is safe and could reduce morbidity and mortality in hospitalized patients infected with SARS -CoV-2 by anti-inflammatory effects. Further studies employing telmisartan are needed for confirmation of our results and to define its true therapeutic value as a tool against Covid-19. Funding Facultad de Medicina (Universidad de Buenos Aires, Argentina), Hospital Espanol de Buenos Aires (Argentina) and Laboratorio Elea (Argentina).

Background Different physiologic changes that occur during pregnancy, such as Hydroureter, dilatation of the renal pelvis, glycosuria and aminoaciduria, and low urine production predispose pregnant women for ascending urinary tract infection. Globally, 2% to 15% of the pregnant women have urinary tract infection without specific symptoms. Therefore, this study aimed to estimate the prevalence of asymptomatic bacteriuria (ABU) in pregnant women in Africa. Methods Systematic search of published studies done on PubMed, EMBASE, Web of Science, SCOPUS, PsychInfo, CINAHL, and google scholar for gray literature. All published observational studies until October 30, 2020 were included. This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality of studies was assessed by modified Newcastle-Ottawa Scale (NOS). Meta-analysis was carried out using a random-effects method with the double arcsine transformation approach using the STATA™ Version 14 software. Trim and fill analysis was done to correct presence of significant publication bias. The study protocol is prospectively registered on PROSPERO, registration number CRD42020212601. Findings From 3393 obtained studies, 48 studies from 12 African countries involving 15, 664 pregnant women included in this Meta-analysis. The overall pooled prevalence of asymptomatic bacteriuria among pregnant women in Africa after correction for publication bias by trim and fill analysis was found to be 11.1% (95% CI: 7.8, 14.4). The most common bacterial isolates involved in the etiology of ABU was Escherichia coli with pooled prevalence 33.4% (95% CI: 27.3 - 39.4) Interpretation Asymptomatic bacteriuria is substantial among pregnant women in Africa. Therefore, all pregnant women should be tested for the presence of asymptomatic bacteriuria. A screening program must be based not only on the incidence but also on a cost-efficacy evaluation and a microbiological evaluation. Funding There was no funding source for this study.

Background: We evaluated features of HIV transmission networks involving persons diagnosed during incident HIV infection (IHI) to assess network-based opportunities to curtail onward transmission. Methods: Transmission networks were constructed using partial pol sequences reported to North Carolina surveillance among persons with recent (2014–2018) and past (90 days prior to an IHI were further characterized. We assessed named partner outcomes among IHI index persons using contact tracing data. Findings: Of 4,405 HIV diagnoses 2014–2018 with sequences, there were 323 (7%) IHI index persons; most were male (88%), Black (65%), young (68%

Aim: We plan to conduct a randomised clinical trial among people likely to witness opioid overdose to compare the educational effectiveness of point-of-care naloxone distribution with best-available care, by observing participants’ resuscitation skills in a simulated overdose. This mixed methods feasibility study aims to assess the effectiveness of recruitment and retention strategies and acceptability of study procedures. Methods: We implemented candidate-driven recruitment strategies with verbal consent and destigmatizing study materials in a family practice, emergency department, and addictions service. People ≥16 years of age who are likely to witness overdose were randomized to point-of-care naloxone distribution or referral to an existing program. We evaluated participant skills as a responder to a simulated overdose 3–14 days post-recruitment. Retention strategies included flexible scheduling, reminders, cash compensation and refreshments. The primary outcome was recruitment and retention feasibility, defined as the ability to recruit 28 eligible participants in 28 days, with

Background Antimicrobial resistance (AMR) in Enterobacterales is a global health threat. Capacity for individual-level surveillance remains limited in many countries, whilst population-level surveillance approaches could inform empiric antibiotic treatment guidelines. Methods In this exploratory study, a novel approach to population-level prediction of AMR in Enterobacterales clinical isolates using metagenomic (Illumina) profiling of pooled DNA extracts from human faecal samples was developed and tested. Taxonomic and AMR gene profiles were used to derive taxonomy-adjusted population-level AMR metrics. Bayesian modelling, and model comparison based on cross-validation, were used to evaluate the capacity of each metric to predict the number of resistant Enterobacterales invasive infections at a population-level, using available bloodstream/cerebrospinal fluid infection data. Findings Population metagenomes comprised samples from 177, 157, and 156 individuals in Kenya, the UK, and Cambodia, respectively, collected between September 2014 and April 2016. Clinical data from independent populations included 910, 3356 and 197 bacterial isolates from blood/cerebrospinal fluid infections in Kenya, the UK and Cambodia, respectively (samples collected between January 2010 and May 2017). Enterobacterales were common colonisers and pathogens, and faecal taxonomic/AMR gene distributions and proportions of antimicrobial-resistant Enterobacterales infections differed by setting. A model including terms reflecting the metagenomic abundance of the commonest clinical Enterobacterales species, and of AMR genes known to either increase the minimum inhibitory concentration (MIC) or confer clinically-relevant resistance, had a higher predictive performance in determining population-level resistance in clinical Enterobacterales isolates compared to models considering only AMR gene information, only taxonomic information, or an intercept-only baseline model (difference in expected log predictive density compared to best model, estimated using leave-one-out cross-validation: intercept-only model = -223 [95% credible interval (CI): -330,-116]; model considering only AMR gene information = -186 [95% CI: -281,-91]; model considering only taxonomic information = -151 [95% CI: -232,-69]). Interpretation Whilst our findings are exploratory and require validation, intermittent metagenomics of pooled samples could represent an effective approach for AMR surveillance and to predict population-level AMR in clinical isolates, complementary to ongoing development of laboratory infrastructures processing individual samples. Funding The study was funded by Bill & Melinda Gates Foundation (grant agreement OPP1160974) and was sponsored by University of Oxford. The study was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, and NIHR Health Protection Research Unit in Healthcare-associated Infections and Antimicrobial Resistance (a partnership between the University of Oxford and Public Health England [PHE]). Kenyan samples were collected in a study funded by the MRC/DfID/Wellcome Joint Clinical Trials scheme: MR/M007367/1.

BackgroundThis first report of the Linköping Covid-19 Study (LinCoS) aimed at determination of Covid-19-associated mortality, impairments, activity and participation limitations denoting rehabilitation needs four months after discharge from hospital.MethodsAn ambidirectional population-based cohort study including all confirmed Covid-19 cases admitted to hospital during 1/03-31/05 and those living in home healthcare settings identified through a regional registry and evaluated through medical records, including WHO Clinical Progression Scale (CPS). All patients discharged from hospital were followed-up by structured telephone interview at 4 months post-discharge. Respondents indicated any new or aggravated persisting problems in any of 25 body functions and 12 activity/participation items and rated them for impact on daily life.FindingsOut of 734 hospitalised patients, 149 were excluded, 125 died, and 460 were alive at 4-month follow-up of whom 433 (94.1%) were interviewed. In total, 40% reported impairments and activity/participation limitations affecting daily life and warranted further multi-professional rehabilitation assessment, predominantly those with severe disease and a considerable proportion of those with moderate disease. Cognitive and affective impairments were equally common in all groups and were reported by 20-40% of cases. Limb weakness was reported by 31%, with CPS 7-9 being four times more likely to report this problem as compared to CPS 4-5. 26% of those working or studying reported difficulties returning to these activities, this being 3.5 times more likely in CPS 7-9 as compared to CPS 4-5. 25% reported problems walking >1 km, with CPS 7-9 over three times more likely to report this as compared to the other two sub-groups. 90-day mortality rate of Covid-19 associated deaths was 15.1%.InterpretationMost rehabilitation needs after Covid-19 involved higher cerebral dysfunction both in patients with moderate and severe disease. This should be considered when designing services aiming at minimizing long-term disability.FundingALF grant and Region Östergötland.

Background Chlamydia trachomatis (CT) is one of the most prevalent bacterial sexually transmitted infections (STIs) globally but has been inadequately detected for intervention. Introduction of point-of-care tests (POCTs) for CT is critical for filling the intervention gaps. We conducted a systematical review and meta-analysis on diagnostic performance of POCTs for CT to assist in guiding the application of these assays in CT screening and detection. Methods We searched PubMed/Medline and Embase databases, from January 2004 to May 2021, for studies reporting the performance of POCTs for identifying CT using specimens collected from urethral, vaginal, cervical, anorectal, or pharyngeal site or of urine. Two investigators independently screened and extracted data for controlling the quality of data extraction. Any discrepancies in study selection and data extraction were resolved through consensus. We only included studies with sufficient data to estimate sensitivity and specificity, and used laboratory-based nucleic acid amplification test (NAAT) as the reference standard. The main outcomes were pooled sensitivity, specificity, and diagnostic odds ratio (DOR) and their corresponding 95% confidence intervals (CIs). Summary estimates were calculated using a random-effects model and summary receiver operator curves (SROCs) were generated using the Moses-Littenberg method. STATA 14.0 and Meta-DiSc 1.4 were used for statistical analysis. The study protocol is registered with PROSPERO, number CRD42019140544. Findings Of 3,038 records identified, 39 studies (42,336 specimens) were included in the study, including 14 studies on evaluation of antigen detection (AD)-based and 25 on NAAT-based POCTs. The overall pooled sensitivity, specificity and DOR were 56% (95% CI 45%–67%), 99% (95% CI 98%–99%) and 86 (95% CI 46–163), respectively, for AD-based POCTs and corresponding values for NAAT-based POCTs were 94% (95% CI 91%–96%), 99% (95% CI 99%–99%) and 1,933(95% CI 1,018–3,669), respectively. The pooled sensitivity of AD-based POCTs varied across the types of specimens, indicating 46% for cervical swabs (95% CI 37%–56%; range 22.7%–71.4%), 52% for vaginal swabs (95% CI 34%–70%; range 17.1%–86.8%) and 57% for male urine (95% CI 36%–75%; range 20.0%–82.6%). For NAAT-based POCTs, the pooled sensitivity was 94% (95% CI 90%–96%) for cervical swabs, 94% (95% CI 86%–98%) for vaginal swabs, 95% (95% CI 91%–97%) for urine specimens and 93% (95% CI 87%–96%) for anorectal swabs. Interpretation NAAT-based POCTs for CT have a significantly better performance particularly in sensitivity for diagnosing the infection with CT than the AD-based POCTs. Screening strategy with AD-based POCTs may potentially result in a substantial under-detection of the infections.

Background Older children have higher SARS-CoV-2 infection rates than younger children. We investigated SARS-CoV-2 infection, seroprevalence and seroconversion rates in staff and students following the full reopening of all secondary schools in England. Methods Public Health England (PHE) invited secondary schools in six regions (East and West London, Hertfordshire, Derbyshire, Manchester and Birmingham) to participate in SARS-CoV-2 surveillance during the 2020/21 academic year. Participants had nasal swabs for RT-PCR and blood samples for SARS-CoV-2 antibodies at the beginning (September 2020) and end (December 2020) of the autumn term. Multivariable logistic regression was used to assess independent risk factors for seropositivity and seroconversion. Findings Eighteen schools in six regions enrolled 2,209 participants, including 1,189 (53.8%) students and 1,020 (46.2%) staff. SARS-CoV-2 infection rates were not significantly different between students and staff in round one (5/948; [0.53%] vs. 2/876 [0.23%]; p = 0.46) or round two (10/948 [1.05%] vs. 7/886 [0.79%]; p = 0.63), and similar to national prevalence. None of four and 7/15 (47%) sequenced strains in rounds 1 and 2 were the highly transmissible SARS-CoV-2 B.1.1.7 variant. In round 1, antibody seropositivity was higher in students than staff (114/893 [12.8%] vs. 79/861 [9.2%]; p = 0.016), but similar in round 2 (117/893 [13.1%] vs.117/872 [13.3%]; p = 0.85), comparable to local community seroprevalence. Between the two rounds, 8.7% (57/652) staff and 6.6% (36/549) students seroconverted (p = 0.16). Interpretation In secondary schools, SARS-CoV-2 infection, seropositivity and seroconversion rates were similar in staff and students, and comparable to local community rates. Ongoing surveillance will be important for monitoring the impact of new variants in educational settings.

Background The locations of subsequent fractures after initial fracture in postmenopausal women are poorly characterized. Methods We conducted a prospective analysis of subsequent fractures after initial fracture in Women's Health Initiative (1993–2018) participants who provided follow-up (mean 15.4 years, SD 6.2 years) data (n = 157,282 participants; baseline age 50–79; 47,458 participants with incident fracture). Cox proportional hazards models were adjusted for age, race/ethnicity, body mass index, and other covariates. Findings The risk of each type of subsequent fracture was increased after each type of initial fracture. Incident lower arm/wrist fracture was associated with significantly elevated risks of subsequent fractures at the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (adjusted hazard ratios [aHRs] ranging 2·63–5·68). The risk of hip fracture was increased after initial lower arm or wrist fracture (aHR 4·80, 95% CI 4·29–5·36), initial upper arm or shoulder fracture (aHR 5·06, 95% CI 4·39–5·82), initial upper leg fracture (aHR 5·11, 95% CI 3·91–6·67), initial knee fracture (aHR 5·03, 95% CI 4·20–6·03), initial lower leg/ankle fracture (aHR 4·10, 95% CI 3·58–4·68), and initial spine fracture (aHR 6·69, 95% CI 5·95–7·53). Associations were significant in all age groups, even women aged 50–59 years. Risks of subsequent fracture were more pronounced among non-Hispanic Black, Hispanic/Latina, and Asian/Pacific Islander than among non-Hispanic White women. Interpretation Increased risk of subsequent fracture is observed for all fracture types across all ages. Women who experience any of these fractures should be targeted for interventions to prevent subsequent fractures. Funding National Institutes of Health HHSN268201600018C,HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.

Background More contagious variants of SARS-CoV-2 have emerged around the world, sparking concerns about impending surge in cases and severe outcomes. Despite the development of effective vaccines, rollout has been slow. We evaluated the impact of accelerated vaccine distribution on curbing the disease burden of novel SARS-CoV-2 variants. Methods We used an agent-based model of SARS-CoV-2 transmission and vaccination to simulate the spread of novel variants with S-Gene Target Failure (SGTF) in addition to the original strain. We incorporated age-specific risk and contact patterns and implemented a two-dose vaccination campaign in accord with CDC-recommended prioritization. As a base case, we projected hospitalizations and deaths at a daily vaccination rate of 1 million doses in the United States (US) and compared with accelerated campaigns in which daily doses were expanded to 1.5, 2, 2.5, or 3 million. Findings We found that at a vaccination rate of 1 million doses per day, an emergent SGTF variant that is 20–70% more transmissible than the original variant would become dominant within 2 to 9 weeks, accounting for as much as 99% of cases at the outbreak peak. Our results show that accelerating vaccine delivery would substantially reduce severe health outcomes. For a SGTF with 30% higher transmissibility, increasing vaccine doses from 1 to 3 million per day would avert 152,048 (95% CrI: 134,772–168,696) hospitalizations and 48,448 (95% CrI: 42,042–54,285) deaths over 300 days. Accelerated vaccination would also prevent additional COVID-19 waves that would otherwise be fuelled by waning adherence to non-pharmaceutical interventions (NPIs). Interpretation We found that the current pace of vaccine rollout is insufficient to prevent the exacerbation of the pandemic that will be attributable to the novel, more contagious SARS-CoV-2 variants. Accelerating the vaccination rate should be a public health priority for averting the expected surge in COVID-19 hospitalizations and deaths that would be associated with widespread dissemination of the SGTF variants. Our results underscore the need to bolster the production and distribution of COVID-19 vaccines, to rapidly expand vaccination priority groups and distribution sites.

Background clinically relevant methods to identify individuals at risk for impaired daily living abilities secondary to neurocognitive impairment (ADLs) remain elusive. This is especially true for complex clinical conditions such as HIV-Associated Neurocognitive Disorders (HAND). The aim of this study was to identify novel and modifiable factors that have potential to improve diagnostic accuracy of ADL risk, with the long-term goal of guiding future interventions to minimize ADL disruption. Methods study participants included 79 people with HIV (PWH; mean age = 63; range = 55–80) enrolled in neuroHIV studies at University California San Francisco (UCSF) between 2016 and 2019. All participants were virally suppressed and exhibited objective evidence of neurocognitive impairment. ADL status was defined as either normative (n = 39) or at risk (n = 40) based on a task-based protocol. Gradient boosted multivariate regression (GBM) was employed to identify the combination of variables that differentiated ADL subgroup classification. Predictor variables included demographic factors, HIV disease severity indices, brain white matter integrity quantified using diffusion tensor imaging, cognitive test performance, and health co-morbidities. Model performance was examined using average Area Under the Curve (AUC) with repeated five-fold cross validation. Findings the univariate GBM yielded an average AUC of 83% using Wide Range Achievement test 4 (WRAT-4) reading score, self-reported thought confusion and difficulty reading, radial diffusivity (RD) in the left external capsule, fractional anisotropy (FA) in the left cingulate gyrus, and Stroop performance. The model allowing for two-way interactions modestly improved classification performance (AUC of 88%) and revealed synergies between race, reading ability, cognitive performance, and neuroimaging metrics in the genu and uncinate fasciculus. Conversion of Neuropsychological Assessment Battery Daily Living Module (NAB-DLM) performance from raw scores into T scores amplified differences between White and non-White study participants. Interpretation demographic and sociocultural factors are critical determinants of ADL risk status among older PWH who meet diagnostic criteria for neurocognitive impairment. Task-based ADL assessment that relies heavily on reading proficiency may artificially inflate the frequency/severity of ADL impairment among diverse clinical populations. Culturally relevant measures of ADL status are needed for individuals with acquired neurocognitive disorders, including HAND.

Background: COVID-19 has put extraordinary stress on healthcare workers. Few studies have evaluated stress by worker role, or focused on experiences of women and people of color. Methods: The “Coping with COVID” survey assessed US healthcare worker stress. A stress summary score (SSS) incorporated stress, fear of exposure, anxiety/depression and workload (Omega 0.78). Differences from mean were expressed as Cohen's d Effect Sizes (ESs). Regression analyses tested associations with stress and burnout. Findings: Between May 28 and October 1, 2020, 20,947 healthcare workers responded from 42 organizations (median response rate 20%, Interquartile range 7% to 35%). Sixty one percent reported fear of exposure or transmission, 38% reported anxiety/depression, 43% suffered work overload, and 49% had burnout. Stress scores were highest among nursing assistants, medical assistants, and social workers (small to moderate ESs, p < 0.001), inpatient vs outpatient workers (small ES, p < 0.001), women vs men (small ES, p < 0.001), and in Black and Latinx workers vs Whites (small ESs, p < 0.001). Fear of exposure was prevalent among nursing assistants and Black and Latinx workers, while housekeepers and Black and Latinx workers most often experienced enhanced meaning and purpose. In multilevel models, odds of burnout were 40% lower in those feeling valued by their organizations (odds ratio 0.60, 95% CIs [0.58, 0.63], p< 0.001). Interpretation: Stress is higher among nursing assistants, medical assistants, social workers, inpatient workers, women and persons of color, is related to workload and mental health, and is lower when feeling valued.

Background Age-related macular degeneration (AMD) is one of the leading causes of vision loss in the elderly population. The application of artificial intelligence (AI) provides convenience for the diagnosis of AMD. This systematic review and meta-analysis aimed to quantify the performance of AI in detecting AMD in fundus photographs. Methods We searched PubMed, Embase, Web of Science and the Cochrane Library before December 31st, 2020 for studies reporting the application of AI in detecting AMD in color fundus photographs. Then, we pooled the data for analysis. PROSPERO registration number: CRD42020197532. Findings 19 studies were finally selected for systematic review and 13 of them were included in the quantitative synthesis. All studies adopted human graders as reference standard. The pooled area under the receiver operating characteristic curve (AUROC) was 0.983 (95% confidence interval (CI):0.979–0.987). The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were 0.88 (95% CI:0.88–0.88), 0.90 (95% CI:0.90–0.91), and 275.27 (95% CI:158.43–478.27), respectively. Threshold analysis was performed and a potential threshold effect was detected among the studies (Spearman correlation coefficient: -0.600, P = 0.030), which was the main cause for the heterogeneity. For studies applying convolutional neural networks in the Age-Related Eye Disease Study database, the pooled AUROC, sensitivity, specificity, and DOR were 0.983 (95% CI:0.978–0.988), 0.88 (95% CI:0.88–0.88), 0.91 (95% CI:0.91–0.91), and 273.14 (95% CI:130.79–570.43), respectively. Interpretation Our data indicated that AI was able to detect AMD in color fundus photographs. The application of AI-based automatic tools is beneficial for the diagnosis of AMD. Funding Capital Health Research and Development of Special (2020–1–2052).

Background Reinfection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been documented, raising public health concerns. SARS-CoV-2 reinfections were assessed in a cohort of antibody-positive persons in Qatar. MethodsAll SARS-CoV-2 antibody-positive persons from April 16 to December 31, 2020 with a PCR-positive swab ≥14 days after the first-positive antibody test were investigated for evidence of reinfection. Viral genome sequencing was conducted for paired viral specimens to confirm reinfection. Incidence of reinfection was compared to incidence of infection in the complement cohort of those who were antibody-negative. FindingsAmong 43,044 antibody-positive persons who were followed for a median of 16.3 weeks (range: 0–34.6), 314 individuals (0.7%) had at least one PCR positive swab ≥14 days after the first-positive antibody test. Of these individuals, 129 (41.1%) had supporting epidemiological evidence for reinfection. Reinfection was next investigated using viral genome sequencing. Applying the viral-genome-sequencing confirmation rate, the incidence rate of reinfection was estimated at 0.66 per 10,000 person-weeks (95% CI: 0.56–0.78). Incidence rate of reinfection versus month of follow-up did not show any evidence of waning of immunity for over seven months of follow-up. Meanwhile, in the complement cohort of 149,923 antibody-negative persons followed for a median of 17.0 weeks (range: 0–45.6), incidence rate of infection was estimated at 13.69 per 10,000 person-weeks (95% CI: 13.22–14.14). Efficacy of natural infection against reinfection was estimated at 95.2% (95% CI: 94.1–96.0%). Reinfections were less severe than primary infections. Only one reinfection was severe, two were moderate, and none were critical or fatal. Most reinfections (66.7%) were diagnosed incidentally through random or routine testing, or through contact tracing. InterpretationReinfection is rare in the young and international population of Qatar. Natural infection appears to elicit strong protection against reinfection with an efficacy ~95% for at least seven months. FundingBiomedical Research Program, the Biostatistics, Epidemiology, and Biomathematics Research Core, and the Genomics Core, all at Weill Cornell Medicine-Qatar, the Ministry of Public Health, Hamad Medical Corporation, and the Qatar Genome Programme. The authors are grateful for support from the Biomedical Research Program, the Biostatistics, Epidemiology, and Biomathematics Research Core, and the Genomics Core, all at Weill Cornell Medicine-Qatar, as well as for support provided by the Ministry of Public Health and Hamad Medical Corporation. The authors are also grateful for support from the Qatar Genome Programme for supporting the viral genome sequencing. The statements made herein are solely the responsibility of the authors.

Background Binary prediction-models for outcome [death, cognition, presence and severity of cerebral palsy (CP)], using MRI and early clinical data applicable for individual outcome prediction have not been developed. Methods From Dec 1st 2006 until Dec 31st 2013, we recruited 178 infants into a population-based cohort with moderate or severe hypoxic-ischaemic encephalopathy (HIE) including postnatal collapse (PNC, n = 12) and additional diagnoses (n = 12) using CoolCap/TOBY-trial entry-criteria including depressed amplitude-integrated EEG (aEEG). Early clinical/biochemical variables and MRI scans (median day 8) were obtained in 168 infants. Injury severity was scored for cortex, basal ganglia/thalami (BGT), white matter (WM) and posterior limb of the internal capsule, summating to a total injury score (TIS, range 0–11). Outcome was categorized as adverse or favourable at 18–24 months from Bayley-III domains (cut-off 85) and neurological examination including CP classification. • View related content for this article Findings HIE and entry-aEEG severity were stable throughout the study. Outcome was favourable in 133/178 infants and adverse in 45/178: 17 died, 28 had low Cognition/Language scores, (including 9 with severe CP and 6 mild); seven had mild CP with favourable cognitive outcome. WMxBGT product scores and TIS were strong outcome predictors, and prediction improved when clinical/biochemical variables were added in binary logistic regression. The Positive Predictive Value for adverse outcome was 88%, increasing to 95% after excluding infants with PNC and additional diagnoses. Using WMxBGT in the regression predicted 8 of the 9 children with severe CP. Interpretation Binary logistic regression with WMxBGT or TIS and clinical variables gave excellent outcome prediction being 12% better than single variable cross-tabulation. Our MRI scoring and regression models are readily accessible and deserve investigation in other cohorts for group and individual prediction. Funding We thank the National Health Service (NHS) and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Lærdal Foundation for Acute Medicine and charitable donations for their support for cooling therapy.

Background Coronavirus disease 2019 (COVID-19) has led to unprecedented changes in the way we live, particularly for people at higher risk of severe illness from COVID-19. People with pre-existing health conditions have been markedly impacted and, in some instances, left unsupported due to reduced provision of routine healthcare services. People living with obesity (PLWO) are identified as at higher risk of severe illness from COVID-19 infection. Currently, there is a paucity of evidence about the impact of the first COVID-19 lockdown on PLWO, including those accessing weight management and bariatric surgery services (WMS). Methods 543 adults (16–80 years) with obesity (BMI ≥ 30 kg/m2) were recruited between 14th May and 9th July 2020 through social media advertisements, professional and patient obesity organisations and WMS. Participants completed an online survey regarding the impact of the first COVID-19 lockdown upon, mental health, well-being, health-related behaviours, risk mitigating behaviours, access to WMS and weight stigma. Findings During the first COVID-19 lockdown, the majority of PLWO reported deterioration of their mental health and health-related behaviours such as diet, physical activity (PA) and sleep. With 55% reporting an unhealthier diet, 61% reduced PA and 80% worsening of their sleep. Higher depression and lower wellbeing scores were found to associate with the greatest adverse impact upon health-related behaviours. PLWO who were attending WMS prior to the first lockdown reported a greater deterioration of their diet, with nearly 50% reporting worsening of their diet and PA worsening compared to PLWO who were not attending WMS. Most participants took two or more risk mitigating actions (73%). PLWO attending WMS reported reduced access (44%) with insufficient information (49%) from their clinical service providers. The majority of participants reported no change in perceived weight stigma. Interpretation This study shows the detrimental impact of the first COVID-19 lockdown on PLWO in relation to health-related behaviours, mental health and access to WMS. Our findings show that PLWO with poor mental health and those attending WMS were most adversely impacted and highlights the need for greater mental health support and continued provision of support from WMS for PLWO during future lockdowns. Funding This research was funded through National Institute for Health Research University College London Hospitals Biomedical Research Centre funding.

Background the incidence of novel coronavirus disease (COVID19) is elevated in areas with heightened socioeconomic vulnerability. Early reports from US hospitals also implicated social disadvantage and chronic disease history as COVID19 mortality risk factors. However, the relationship between race and COVID19 mortality remains unclear. Methods we examined in-hospital COVID19 mortality risk factors in a multi-hospital tertiary health care system that serves greater Detroit, Michigan, a predominantly African American city with high rates of poverty and chronic disease. Consecutive adult patients who presented to emergency departments and tested positive for COVID19 from 3/11/2020 through 4/18/2020 were included. Using log-binomial regression, we assessed the relationship between in-hospital mortality and residence in census tracts that were flagged for extreme socioeconomic vulnerability, patient-level demographics, and clinical comorbidities. Findings a total of 1,015 adults tested positive for COVID19 during the study period; 80% identified as Black people, 52% were male and 53% were ≥ 65 years of age. The median body mass index was 30•4 and the median Charlson Comorbidity Index score was 4. Patients from census tracts that were flagged for vulnerability related to socioeconomic status had a higher mortality rate than their peers who resided in less vulnerable census tracts (β 0.26, standard error (SE) 0.11, degrees of freedom (df) 378, t-value (t) 2.27, exp(β) 1.29, p-value 0.02). Adjustment for age category, Black race, sex and/or the Charlson Comorbidity Index score category reduced the magnitude of association by less than 10% [exp(β) 1.29 vs. 1.21]. Black race [p = 0.38] and sex [p = 0.62] were not associated with mortality in this sample. Interpretation people who lived in areas flagged for extreme socioeconomic vulnerability had elevated mortality risk in our predominantly African-American cohort of COVID19 patients who were able to seek hospital care during the so-called ‘first wave’ of the pandemic. By contrast, Black race was not associated with mortality in our sample.

Background These studies assessed the efficacy and safety of fevipiprant, an oral antagonist of the prostaglandin D2 (PGD2) receptor (DP2), compared with placebo when added to standard-of-care (SoC) asthma therapy in patients with uncontrolled asthma. Methods ZEAL-1 (NCT03215758) and ZEAL-2 (NCT03226392) are two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies in which fevipiprant 150 mg once daily (o.d.) or placebo was added to SoC asthma therapy in patients aged ≥12 years with uncontrolled asthma. Primary endpoint: change from baseline in pre-dose forced expiratory volume in 1 s (FEV1) after 12 weeks’ treatment. Key secondary endpoints: daytime asthma symptom score, short-acting β-agonist (SABA) use and Asthma Quality-of-Life Questionnaire (AQLQ+12) score after 12-weeks treatment. Findings 662 patients in ZEAL-1 and 685 patients in ZEAL-2 completed the treatment period. In ZEAL-1, the least squares (LS) mean change from baseline in pre-dose FEV1 was 112 mL in fevipiprant vs 71 mL in placebo group (difference [∆]:41 mL; 95% CI: −6, 88; adjusted p-value 0·088). In ZEAL-2, the LS mean change in pre-dose FEV1 was 126 mL and 157 mL in the fevipiprant and placebo groups, respectively (∆:−31 mL; 95% CI: −80, 18; adjusted p-value 0·214). For both studies, there were no statistically significant differences in the key secondary objectives between the treatment groups. Interpretation The ZEAL studies did not demonstrate significant improvement in lung function or other clinical outcomes. These results suggest that DP2 receptor inhibition with fevipiprant is not effective in the studied patient population.

Background: There is limited evidence on the impact of the use of progestin-only hormonal contraception (POC) on weight change. We conducted a secondary analysis of prospective weight change among women enrolled in the Evidence for Contraceptive options and HIV Outcomes (ECHO) trial. Methods: The ECHO trial was conducted at 12 sites in eSwatini, Kenya, South Africa and Zambia. HIV negative, women aged 16-35 years, desiring contraception, were randomized (1:1:1) to either 3-monthly intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implant or copper intrauterine device (IUD). Follow-up was up to 18 months. Weight (kgs) was measured at baseline and study exit. Analysis was performed as intention to treat (ITT) and time on continuous contraceptive use. Findings: 7829 women were randomly assigned to DMPA-IM (n=2609), copper IUD (n=2607) or LNG implant (n=2613). The ITT population included 7014 women 2293 DMPA-IM group, 2372 copper IUD group and 2349 LNG group) who were not lost to follow-up, pregnant on study, or missing weight data. The mean weight increased in all groups but was significantly different in magnitude: 3.5kg (SD=6.3), 2.4kg (SD=5.9) and 1.5kg (SD=5.7) in the DMPA-IM, LNG implant and copper IUD groups, respectively. Comparative differences between groups were (2.02 kg 95% CI, 1.68,2.36, p

Background Surgery is the primary treatment for basal cell carcinoma (BCC). In locally advanced basal cell carcinoma (laBCC), surgery may cause functional or aesthetic damage. In laBCC, neoadjuvant administration of vismodegib, an inhibitor of the Hedgehog signaling pathway, may reduce tumor size, facilitate resection, and reduce functional and aesthetic consequences of surgery. The VISMONEO study assessed efficacy and safety of vismodegib in neoadjuvant treatment of laBCC. Methods VISMONEO (NCT02667574) is an open-label, noncomparative, multicenter, phase 2 study. Patients with ≥1 histologically confirmed facial BCC, inoperable or operable with functional or major aesthetic sequelae risk, were included. Oral vismodegib 150 mg was administered once daily for 4 to 10 months before planned surgery, which was performed once the best response under vismodegib was observed. Primary endpoint was percentage of patients with BCC with tumor downstaging following surgical resection after neoadjuvant vismodegib. Downstaging was defined according to a 6-stage surgical classification related to the aesthetic and functional consequences of surgery. Findings 55 patients (median age: 73 years) with laBCC were included from November 2014 to June 2015. At inclusion, 4 patients were inoperable, 15 were operable with a major functional risk, and 36 were operable with a minor functional risk or a major aesthetic risk. Mean size of target lesion was 47.3 mm (SD: 27.2 mm). 44 patients presented with downstaging after vismodegib treatment (80%; 95% confidence interval [CI], 67 to 90). Of these 44 patients, 27 had a complete response (25 proved by biopsy). Mean treatment duration was 6.0 months. Overall Response Rate according to RECIST 1.1 criteria was 71% (95% CI, 59 to 88). At 3-years of follow-up, 16/44 patients had known recurrence (36%; 95%CI, 22 to 51). Interpretation Neoadjuvant vismodegib allows for a downstaging of the surgical procedure for laBCCs in functionally sensitive locations. Funding VISMONEO was funded by F. Hoffmann-La Roche Ltd.

Objective: To understand ethnic differences in SARS-CoV-2 infection risk and symptoms in hospital healthcare workers (HCW). Methods: A Prospective longitudinal observational cohort study. 1364 HCW at five UK hospitals were studied with up to 16 weeks of symptom questionnaires and antibody testing (to both nucleocapsid and spike protein) during the first UK wave in five NHS hospitals. The main outcome measures were SARS-CoV-2 infection (seropositivity at any time-point) and symptoms. Results: 272 of 1364 HCW (mean age 40.7 years, 72% female, 74% white, ≥6 samples per participant) seroconverted, reporting predominantly mild or no symptoms. Seropositivity was lower in ITU workers (OR=0.43 95%CI 0.24, 0.76; p=0.0033). Seropositivity was higher in black (compared to white) participants, independent of age, sex, role and index of multiple deprivation (OR=2.61 95%CI 1.47-4.62 p=0.0009). No association was seen with other ethnic groups. Conclusions: In the UK first wave, black ethnicity (but not other ethnicities) more than doubled HCW infection risk, independent of age, sex, measured socio-economic factors and role. Trial Registration: NCT04318314 Funding Statement: Funding for the PANTHER study was from the UKRI/MRC (Cov-0331 - MR/V027883/1 ), with additional institutional support from the Nottingham NIHR BRC. Funding for COVIDsortium was donated by individuals, charitable Trusts, and corporations including Goldman Sachs, Citadel and Citadel Securities, The Guy Foundation, GW Pharmaceuticals, Kusuma Trust, and Jagclif Charitable Trust, and enabled by Barts Charity with support from UCLH Charity. Wider support is acknowledged on the COVIDsortium website. Institutional support from Barts Health NHS Trust and Royal Free NHS Foundation Trust facilitated study processes, in partnership with University College London and Queen Mary University London. Serology tests (anti-S1 and anti-NP) were funded by Public Health England. JCM, CMa and TAT are directly and indirectly supported by the University College London Hospitals (UCLH) and Barts NIHR Biomedical Research Centres and through the British Heart Foundation (BHF) Accelerator Award (AA/18/6/34223). TAT is funded by a BHF Intermediate Research Fellowship (FS/19/35/34374). MN is supported by the Wellcome Trust (207511/Z/17/Z) and by NIHR Biomedical Research Funding to UCL and UCLH. None of the aforementioned funding bodies have contributed to the design, collection, or analysis of the data. Declaration of Interests: None to declare. Ethics Approval Statement: The study was approved by a UK Research Ethics Committee (South Central - Oxford A Research Ethics Committee, reference 20/SC/0149).

Background Consecutive negative SARS-CoV-2 PCR test results are being considered to estimate viral clearance in COVID-19 patients. However, there are anecdotal reports of hospitalization from protracted COVID-19 complications despite such confirmed viral clearance, presenting a clinical conundrum. Methods We conducted a retrospective analysis of 222 hospitalized COVID-19 patients to compare those that were readmitted post-viral clearance (hospitalized post-clearance cohort, n = 49) with those that were not re-admitted post-viral clearance (non-hospitalized post-clearance cohort, n = 173) between February and October 2020. In order to differentiate these two cohorts, we used neural network models for the ‘augmented curation’ of comorbidities and complications with positive sentiment in the Electronic Hosptial Records physician notes. Findings In the year preceding COVID-19 onset, anemia (n = 13 [26.5%], p-value: 0.007), cardiac arrhythmias (n = 14 [28.6%], p-value: 0.015), and acute kidney injury (n = 7 [14.3%], p-value: 0.030) were significantly enriched in the physician notes of the hospitalized post-clearance cohort. Interpretation Overall, this retrospective study highlights specific pre-existing conditions that are associated with higher hospitalization rates in COVID-19 patients despite viral clearance and motivates follow-up prospective research into the associated risk factors. Funding This work was supported by Nference, inc.

Background In the absence of accessible, good quality eye health services and inclusive environments, vision loss can impact individuals, households and communities in many ways, including through increased poverty, reduced quality of life and reduced employment. We aimed to estimate the annual potential productivity losses associated with reduced employment due to blindness and moderate and severe vision impairment (MSVI) at a regional and global level. Methods We constructed a model using the most recent economic, demographic (2018) and prevalence (2020) data. Calculations were limited to the working age population (15–64 years) and presented in 2018 US Dollars purchasing power parity (ppp). Two separate models, using Gross Domestic Product (GDP) and Gross National Income (GNI), were calculated to maximise comparability with previous estimates. Findings We found that 160.7 million people with MSVI or blindness were within the working age and estimated that the overall relative reduction in employment by people with vision loss was 30.2%. Globally, using GDP we estimated that the annual cost of potential productivity losses of MSVI and blindness was $410.7 billion ppp (range $322.1 - $518.7 billion), or 0.3% of GDP. Using GNI, overall productivity losses were estimated at $408.5 billion ppp (range $320.4 - $515.9 billion), 0.5% lower than estimates using GDP. Interpretation These findings support the view that blindness and MSVI are associated with a large economic impact worldwide. Reducing and preventing vision loss and developing and implementing strategies to help visually impaired people to find and keep employment may result in significant productivity gains Funding MJB is supported by the Wellcome Trust (207472/Z/17/Z). JR's appointment at the University of Auckland is funded by the Buchanan Charitable Foundation, New Zealand. The Lancet Global Health Commission on Global Eye Health was supported by grants from The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity (GR001061), NIHR Moorfields Biomedical Research Centre, The Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The SEVA Foundation, The British Council for the Prevention of Blindness and Christian Blind Mission. The funders had no role in the design, conduct, data analysis of the study, or writing of the manuscript.

Background: Robotic-assisted percutaneous coronary intervention (R-PCI) has been successfully employed in the United States since 2011. Performing R-PCI from a remote location has never been reported but if feasible would extend availability of treatment to many patients with coronary artery disease (CAD) who would otherwise go without. Objective: To assess the feasibility of remote tele-R-PCI with the operator 20 miles away from the patients. Methods: Five patients with single, type A coronary artery lesions treatable by PCI consented to participate. The primary endpoint was procedural success with no major adverse cardiac events (MACE) before discharge. Procedural success was defined as achieving

Background: This study examines associations between sex composition of older siblings and infant mortality by sex, to guide efforts to address excess female infant mortality in India. Methods: We conducted a retrospective cross-sectional study of infant mortality in India using four waves of data from the nationally-representative National Family Health Survey, collected between 1992 and 2016 (unweighted N = 338,504 for children aged 1–5). We used sex-stratified multivariable logistic regression models to assess the associations between sex composition of older siblings and risk of infant mortality. Findings: Male infants with two living older sisters and no living older brothers had lower odds of infant mortality relative to those with one living older brother (e.g., 2015–16 AOR 0.62, 95% CI 0.50–0.76); this effect was significant for boys across all waves of data but was not seen for girls in any wave. Exploratory models focused on third order births found that boys were less likely than girls to die in infancy if born subsequent to two older sisters (2015–16 AOR 0.48, 95% CI 0.31–0.74); analysis of crude prevalence data indicated that this converts into a 64% greater risk for infant mortality for girls relative to boys in this third-order group. Interpretation: Higher birth order males with older sisters have greater protection against infant mortality, a finding that has persisted for over 25 years. To address ongoing gender inequities in infant survival in India, greater focus is needed to support higher birth order girls and social norm movements against son preference. Keywords: Infant mortality, India, Gender analysis, Sex-disaggregated analyses, Sibling composition