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Background: COVID-19 prevention and control policies have entailed lockdowns and confinement. This study aimed to summarize the global research evidence describing the effect of COVID-19 isolation measures on the health of people living with dementia. Methods: We searched Pubmed, PsycINFO and CINAHL up to 27th of February 2021 for peer-reviewed quantitative studies about the effects of isolation during COVID-19 on the cognitive, psychological and functional symptoms of people with dementia or mild cognitive impairment. The Joanna Briggs Institute critical appraisal tool was used to conduct the quality assessment. PROSPERO registration: CRD42021229259. Findings: 15 eligible papers were identified, examining a total of 6442 people with dementia. 13/15 studies investigated people living in the community and 2 in care homes. Out of 15 studies, 9 (60%) reported changes in cognition and 14 (93%) worsening or new onset of behavioral and psychological symptoms. Six studies (46%) reported a functional decline in daily activities in a variable proportion of the population analyzed. Interpretation: COVID-19 isolation measures have damaged the cognitive and mental health of people with dementia across the world. It is urgent to issue guidance that balances infection control measures against the principles of non-maleficence to guarantee fair and appropriate care during pandemic times for this population. Funding: ASG receives funding from a grant jointly funded by the Economic and Social Research Council (UK) and the National Institute for Health Research (UK) (ES/S010467/1). GL is supported by UCLH National Institute for Health Research (NIHR) Biomedical Research Centre, and by NIHR North Thames ARC as a NIHR senior investigator. JR is supported by a UK Research and Innovation's Global Challenges Research Fund (UKRI GCRF) (ES/P0109381).

Background: Country-specific evidence is needed to guide decisions regarding whether and how to implement lung cancer screening in different settings. For this study, we estimated the potential numbers of individuals screened and lung cancer deaths prevented in Brazil after applying different strategies to define screening eligibility. Methods: We applied the Lung Cancer Death Risk Assessment Tool (LCDRAT) to survey data on current and former smokers (ever-smokers) in 15 Brazilian state capital cities that comprise 18% of the Brazilian population. We evaluated three strategies to define eligibility for screening: (1) pack-years and cessation time (≥30 pack-years and

Background Water, Sanitation, and Hygiene (WASH) systems aim to reduce the spread of enteric pathogens, particularly amongst children under five years old. The most common primary outcome of WASH trials is carer-reported diarrhoea. We evaluate different diarrhoea survey instruments as proxy markers of enteric pathogen presence in stool. Methods We recruited 800 community-based participants from the Cox's Bazar Displaced Person's Camp in Bangladesh, split evenly between the rainy (July/August 2020) and dry (November/December 2020) periods. Participants were randomized evenly into either a standard survey asking carers if their child under five years old has had diarrhoea in the past fortnight, or a pictorial survey asking carers to pick from a pictorial chart which stools their child under five years old has had in the past fortnight. We collected stools from a random sub-sample of 120. Stools were examined visually, and tested for proteins associated with enteric infection and 16 enteric pathogens. We calculated sensitivities and specificities for each survey type, visual examination, and proteins with respect to enteric pathogen presence. Findings The sensitivity of the standard survey for enteric pathogen presence was 0.49[95%CI:0.32,0.66] and the specificity was 0.65[0.41,0.85]. Similar sensitivities and specificities were observed for pictorial survey, visual inspection, and proteins. Interpretation While diarrhoea is an important sign in clinical practice it appears that it is a poor proxy for enteric pathogen presence in stool in epidemiological surveys. When enteric infection is of interest, this should be measured directly. Funding The project was funded by the National Institutes for Health Research Global Health Research Unit on Improving Health in Slums (16/136/87) and by the University of Warwick.

Background: Comparative effectiveness of 7 glucagon-like peptide 1 (GLP-1) agents on weight loss (WL) in obesity is unknown. Methods: Study Design: Systematic review, network meta-analysis (NMA) Data Sources: MEDLINE, EMBASE, Scopus, Cochrane Central and clinical trial registries, from inception to March 2, 2021 Prespecified Criteria for Study Inclusion: Randomized clinical trials (RCTs) of >12 weeks’ duration. Data Appraisal and Extraction: Two investigators independently, using published reports. Main Outcomes and Statistical Methods: WL over placebo (WLOP) and adverse events (AEs) among GLP-1 agents using random-effects NMA (frequentist approach); relative ranking using surface under the cumulative ranking (SUCRA) method and certainty of evidence using GRADE. Registration: None Findings: Data Synthesis: 64 RCTs (2004-2021) had 27018 patients (medians of age, 55.1y; 57.4% women; baseline weight 94.8kg and BMI 33.0kg/m2; trial duration 26 weeks). Direct meta-analysis showed significant WLOP with: -1.44kg (95% CI, -2.14 to ‑0.74) with dulaglutide ≥1.5 mg; -1.82kg (‑2.42 to ‑1.23) with exenatide IR; -2.20kg (-4.31 to -0.08) with exenatide ER; -3.20kg (-6.53 to 0.15) with efpeglenatide; -2.72kg (‑3.35 to -2.09) with liraglutide ≤1.8mg; -4.49kg (-5.26 to -3.72) with liraglutide >1.8mg; ‑0.62kg (-1.22 to -0.02) with lixisenatide; ‑4.33kg (-5.71 to -3.00) with semaglutide SQ 1.8mg (SUCRAs 100, 86.1, 82.8 respectively). Highest SUCRAs for discontinuation due to AEs were with taspoglutide and liraglutide >1.8mg.Risk of bias was high or unclear for random sequence generation (29.7%), allocation concealment (26.6%), and incomplete outcome data (26.6%). Heterogeneity (I 2 >50%) in WL and AEs reflected magnitude, not direction of effect. Interpretation: Semaglutide (SQ, oral) and liraglutide (SQ) were the most efficacious GLP-1 agents to induce WL during > 12 weeks’ treatment. Funding: NIH R01-DK67071 (Camilleri) Declaration of Interest: Dr. Michael Camilleri serves on an advisory board for Phenomix Sciences regarding the company’s development of a test to predict weight loss response to obesity therapy, and he is a stockholder in the company. Phenomix Sciences has obtained an exclusive license to Dr. Michael Camilleri’s and Dr. Andres Acosta’s biomarker technology, submitted patent, and know-how to develop a biomarker to predict response to obesity pharmacotherapy. Dr. Camilleri also serves as a consultant to Kallyope for the company’s development program regarding obesity (the consulting fee is paid to his employer, Mayo Clinic). All other authors have nothing to declare.

Background Clinical scores for sepsis have been primarily developed for, and applied in High-Income Countries. This systematic review and meta-analysis examined the performance of the quick Sequential Organ Failure Assessment (qSOFA), Systemic Inflammatory Response Syndrome (SIRS), Modified Early Warning Score (MEWS), and Universal Vital Assessment (UVA) scores for diagnosis and prediction of mortality in patients with suspected infection in Low-and-Middle-Income Countries. Methods PubMed, Science Direct, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched until May 18, 2021. Studies reporting the performance of at least one of the above-mentioned scores for predicting mortality in patients of 15 years of age and older with suspected infection or sepsis were eligible. The Quality Assessment of Diagnostic Accuracy Studies tool was used for risk-of-bias assessment. PRISMA guidelines were followed (PROSPERO registration: CRD42020153906). The bivariate random-effects regression model was used to pool the individual sensitivities, specificities and areas-under-the-curve (AUC). Findings Twenty-four articles (of 5669 identified) with 27,237 patients were eligible for inclusion. qSOFA pooled sensitivity was 0·70 (95% confidence interval [CI] 0·60–0·78), specificity 0·73 (95% CI 0·67–0·79), and AUC 0·77 (95% CI 0·72–0·82). SIRS pooled sensitivity, specificity and AUC were 0·88 (95% CI 0·79 -0·93), 0·34 (95% CI 0·25–0·44), and 0·69 (95% CI 0·50–0·83), respectively. MEWS pooled sensitivity, specificity and AUC were 0·70 (95% CI 0·57 -0·81), 0·61 (95% CI 0·42–0·77), and 0·72 (95% CI 0·64–0·77), respectively. UVA pooled sensitivity, specificity and AUC were 0·49 (95% CI 0·33 -0·65), 0·91(95% CI 0·84–0·96), and 0·76 (95% CI 0·44–0·93), respectively. Significant heterogeneity was observed in the pooled analysis. Interpretation Individual score performances ranged from poor to acceptable. Future studies should combine selected or modified elements of different scores. Funding Partially funded by the UK National Institute for Health Research (NIHR) (17/63/42).

Background Neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) followed by surgery are two standard strategies in treating locally advanced esophageal cancer (EC). We aim to compare NCRT and NCT in the management of locally advanced EC patients. Methods MEDLINE, Embase, CENTRAL, and conferences were systematically searched for clinical trials published up to September 2021. Pairwise comparisons and Bayesian network meta-analyses were conducted to compare overall survival (OS) and disease-free survival (DFS) by reporting the hazard ratio (HR) and 95% credible intervals (CrIs). The study was registered at PROSPERO (CRD42020170619). Findings 25 trials with 4563 EC patients met inclusion criteria. NCRT improved OS (HR: 0·72, 95%CrI: 0·63–0·82) and DFS (HR: 0·72, 95%CrI: 0·63–0·81) compared to surgery alone. NCRT improved OS (HR: 0·83, 95%CrI: 0·69–0·99) and DFS (HR: 0·83, 95%CI: 0·69–0·99) compared to NCT. Subgroup analysis demonstrated that both NCRT (HR: 0·77, 95%CrI: 0·65–0·90) and NCT (HR: 0·81, 95%CrI: 0·67–0·99) improved OS than surgery in esophageal squamous cell carcinoma (ESCC) patients. No significant differences were observed between NCRT and NCT regarding OS (HR: 0·95, 95%CrI: 0·75–1·19) and DFS (HR: 0·90, 95%CrI: 0·50–1·62) in ESCC. The short-term outcomes were similar between NCRT and NCT. The three treatment strategies were comparable in esophageal adenocarcinoma (EAC) subpopulations. Interpretation The study corroborated current guidelines in addressing the importance of analysing EC according to histopathological types. The analysis suggested that in locally advanced ESCC patients, both NCRT and NCT improved OS as compared to surgery alone, whereas no clear evidence supported the optimal strategies between NCRT and NCT. More RCTs comparing different therapeutic strategies in EAC patients are warranted. Funding Koln Fortune Program, University of Cologne.

Background: Ensuring that patients have high quality, equitable experiences in healthcare is a high priority in the UK. As such, identifying and addressing areas where patient experiences are unsatisfactory and inequitable is of high priority, and has been included as part of the National Health Service (NHS) England equity objectives. Methods: The healthcare experiences of people who identified as living with overweight or obesity were gathered from freely available websites using the Patient Experience Platform (PEP). PEP was used to gather and analyse all comments from NHS UK, Google, Facebook and Twitter that related to care experiences of people who identified as living with overweight or obesity across all NHS Acute and Specialist Trusts and all general practitioners (GPs) in England from 01/01/2018 to 31/12/2020. These healthcare experiences were analysed to provide care quality metrics, a comparison of care across regions of England, and to explore associations between behavioural clusters of personality attributes, values and sentiment with care quality metrics. Findings: Perceptions of the quality of care were significantly lower for people who identified as living with overweight or obesity compared to people who didn't identify as living with overweight or obesity across all regions for ‘Effective Treatment’ and ‘Emotional Support’. The perceived quality of care metrics can be predicted by the behavioral clusters, where for instance, the experiences of people who identified as living with overweight or obesity in the negative behavioral cluster have a lower overall perceived quality of care score. Themes arising from the data also highlighted that barriers quality care experienced by people who identified as living with obesity include the speed of access, effective treatment, and emotional support, with stigmatising healthcare experiences are reported. Interpretation: The findings of this study provide insights into the experiences reported via freely available websites, of people who self-identified as living with overweight or obesity in healthcare in England. These insights demonstrate that the perceived quality of care was lower for people who identified as living with overweight or obesity compared to the general population, and that there is regional variation in care quality. The study has also shown that patient experiences differ based on personality attributes, values and sentiment, highlighting the need for patient-centred care and personalised approaches. These findings hold important considerations for healthcare and policy makers aiming to address healthcare inequity. Funding: Novo Nordisk.

Background Cognitive function among apparently healthy adolescents has been associated with cardiovascular morbidity and mortality. We examined the relationship between global and subdomain cognitive scores in adolescence and early-onset type 2 diabetes (T2D) in men and women. Methods A nationwide, population-based study of 971,677 Israeli born adolescents (56% men; mean age 17.4 years) who were medically examined and their cognitive performance was assessed before compulsory military service during 1992–2010. Data included global and subdomain cognitive Z-scores (problem-solving, verbal abstraction and categorization, verbal comprehension, and mathematical abilities). Data were linked to the Israeli National Diabetes Registry. The relations between global and subdomain scores and incident T2D was determined using Cox proportional hazard models and logistic regression models. Analyses were conducted separately for men and women. Findings During 16,095,122 person-years, 3,570 individuals developed T2D. After adjustment, those in the low compared to the high quintile of global cognitive Z-score had the highest risk for T2D; HR 2.46, (95% CI 2.10–2.88) for men and 2.33 (95% CI 1.88–2.89) for women. A one-unit lower global cognitive Z-score was associated with 1.41 (95% CI 1.34–1.48) and 1.46 (95% CI 1.36–1.56) increased risks for men and women, respectively. The relationship was noted for the cognitive subdomains scores as well as for the global cognitive score, with no heterogeneity across cognitive subdomains. Interpretation This large nationally representative cohort suggests relationship between global, as well as subdomain cognitive scores in late adolescence, and incident early onset T2D in both sexes, which was independent of socioeconomic status. Funding None.

Background In Sub-Saharan Africa cross-sectional studies report a high prevalence of abnormal lung function indicative of chronic respiratory disease. The natural history and health impact of this abnormal lung function in low-and middle-income countries is largely unknown. Methods A cohort of 1481 adults representative of rural Chikwawa in Malawi were recruited in 2014 and followed-up in 2019. Respiratory symptoms and health-related quality of life (HRQoL) were quantified. Lung function was measured by spirometry. Findings 1232 (83%) adults participated; spirometry was available for 1082 (73%). Mean (SD) age 49.5 (17.0) years, 278(23%) had ever smoked, and 724 (59%) were women. Forced expiratory volume in one second (FEV1) declined by 53.4 ml/year (95% CI: 49.0, 57.8) and forced vital capacity (FVC) by 45.2 ml/year (95% CI: 39.2, 50.5) . Chronic airflow obstruction increased from 9.5% (7.6, 11.6%) in 2014 to 17.5% (15.3, 19.9%) in 2019. There was no change in diagnosed asthma or in spirometry consistent with asthma or restriction. Rate of FEV1 decline was not associated with diagnosed Chronic obstructive pulmonary disease (COPD), asthma, or spirometry consistent with asthma, COPD, or restriction. HRQoL was adversely associated with respiratory symptoms (dyspnoea, wheeze, cough), previous tuberculosis, declining FEV1 and spirometry consistent with asthma or restriction. These differences exceeded the minimally important difference. Interpretation In this cohort, the increasing prevalence of COPD is associated with the high rate of FEV1 decline and lung function deficits present before recruitment. Respiratory symptoms and sub-optimal lung function are independently associated with reduced HRQoL.

Background The effectiveness and safety of initiating sacubitril/valsartan therapy among patients who are hospitalized for acute heart failure (HF) is unclear. Methods A cohort of 3736 patients with HF with reduced ejection fraction (HFrEF) hospitalized for acute HF was identified from Chang Gung Research Database between January 1, 2016 and August 31, 2019. The risks of rehospitalization for HF and death associated with sacubitril/valsartan therapy compared to angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy were evaluated. We used stabilized inverse probability of treatment weighting to balance the baseline covariates. The risks of fatal and non-fatal outcomes between the groups were compared using a Cox proportional hazard model and Fine and Gray subdistribution hazard model, respectively. Findings The composite of rehospitalization for HF and death occurred in 22.9% of the patients in the sacubitril/valsartan group compared to 32.6% in the ACEI/ARB group (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52–0.97) after a mean follow-up period of 11.8 months. The sacubitril/valsartan group had a lower risk of rehospitalization for HF (subdistribution HR 0.83, 95% CI 0.74–0.92) and all-cause death (HR 0.51, 95% CI 0.27–0.94). There were no significant differences in the rates of worsening renal function or severe hyperkalemia between the two groups. Interpretation In real-world practice, initiating sacubitril/valsartan therapy among patients with HFrEF who were hospitalized for acute HF was associated with a lower rate of rehospitalization for HF and death compared with ACEI/ARB therapy. Funding This study was supported by Novartis Pharmaceuticals.

Background PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. This study determined its optimal dose, safety, pharmacokinetics, and pharmacodynamics in Chinese patients with type 2 diabetes. Methods In this double-blind, randomised, four-period, crossover, phase 1 trial in China, conducted at the Peking University Third Hospital, adult patients with drug-naive type 2 diabetes were randomised (1:1:1:1) to four sequence groups using a computer-generated randomisation table. In each period, they received oral placebo or PB-201 (50+50, 100+50, or 100+100 mg split doses) for 7 days. Investigators and patients were masked to treatment assignment. The primary endpoints were safety and pharmacokinetics. Continuous glucose monitoring was used to delineate the glucose excursion profile. Trial registration number: NCT03973515. Findings Between August 27, 2019 and December 19, 2019, 16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile without apparent accumulation in the body and induced dose-dependent lowering of blood glucose. PB-201 at 50+50, 100+50, and 100+100 mg increased mean time in range (49·210% [standard deviation 27], 56·130% [25], and 63·330% [20] with three doses, respectively) versus placebo (49·380% [27]) and reduced estimated glycated haemoglobin from baseline (-0·5445% [1·654], -1·063% [1·236], and -1·888% [1·381] vs -0·581% [1·200]). Fifteen patients (93·8%) had treatment-emergent adverse events, which were mild. No patients had hypoglycaemia with venous/capillary glucose

Background: Opioid analgesics play a key role in pain management but providing access while mitigating risk of misuse and dependence remains a challenge. Tracking global consumption of all opioids over time can help identify emerging patterns and drivers of use. Methods: Prescription opioid analgesic consumption was estimated for 76 countries between 2009 and 2019 using IQVIA MIDAS data. We reported country-level consumption trends in morphine milligram equivalents (MMEs), assessed differences in consumption between high-income (HICs), upper-middle income (UMICs), and low- and lower-middle income countries (LMICs), and identified country-level socioeconomic drivers of consumption using fixed-effects panel regression models. Findings: Global opioid consumption rate declined from 216·3 to 151·5 morphine milligram equivalents per 1,000 inhabitants per day (MID) between 2009 and 2019, with consumption declines in the US and Germany. Overall, consumption rates increased in HICs by a median 36·6 MID (IQR, -7·5 -124·5) with substantial heterogeneity between countries. Median consumption rates were lower in UMICs (23·6 MID) and LMICs (8·3 MID) compared to HICs (345·1 MID) and increased by median 10·4 and 3·7 MID from 2009-2019, respectively. Consumption rates were associated with income (coefficient 18·84, 95% confidence interval 3·8-33·9) and trade (13·59, 1·3-25·8) in UMICs, and physician density (1·95, 1·2-2·7) in LMICs. Tramadol consumption rate increased in the study period and accounted for a relatively large proportion of total opioid volume consumed across all country-income groups. Interpretation: Substantial heterogeneity in global opioid consumption patterns reflect the challenges involved with providing adequate access to opioid treatment while avoiding potential misuse.

Background Achieving a functional or sterilizing cure for HIV will require identification of therapeutic interventions that reduce HIV reservoir size in infected individuals. Proteasome inhibitors, such as ixazomib, impact multiple aspects of HIV biology including latency, transcription initiation, viral replication, and infected cell killing through the HIV protease – Casp8p41 pathway, resulting in latency reversal and reduced measures of HIV reservoir size ex vivo. Methods We conducted a phase 1b/2a dose escalating, open label trial of weekly oral ixazomib for 24 weeks in antiretroviral (ART)-suppressed, HIV positive adults (NCT02946047). The study was conducted from March 2017 to August 2019 at two tertiary referral centers in the United States. The primary outcomes were safety and tolerability of oral ixazomib. Secondary outcomes included changes in immunologic markers and estimates of HIV reservoir size after ixazomib treatment. Findings Sixteen participants completed the study. Ixazomib up to 4mg weekly was safe and well-tolerated, yielding no treatment-emergent events above grade 1. In exploratory analyses, ixazomib treatment was associated with detectable viremia that was below the lower limit of quantification (LLQ) in 9 participants, and viremia that was above LLQ in 4 of 16 participants. While treatment was associated with reduced CD4 counts [baseline 783 cells/ mm3 vs. week-24 724 cells/ mm3 p=0.003], there were no changes in markers of cellular activation, exhaustion or inflammation. Total HIV DNA and proviral sequencing were not altered by ixazomib treatment. Intact proviral DNA assay (IPDA) identified intact proviruses in 14 patients pre-treatment, and in 10/14 of those subjects post treatment values were reduced (P=0.068), allowing a calculated intact proviral half life of 0.6 years (95% CI 0.3, 2.5), compared to 7.1 years (95% CI 3.9, 18, p=0.004) in historical controls. Differentiation Quantitative Viral Outgrowth Assays (dQVOA) identified measurable proviruses in 15 subjects pre-treatment; post-treatment values were numerically reduced in 9, but overall differences were not significantly different. Interpretation Our study successfully met its primary endpoint of demonstrating the safety of ixazomib for 24 weeks in HIV infected persons. Exploratory analyses suggest that the effects observed ex vivo of latency reversal and reductions in HIV reservoir size, also occur in vivo. Future controlled studies of ixazomib are warranted. Funding This study was funded by Millennium Pharmaceuticals Inc..; the Mayo Clinic Foundation; the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases, Division of AIDS, the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Drug Abuse. Mayo Clinic also acknowledges generous funding support from Mr. Joseph T. and Mrs. Michele P. Betten.

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. Findings: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. Funding: Vicore Pharma AB and LifeArc, UK.

Background Research and practice typically focus upon unimodal hallucinations, especially auditory verbal hallucinations. Contemporary research has however indicated that voice-hearing may co-occur within a broader milieu of feelings, and multimodal hallucinations may be more common than previously thought. Methods An observational design asked participants to prospectively document the feeling and modality of hallucinations for one week prior to an interview. Novel visual diary methods involving drawing, writing and body-mapping generated 42 MUSE maps (multimodal unusual sensory experience), analysed with a participatory qualitative method. Twelve people took part: all experiencing hallucinations daily, accessing early intervention in psychosis services, given psychotic-spectrum diagnoses, and living in the community. The study took place during a seven-month period in 2018 at Leicestershire and Rutland's Psychosis Intervention and Early Recovery service (UK). Findings All documented hallucinations co-occurred with bodily feelings. Feelings were localised to specific body areas, generalised across the body and extended beyond the body into peripersonal space. Co-occurring emotional feelings most commonly related to confusion, fear and frustration. Interpretation Hallucinations were characterised by numerous feelings arising at once, often including multimodal, emotional, and embodied features. Within this study, the immediate feeling of hallucination experiences were readily communicated through prospective, visual, and ecological information gathering methods and particularly those which offer multiple modes of communication (e.g. body-map, visual, written, oral). Uptake of visual, ecological and prospective methods may enhance understandings of lived experiences of hallucinations. Funding: University of Leicester.

The duration of immunity in SARS-CoV-2 infected people remains unclear. Neutralizing antibody responses are the best available correlate of protection against re-infection. Recent studies have estimated that the correlate of 50% protection from re-infection was 20% of the mean convalescent neutralizing antibody titre. We used sera collected from a cohort of 125 individuals with RT-PCR confirmed SARS-CoV-2 infections up to 386 days after symptom onset. In the subset of 65 sera collected from day 151 to 386 after symptom onset, all remained positive in 50% plaque reduction neutralization tests (PRNT50). Because antibody waning follows a bimodal pattern with slower waning beyond day 90 after illness, we fitted lines of decay to 115 sera from 62 patients collected beyond 90 after symptom onset and estimate that PRNT50 antibody will remain detectable for around 1,717 days after symptom onset and that 50% protective antibody titers will be maintained for around 990 days post-symptom onset, in symptomatic patients. Peak PRNT titres in mildly symptomatic children did not differ from those in mildly symptomatic adults but these antibody titres appear to wane faster in children. There was a high level of correlation between PRNT50 antibody titers and the % of inhibition in surrogate virus neutralization tests. We conclude that there will be relatively long-lived protection from re-infection following symptomatic COVID-19 disease. Funding Information: The study was supported by the Health and Medical Research Fund, Commissioned research on Novel Coronavirus Disease (COVID-19) (Reference no COVID190126) from the Food and Health Bureau, Hong Kong SAR Government and the Theme-based Research Scheme project no. T11-712/19-N, the University Grants Committee of the Hong Kong Government. Declaration of Interests: None of the authors have any conflicts of interest to declare. Ethics Approval Statement: Written informed consent was obtained from the participants or their parents (when the participant was a child) and the studies were approved by the institutional review boards of the respective hospitals, viz. Kowloon West Cluster (KW/EX-20-039 (144-27)), Kowloon Central / Kowloon East cluster (KC/KE-20-0154/ER2) and HKU/HA Hong Kong West Cluster (UW 20-273).

Publisher Copyright: © 2021 The Authors Background: Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies focusing on such children currently exist. We investigated the aetiology, clinical features, and auxological clues indicative of syndromic tall stature in extremely tall children subject to population-wide growth monitoring and screening rules. Methods: Subjects with HSDS ≥+3 after three years of age born between 1990 and 2010 were identified from the Helsinki University Hospital district growth database. We comprehensively reviewed their medical records up to December 2020 and recorded underlying diagnoses, auxological data, and clinical features. Findings: We identified 424 subjects (214 girls and 210 boys) who fulfilled the inclusion criteria. Underlying growth disorder was diagnosed in 61 (14%) patients, in 36 (17%) girls and 25 (12%) boys, respectively (P=0•15). Secondary causes were diagnosed in 42 (10%) patients and the two most frequent secondary diagnoses, premature adrenarche, and central precocious puberty were more frequent in girls. Primary disorder, mainly Marfan or Sotos syndrome, was diagnosed in 19 (4%) patients. Molecular genetic studies were used as a part of diagnostic work-up in 120 subjects. However, array CGH or next-generation sequencing studies were seldom used. Idiopathic tall stature (ITS) was diagnosed in 363 (86%) subjects, and it was considered familial in two-thirds. Dysmorphic features or a neurodevelopmental disorder were recorded in 104 (29%) children with ITS. The probability of a monogenic primary growth disorder increased with the degree of tall stature and deviation from target height. Interpretation: A considerable proportion of extremely tall children have an underlying primary or secondary growth disorder, and their risk is associated with auxological parameters. Clinical features related to syndromic tall stature were surprisingly frequent in subjects with ITS, supporting the view that syndromic growth disorders with mild phenotypes may be underdiagnosed in extremely tall children. Our results lend support to comprehensive diagnostic work-up of extremely tall children. Funding: Päivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, and Helsinki University Hospital research grants.

Background In sub-Saharan Africa, the efficacy of intermittent preventive therapy in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) for malaria in pregnancy is threatened by parasite resistance. We conducted an individual-participant data (IPD) meta-analysis to assess the efficacy of intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with artemisinin-based combination therapy (ISTp-ACT) compared to IPTp-SP, and understand the importance of subpatent infections. Methods We searched MEDLINE and the Malaria-in-Pregnancy Library on May 6, 2021 for trials comparing ISTp-ACT and IPTp-SP. Generalised linear regression was used to compare adverse pregnancy outcomes (composite of small-for-gestational-age, low birthweight (LBW), or preterm delivery) and peripheral or placental Plasmodium falciparum at delivery. The effects of subpatent (PCR-positive, RDT/microscopy-negative) infections were assessed in both arms pooled using multi-variable fixed-effect models adjusting for the number of patent infections. PROSPERO registration: CRD42016043789. Findings Five trials conducted between 2007 and 2014 contributed (10,821 pregnancies), two from high SP-resistance areas where dhfr/dhps quintuple mutant parasites are saturated, but sextuple mutants are still rare (Kenya and Malawi), and three from low-resistance areas (West-Africa). Four trials contributed IPD data (N=10,362). At delivery, the prevalence of any malaria infection (relative risk [RR]=1.08, 95% CI 1.00-1.16, I2=67.0 %) and patent infection (RR=1.02, 0.61-1.16, I2=0.0%) were similar. Subpatent infections were more common in ISTp recipients (RR=1.31, 1.05-1.62, I2=0.0%). There was no difference in adverse pregnancy outcome (RR=1.00, 0.96-1.05; studies=4, N=9,191, I2=54.5%). Subpatent infections were associated with LBW (adjusted RR=1.13, 1.07-1.19), lower mean birthweight (adjusted mean difference=32g, 15-49), and preterm delivery (aRR=1.35, 1.15-1.57). Interpretation ISTp-ACT was not superior to IPTp-SP and may result in more subpatent infections than the existing IPTp-SP policy. Subpatent infections were associated with increased LBW and preterm delivery. More sensitive diagnostic tests are needed to detect and treat low-grade infections. Funding Centers for Disease Control and Prevention and Worldwide Antimalarial Resistance Network.

Background Severe Mental Disorders (SMDs) affect multiple generations although this is poorly studied. The aim of this study was to investigate the intergenerational and multidimensional impacts of SMD in rural Ethiopia. Methods This comparative study was nested within an existing population-based cohort study. We collected data from a total 5762 family members of 532 households (266 households with at least one family member with SMD and 266 sex and age matched mentally well controls from the neighborhood) in 2019. The main outcomes were multidimensional poverty, mortality, food insecurity, and family satisfaction. Findings Multidimensional poverty Index was higher in the households of persons with SMD (74·44%) than the comparison households (38·35%). School attendance was lower in children of people with SMD (63·28%) than children of the comparisons (78·08%). The median years of schooling was also lower among children of people with SMD than the controls. This lower attendance was also true among siblings of people with SMD (35·52%) than the comparisons (49·33%). Over the course of 20 years, family members who have a person with SMD in their household had 23% increased risk of death compared to family members who did not have a person with SMD in their household. Severe food insecurity was also higher in the SMD households (20·68%) than the comparison (13·53%) while family satisfaction was lower. Interpretation Families of people with SMD experience pervasive multidimensional and intergenerational impacts. Interventions should consider the broader family social and healthcare needs of the broader family.

Background Mesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS. Methods REALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143. Findings Nine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9). Interpretation A single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells. Funding The trial was funded by the Wellcome Trust Health Innovation Challenge Fund [Reference 106939/Z/15/Z].

Background There is currently no commonly accepted method of stratifying complexity of prosthetic joint infection (PJI). This study assesses a new classification, the Joint-Specific, Bone involvement, Anti-microbial options, Coverage of the soft tissues, Host status (JS-BACH) classification, for predicting clinical and patient reported outcomes in PJI. Methods Patients who received surgery for PJI at two centres in the UK between 2010 and 2015 were classified using JS-BACH as 'uncomplicated', 'complex' or 'limited treatment options'. Patient reported outcomes were recorded at 365-days following the index operation and included the EuroQol EQ-5D-3L index score and the EQ-visual analogue score (VAS). Clinical outcome data were obtained from the most recent follow-up appointment. Findings 220 patients met the inclusion criteria. At 365-days following the index operation, patients with 'uncomplicated' PJI reported similar EQ-index scores (0.730, SD:0.326) and EQ-VAS (79.4, SD:20.9) compared to the age-matched population. Scores for 'uncomplicated' PJI were significantly higher than patients classified as having 'complex' (EQ-index:0.515 SD:0.323, p = 0.012; EQ-VAS:68.4 SD:19.4, p = 0.042) and 'limited treatment options' PJI (EQ-index:0.333 SD:0.383, p

Background: Chagas disease (caused by Trypanosoma cruzi infection) evolves to chronic chagasic cardiomyopathy (CCC) affecting 1.8 million people worldwide. This is the first randomized, placebo-controlled, double-blinded, clinical trial designed to estimate efficacy and safety of selenium (Se) treatment in CCC. Methods: 66 patients with CCC stages B1 (left ventricular ejection fraction [LVEF] > 45% and no heart failure; n = 54) or B2 (LVEF < 45% and no heart failure; n = 12) were randomly assigned to receive 100 mcg/day sodium selenite (Se, n = 32) or placebo (Pla, n = 34) for one year (study period: May 2014-September 2018). LVEF changes over time and adverse effects were investigated. Trial registration number: NCT00875173 (clinicaltrials.gov). Findings: No significant differences between the two groups were observed for the primary outcome: mean LVEF after 6 (β= +1.1 p = 0.51 for Se vs Pla) and 12 months (β= +2.1; p = 0.23). In a subgroup analysis, statistically significant longitudinal changes were observed for mean LVEF in the stage B2 subgroup (β= +10.1; p = 0.02 for Se [n = 4] vs Pla [n = 8]). Se treatment was safe for CCC patients, and the few adverse effects observed were similarly distributed across the two groups. Interpretation: Se treatment did not improve cardiac function (evaluated from LVEF) in CCC. However, in the subgroup of patients at B2 stage, a potential beneficial influence of Se was observed. Complementary studies are necessary to explore diverse Se dose and/or associations in different CCC stages (B2 and C), as well as in A and B1 stages with longer follow-up. Funding: Brazilian Ministry of Health, Fiocruz, CNPq, FAPERJ.

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 A first-dose of various vaccines provides acceptable protection against infections by SARS-CoV-2 and evolution to the most severe forms of COVID-19. The recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), was proven efficacious but information about effectiveness in the real-world setting is lacking. The aim of our study was to investigate the association between the rollout of the first component (rAd26) of Gam-COVID-Vac and PCR-positive tests, hospitalisations and deaths. Methods We conducted a retrospective cohort study which analyzed individuals aged 60-79 who self-registered in the online vaccination system of the Province of Buenos Aires, Argentina, from December 29, 2020 to March 21, 2021. Exclusion criteria were having a previous positive RT-PCR or antigen tests for SARS-CoV-2, having received other vaccines, or two doses of any vaccine. Proportions of new laboratory-confirmed SARS-CoV-2 infections, hospitalisations and deaths until 83 days of vaccination were compared between vaccinated and unvaccinated subjects. Vaccine effectiveness for the three outcomes was calculated as (1–OR) × 100. Kaplan-Meier cumulative incidence curves were constructed. Findings During the study period 415995 registered subjects received the first component of Gam-COVID-Vac; 40387 belonged to the 60-79 age group, and were compared to 38978 unvaccinated. Vaccine effectiveness for preventing laboratory-confirmed infections was 78•6% [CI95% 74·8 - 81·7]; and for reducing hospitalizations and deaths was, respectively, 87·6% [CI95% 80·3 - 92·2] and 84·8% [CI95% 75·0 - 90·7]. Effectiveness was high across all subgroups. Interpretation Similarly to other vaccines, the administration of one dose of Gam-COVID-Vac was effective for a wide range of COVID-19–related outcomes., Facultad de Ciencias Médicas

Background Currently there are trials in Africa and Asia investigating whether prophylactic azithromycin during pregnancy reduces infection-related neonatal morbidity and mortality. We undertook a systematic review and meta-analysis to determine the effect of azithromycin during pregnancy on perinatal and neonatal outcomes. Methods We identified articles between January 1990 and 13th June 2021 by searching five electronic databases. Randomised control trials (RCTs) that included pregnant women administered azithromycin alone or in combination with other medications, and that reported outcomes of low birthweight (LBW), prematurity, stillbirth, and neonatal deaths, infections, and admissions, were eligible. Fixed effects meta-analyses were used for primary analysis. Quality appraisal was performed using Cochrane's Risk of Bias 2 tool. This review was registered with PROSPERO, CRD42019127099. Findings The search generated 5777 studies, of which 14 studies were included involving 17,594 participants. Most studies investigated azithromycin as Intermittent Preventive Treatment in Pregnancy (IPTp) for malaria. More than 50% of the studies had low risk of bias for all outcomes, except for LBW and neonatal admissions. Fixed-effects meta-analyses found that azithromycin reduced the risk of LBW (seven studies, Pooled RR 0·79; 95% CI 0·68-0·93; I2 = 0·00%), and prematurity compared to controls (eight studies, Pooled RR 0·87; 95% CI 0·78-0·98; I2 = 23·28%). There was no strong evidence of any effect on neonatal mortality, infections and admissions. There was an increase in stillbirth but the 95% CI crossed the null value (seven studies, Pooled RR 1·39; 95% CI 0·94 – 2.07; I2=0·00%). However this review was limited by differences in the types of intervention and study populations, and inconsistency in outcome reporting between studies. Interpretation Prophylactic azithromycin during pregnancy reduces LBW and prematurity. However, as azithromycin has been investigated as part of IPTp, it is unclear whether it would improve perinatal and neonatal outcomes in non-malaria endemic settings. The potential harm on stillbirth rates needs further investigation. Funding None

Background We investigate whether deep learning (DL) neural networks can reduce erroneous human “judgment calls” on bedside echocardiograms and help distinguish Takotsubo syndrome (TTS) from anterior wall ST segment elevation myocardial infarction (STEMI). Methods We developed a single-channel (DCNN[2D SCI]), a multi-channel (DCNN[2D MCI]), and a 3-dimensional (DCNN[2D+t]) deep convolution neural network, and a recurrent neural network (RNN) based on 17,280 still-frame images and 540 videos from 2-dimensional echocardiograms in 10 years (1 January 2008 to 1 January 2018) retrospective cohort in University of Iowa (UI) and eight other medical centers. Echocardiograms from 450 UI patients were randomly divided into training and testing sets for internal training, testing, and model construction. Echocardiograms of 90 patients from the other medical centers were used for external validation to evaluate the model generalizability. A total of 49 board-certified human readers performed human-side classification on the same echocardiography dataset to compare the diagnostic performance and help data visualization. Findings The DCNN (2D SCI), DCNN (2D MCI), DCNN(2D+t), and RNN models established based on UI dataset for TTS versus STEMI prediction showed mean diagnostic accuracy 73%, 75%, 80%, and 75% respectively, and mean diagnostic accuracy of 74%, 74%, 77%, and 73%, respectively, on the external validation. DCNN(2D+t) (area under the curve [AUC] 0·787 vs. 0·699, P = 0·015) and RNN models (AUC 0·774 vs. 0·699, P = 0·033) outperformed human readers in differentiating TTS and STEMI by reducing human erroneous judgement calls on TTS. Interpretation Spatio-temporal hybrid DL neural networks reduce erroneous human “judgement calls” in distinguishing TTS from anterior wall STEMI based on bedside echocardiographic videos. Funding University of Iowa Obermann Center for Advanced Studies Interdisciplinary Research Grant, and Institute for Clinical and Translational Science Grant. National Institutes of Health Award (1R01EB025018–01).

Background This study provides the first systematic review and meta-analysis to identify the predictors of unfavorable prognosis of COVID-19 in children and adolescents. Methods We searched literature databases until July 2021 for studies that investigated risk factors for unfavorable prognosis of children and adolescents with COVID-19. We used random-effects models to estimate the effect size with 95% confidence interval (CI). Findings We identified 56 studies comprising 79,104 individuals. Mortality was higher in patients with multisystem inflammatory syndrome (MIS-C) (odds ratio [OR]=58.00, 95% CI 6.39–526.79) and who were admitted to intensive care (OR=12.64, 95% CI 3.42–46.68). Acute respiratry distress syndrme (ARDS) (OR=29.54, 95% CI 12.69–68.78) and acute kidney injury (AKI) (OR=55.02, 95% CI 6.26–483.35) increased the odds to be admitted to intensive care; shortness of breath (OR=16.96, 95% CI 7.66–37.51) increased the need of respiratory support; and neurological diseases (OR=5.16, 95% CI 2.30–11.60), C-reactive protein (CRP) level ≥80 mg/L (OR=11.70, 95% CI 4.37–31.37) and D-dimer level ≥0.5ug/mL (OR=20.40, 95% CI 1.76–236.44) increased the odds of progression to severe or critical disease. Interpretation Congenital heart disease, chronic pulmonary disease, neurological diseases, obesity, MIS-C, shortness of breath, ARDS, AKI, gastrointestinal symptoms, elevated CRP and D-dimer are associated with unfavourable prognosis in children and adolescents with COVID-19. Funding None.

Background: Reducing socioeconomic inequalities in access to good quality health care is key for countries to achieve Universal Health Coverage. This study aims to assess socioeconomic inequalities in effective coverage of reproductive, maternal, newborn and child health (RMNCH) in low- and middle-income countries (LMICs). Methods: Using the most recent national health surveys from 39 LMICs (between 2014 and 2018), we calculated coverage indicators using effective coverage care cascade that consists of service contact, crude coverage, quality-adjusted coverage, and user-adherence-adjusted coverage. We quantified wealth-related and education-related inequality using the relative index of inequality, slope index of inequality, and concentration index. Findings: The quality-adjusted coverage of RMNCH services in 39 countries was substantially lower than service contact, in particular for postnatal care (64 percentage points [pp], p-value

Background: Androgenetic alopecia (AGA) is the most common hair loss disorder seen in men. It can have an early onset but has also been associated with ageing and senescence. It often induces pronounced psychological impact. ALRV5XR, a new hair loss treatment herein evaluated, was designed to target multiple molecular pathways involved in hair growth and hair follicle stem cell biology. The main objectives of the study were the assessment of safety and efficacy profiles of ALRV5XR in men.Methods: This 24-week, parallel randomised, placebo-controlled, double-blinded clinical trial was performed in a USA community clinic. Healthy men (age 22-65) with AGA and belonging to the Hamilton-Norwood (HN) classification I-VII and Fitzpatrick skin type (FST) I-VI, were randomly allocated in a 1:1 ratio into ALRV5XR or placebo treatment groups. Dermatologist assessment, phototrichograms, and blood samples were obtained in a blinded fashion at baseline, 12 and 24 weeks. Subjects were given a masked treatment consisting of oral capsules, shampoo, conditioner, and follicle serum, which was intended for daily use. Efficacy was assessed via absolute and per cent changes in terminal hair (TH) density, and response rates. The trial was registered with clinicaltrials.gov (NCT04450589) and is completed.Findings: Forty-six subjects were enroled in the study, 23 allocated to the ALRV5XR treatment and 23 to the placebo group. Enrolment occurred from April 11 to October 23, 2018. Thirty-six subjects completed the trial (17 ALRV5XR, 19 placebo) and 11 subjects in each group were evaluable for TH outcomes. At 24 weeks, the absolute change in TH density improved by 21.0 THs/cm(2) (95% CI: 9.2-32.8; p = 0.0014), and the relative density increased by 16.4% (95% CI: 7.4%-25.5%; p = 0.0012). The odds ratio for being a responder ( >= 0 change) was 87.4. TH density increased linearly and was not affected by HN, FST, ethnicity, age, or body mass index. All subjects in the ALRV5XR group responded to treatment while 81.8% of the placebo group decreased TH density. ALRV5XR induced statistically significant changes in both decrease in vellus hair (VH) density as well as in concomitant increase of the TH/VH ratio when compared to placebo. ALRV5XR was well tolerated, and no adverse events were observed.Interpretation: ALRV5XR treatment resulted in clinically significant TH regrowth in men with AGA. Furthermore, it appeared to reverse the characteristic hair miniaturisation seen in this condition. When compared to results of published trials of standard therapy, ALRV5XR showed a multi-fold increase both in efficacy and in response rates. In addition, the continuance of TH regrowth from 12 to 24 weeks suggests that the normal structure and function of non-productive telogen follicles is restored and that a normal hair phenotype may be attained by extended ALRV5XR treatment. (C) 2021 The Author(s). Published by Elsevier Ltd.

Background: Management and control of the COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus SARS-CoV-2 is critically dependent on quick and reliable identification of the virus in clinical specimens. Detection of viral RNA by a colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a simple, reliable and cost-effective assay, deployable in resource-limited settings (RLS). Our objective was to evaluate the intrinsic and extrinsic performances of RT-LAMP in RLS. Methods: This is a multicenter prospective observational study of diagnostic accuracy, conducted from October 2020 to February 2021 in four African Countries: Cameroon, Ethiopia, Kenya and Nigeria; and in Italy. We enroled 1657 individuals who were either COVID-19 suspect cases, or asymptomatic and presented for screening. RNA extracted from pharyngeal swabs was tested in parallel by a colorimetric RT-LAMP and by a standard real time polymerase chain reaction (RT-PCR). Findings: The sensitivity and specificity of index RT LAMP compared to standard RT-PCR on 1657 prospective specimens from infected individuals was determined. For a subset of 1292 specimens, which underwent exactly the same procedures in different countries, we obtained very high specificity (98%) and positive predictive value (PPV = 99%), while the sensitivity was 87%, with a negative predictive value NPV = 70%, Stratification of RT-PCR data showed superior sensitivity achieved with an RT-PCR cycle threshold (Ct) below 35 (97%), which decreased to 60% above 35. Interpretation: In this field trial, RT-LAMP appears to be a reliable assay, comparable to RT-PCR, particularly with medium-high viral loads (Ct

Background Optimal ω-6/ω-3 polyunsaturated fatty acids ratio (PUFAR) is reported to exert protective effects against chronic diseases. However, data on PUFAR and diabetic retinopathy (DR) remains scarce. We aimed to thoroughly quantify whether and how PUFAR was related to DR as well as its role in DR detection. Methods This two-centre case-control study was conducted from August 2017 to June 2018 in China, participants were matched using a propensity score matching algorithm. We adopted multivariable logistic regression models and restricted cubic spline analyses to estimate the independent association of PUFAR with DR, adjusting for confounders identified using a directed acyclic graph. The value of PUFAR as a biomarker for DR identification was further evaluated by receiver operating characteristic analyses and Hosmer-Lemeshow tests. Findings An apparent negative relationship between PUFAR and DR was observed. Adjusted odds of DR decreased by 79% (OR: 0·21, 95% CI: 0·10–0·40) with an interquartile range increase in PUFAR. Similar results were also obtained in tertile analysis. As compared to those in the 1st tertile of PUFAR, the adjusted odds of DR decreased by 76% (OR: 0·24, 95% CI: 0·08–0·66) and 93% (OR: 0·07, 95% CI: 0·03–0·22) for subjects in the 2nd and 3rd tertiles, respectively. Good calibration and discrimination of the PUFAR associated predictive model were detected and PUFAR = 35 would be an ideal cut-off value for DR identification. Interpretation Our results suggest that serum PUAFR is inversely associated with DR. Although PUFAR-alteration is not observed amongst different stages of DR, it can serve as an ideal biomarker in distinguishing patients with DR from those without DR. Funding This study was funded by Natural Science Foundation of Zhejiang Province, Zhejiang Basic Public Welfare Research Project, the Major Project of the Eye Hospital of Wenzhou Medical University, and the Academician's Science and Technology Innovation Program in Zhejiang province. Part of this work was also funded by the National Nature Science Foundation of China, and Research Project for College Students in Wenzhou Medical University.

Background SARS-CoV-2 has challenged health service provision worldwide. This work evaluates safe surgical pathways and standard operating procedures implemented in the high volume, global city of London during the first wave of SARS-CoV-2 infection. We also assess the safety of minimally invasive surgery(MIS) for anatomical lung resection. Methods This multicentre cohort study was conducted across all London thoracic surgical units, covering a catchment area of approximately 14.8 Million. A Pan-London Collaborative was created for data sharing and dissemination of protocols. All patients undergoing anatomical lung resection 1st March-1st June 2020 were included. Primary outcomes were SARS-CoV-2 infection, access to minimally invasive surgery, post-operative complication, length of intensive care and hospital stay (LOS), and death during follow up. Findings 352 patients underwent anatomical lung resection with a median age of 69 (IQR: 35–86) years. Self-isolation and pre-operative screening were implemented following the UK national lockdown. Pre-operative SARS-CoV-2 swabs were performed in 63.1% and CT imaging in 54.8%. 61.7% of cases were performed minimally invasively (MIS), compared to 59.9% pre pandemic. Median LOS was 6 days with a 30-day survival of 98.3% (comparable to a median LOS of 6 days and 30-day survival of 98.4% pre-pandemic). Significant complications developed in 7.3% of patients (Clavien-Dindo Grade 3–4) and 12 there were re-admissions(3.4%). Seven patients(2.0%) were diagnosed with SARS-CoV-2 infection, two of whom died (28.5%). Interpretation SARS-CoV-2 infection significantly increases morbidity and mortality in patients undergoing elective anatomical pulmonary resection. However, surgery can be safely undertaken via open and MIS approaches at the peak of a viral pandemic if precautionary measures are implemented. High volume surgery should continue during further viral peaks to minimise health service burden and potential harm to cancer patients. Funding This work did not receive funding.

Background The Italian Lombardy region has been the epicenter of COVID-19 since February 2020. This study analyses the epidemiology of pediatric type 1 diabetes (T1D) onset during the first two pandemic waves and three previous years. Methods All the 13 pediatric diabetes centers in Lombardy prospectively evaluated charts of children at T1D onset (0–17 years), during year 2020. After calculating the annual incidence, the data were compared with those of the 3 previous years, using generalized linear models, adjusted for age and sex. Monthly T1D new onsets and diabetic ketoacidosis (DKA) were investigated yearly from 2017 to 2020. Data were extracted from outpatients charts of the pediatric diabetes centers and from the database of the national institute of statistics. Findings The estimated incidence proportion of T1D was 16/100·000 in 2020, compared to 14, 11 and 12 in 2019, 2018 and 2017, respectively. When adjusting for age and gender, the incidence was significantly lower in 2018 and 2017 compared to 2020 (adjusted incidence ratio: 0.73 and 0.77 respectively, with 95% CI: 0.63 to 0.84, and 0.67 to 0.83; p = 0·002 and p = 0·01), but no difference was found between the years 2020 and 2019. A reduction trend in the percentage of T1D diagnosis during the first wave (March-April) over the total year diagnoses was observed compared to previous years (11·7% in 2020, 17·7% in 2019, 14·1% in 2018 and 14·4% 2017). No difference was observed during the second wave (October-December) (32·8% in 2020, 33·8% in 2019, 34% in 2018, 30·7% in 2017). The proportion of DKA over the total T1D diagnoses during the second wave had higher trend than the first one (41·7% vs 33·3%), while severe DKA over the total DKA appeared higher during the first wave (60% vs 37·1%). Interpretation The study suggests an increase in the incidence of pediatric T1D in Lombardy throughout the past five years. Pandemic waves may have affected the clinical presentation at onset. Funding None.

Background: We describe the epidemiology of COVID-19 in South Africa following importation and during implementation of stringent lockdown measures. Methods: Using national surveillance data including demographics, laboratory test data, clinical presentation, risk exposures (travel history, contacts and occupation) and outcomes of persons undergoing COVID-19 testing or hospitalised with COVID-19 at sentinel surveillance sites, we generated and interpreted descriptive statistics, epidemic curves, and initial reproductive numbers (Rt). Findings: From 4 March to 30 April 2020, 271,670 SARS-CoV-2 PCR tests were performed (462 tests/100,000 persons). Of these, 7,892 (2.9%) persons tested positive (median age 37 years (interquartile range 28-49 years), 4,568 (58%) male, cumulative incidence of 13.4 cases/100,000 persons). Hospitalization records were found for 1,271 patients (692 females (54%)) of whom 186 (14.6%) died. Amongst 2,819 cases with data, 489/2819 (17.3%) travelled internationally within 14 days prior to diagnosis, mostly during March 2020 (466 (95%)). Cases diagnosed in April compared with March were younger (median age, 37 vs. 40 years), less likely female (38% vs. 53%) and resident in a more populous province (98% vs. 91%). The national initial Rt was 2.08 (95% confidence interval (CI): 1.71-2.51). Interpretation: The first eight weeks following COVID-19 importation were characterised by early predominance of imported cases and relatively low mortality and transmission rates. Despite stringent lockdown measures, the second month following importation was characterised by community transmission and increasing disease burden in more populous provinces. Funding Statement: South African National and provincial health departments. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: Surveillance activities for NMC including SARS-COV-2 infection are conducted by the NICD according to National Health Act Regulations. Publication of surveillance data in the peer-reviewed literature was approved by the University of the Witwatersrand Human Research Ethics Committee (Medical) protocol M160667.

Background Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) offers comprehensive assessment of dyspnea to characterize pulmonary PASC. Methods We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era. Findings Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope. Interpretation Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2. Funding The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542–02) from Harvard Catalyst.

Background IBI362 (LY3305677) is a novel weekly-dose glucagon-like peptide-1 and glucagon receptor dual agonist being developed for the treatment of obesity and type 2 diabetes. The aim of this randomised, placebo-controlled, multiple ascending dose phase 1b study was to evaluate the safety, tolerability, pharmacokinetics and efficacy of IBI362 in Chinese adults with overweight or obesity. Methods This study enrolled adults with overweight (body mass index [BMI]≥24 kg/m2) accompanied by hyperphagia and/or at least one comorbidity or obesity (BMI≥28 kg/m2) from six study centres in China. Eligible participants were randomised 2:1 to receive once-weekly subcutaneous injection of IBI362 or placebo in each of the three ascending dose cohorts for 12 weeks with additional 8 weeks of safety follow-up. The dose-escalation regimens were: 3.0 mg cohort (1.0 mg weeks 1–4; 2.0 mg weeks 5–8; 3.0 mg weeks 9–12); 4.5 mg cohort (1.5 mg weeks 1–4; 3.0 mg weeks 5–8; 4.5 mg weeks 9–12); 6.0 mg cohort (2.0 mg weeks 1–4; 4.0 mg weeks 5–8; 6.0 mg weeks 9–12). The participants, investigators and study site personnel involved in treating and assessing participants within each cohort were masked to treatment allocation. The primary endpoints were safety and tolerability of IBI362. This study is registered with ClinicalTrials.gov, number NCT04440345. Findings Between June 15th, 2020 and January 15th, 2021, 12 participants were enrolled and randomised in each cohort. Throughout the study, no participant discontinued the treatment due to safety reason and no serious adverse event was reported. Gastrointestinal adverse events and decreased appetite were the most common adverse events and mostly mild in severity. Three participants receiving IBI362 reported mild and asymptomatic cardiac disorders revealed by electrocardiogram. Estimated percent changes in mean body weight from baseline to week 12 were −4.81% (95%CI −6.61 to −3.02), −6.40% (−8.23 to −4.58) and −6.05% (−7.91 to −4.18) for participants receiving IBI362 in the 3.0 mg, 4.5 mg and 6.0 mg cohort, respectively, compared with 0.60% (−0.86 to 2.07) for those receiving placebo. Interpretation IBI362 was well tolerated and showed a body weight-lowering effect in Chinese adults with overweight or obesity. Funding Innovent Biologics.

Background Because Forced Vital Capacity (FVC) is reduced in Black relative to White Americans of the same age, sex, and height, standard lung function prediction equations assign a lower "normal" range for Black patients. The prognostic implications of this race correction are uncertain. Methods We analyzed 5,294 White and 3,743 Black participants age 20–80 in NHANES III, a nationally-representative US survey conducted 1988–94, which we linked to the National Death Index to assess mortality through December 31, 2015. We calculated the FVC-percent predicted among Black and White participants, first applying NHANES III White prediction equations to all persons, and then using standard race-specific prediction equations. We used Cox proportional hazard models to calculate the association between race and all-cause mortality without and with adjustment for FVC (using each FVC metric), smoking, socioeconomic factors, and comorbidities. Findings Black participants’ age- and sex-adjusted mortality was greater than White participants (HR 1.46; 95%CI:1.29, 1.65). With adjustment for FVC in liters (mean 3.7 L for Black participants, 4.3 L for White participants) or FVC percent-predicted using White equations for everyone, Black race was no longer independently predictive of higher mortality (HR∼1.0). When FVC-percent predicted was “corrected” for race, Black individuals again showed increased mortality hazard. Deaths attributed to chronic respiratory disease were infrequent for both Black and White individuals. Interpretation Lower FVC in Black people is associated with elevated risk of all-cause mortality, challenging the standard assumption about race-based normal limits. Black-White disparities in FVC may reflect deleterious social/environmental exposures, not innate differences. Funding No funding.

Background: The COVID-19 pandemic restrictions affect provision and quality of neonatal care. This global study explores parents' experiences regarding the impact of the restrictions on key characteristics of infant and family-centred developmental care (IFCDC) during the first year of the pandemic. Methods: For this cross-sectional study, a pre-tested online survey with 52 questions and translated into 23 languages was used to collect data between August and November 2020. Parents of sick or preterm infants born during the pandemic and receiving special/intensive care were eligible for participation. Data analysis included descriptive statistics and statistical testing based on different levels of restrictive measures. Findings: In total, 2103 participants from 56 countries provided interpretable data. Fifty-two percent of respondents were not allowed to have another person present during birth. Percentages increased with the extent of restrictions in the respondents' country of residence (p = 0.002). Twenty-one percent of total respondents indicated that no-one was allowed to be present with the infant receiving special/intensive care. The frequency (p < 0.001) and duration (p = 0.001) of permitted presence largely depended on the extent of restrictions. The more restrictive the policy measures were, the more the respondents worried about the pandemic situation during pregnancy and after birth. Interpretation: COVID-19 related restrictions severely challenged evidence-based cornerstones of IFCDC, such as separating parents/ legal guardians and their newborns. Our findings must therefore be considered by public health experts and policy makers alike to reduce unnecessary suffering, calling for a zero separation policy. Funding: EFCNI received an earmarked donation by Novartis Pharma AG in support of this study. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Background: COVID-19 symptomatology in Africa appears significantly less serious than in the industrialized world. We and others previously postulated a partial explanation for this phenomenon, being a different, more activated immune system due to parasite infections. We investigated this hypothesis in an endemic area in Africa. Methods: Ethiopian COVID-19 patients were enrolled and screened for intestinal parasites. The primary outcome was the proportion of patients with severe COVID-19. Logistic regression models were used to estimate the association between parasite infection, and COVID-19 severity. Models were adjusted for sex, age, residence, and comorbidities. Findings: 751 SARS-CoV-2 infected patients were enrolled, of whom 284 (37·8%) had intestinal parasitic infection. Only 27/255 (10·6%) severe COVID-19 patients were co-infected with intestinal parasites, while 257/496 (51·8%) non-severe COVID-19 patients appeared parasite positive (p

Background Plasma ferritin is a widely used indicator to detect iron deficiency, but the threshold ferritin that defines iron deficiency remains uncertain. Our aim was to define the ferritin concentration at which the body begins to upregulate iron absorption from the diet; this could provide a functionally-defined threshold of incipient iron deficiency. We hypothesized this threshold ferritin concentration would correspond to the threshold hepcidin concentration at which iron absorption begins to increase. Methods We performed a pooled analysis of our stable iron isotope studies (n = 1058) conducted from 2006 to 2019 in healthy women (age 18–50 years; mean±SD ferritin 33.7 ± 27.1 μg/L) that measured iron absorption from labeled test meals providing physiological amounts of iron. To fit relationships between iron absorption, ferritin and hepcidin, we used generalized additive modeling, and to identify thresholds, we estimated the first derivatives of the fitted trend to assess inflection points in these relationships. Findings Hepcidin increased linearly with increasing ferritin over the entire range of ferritin values. Iron absorption began to increase below a threshold hepcidin value of 3.09 (95%CI: 2.80, 3.38) nmol/l, above which iron absorption remained stable. Iron absorption began to increase below a threshold ferritin value of 51.1 (95%CI: 49.1, 53.1) µg/l, above which iron absorption remained stable. The latter two findings were internally consistent in that, in the relationship between hepcidin and ferritin, a hepcidin of ~3 nmol/l corresponded to a ferritin of ~51 µg/l. Interpretation Based on physiological upregulation of iron absorption, a threshold ferritin of, EClinicalMedicine, 39

Background: Prolonged QT intervals are reported in patients with COVID-19. Additionally, virus particles in heart tissue and abnormal troponin levels have been reported. Consequently, we hypothesize that cardiac electrophysiologic abnormalities may be associated with COVID-19. Methods: This is a retrospective study between March 15th, 2020 and May 30th, 2020 of 828 patients with COVID-19 and baseline ECG. Corrected QT (QTc) and QRS intervals were measured from ECGs performed prior to intervention or administration of QT prolonging drugs. QTc and QRS intervals were evaluated as a function of disease severity (patients admitted versus discharged; inpatients admitted to medical unit vs ICU) and cardiac involvement (troponin elevation >0.03 ng/ml, elevated B-natriuretic peptide (BNP) or NT pro-BNP >500 pg/ml). Multivariable analysis was used to test for significance. Odds ratios for predictors of disease severity and mortality were generated. Findings: Baseline QTc of inpatients was prolonged compared to patients discharged (450.1±30.2 versus 423.4±21.7 msec, p

Background Machine learning techniques can explore low prevalence data to offer insight into identification of factors associated with non-marital sexual violence (NMSV). NMSV in India is a health and human rights concern that disproportionately affects adolescents, is under-reported, and not well understood or addressed in the country. Methods We applied machine learning methods to retrospective cross-sectional data from India's nationally-representative National Family Health Survey 4, a demographic and health study conducted in 2015–16, which offers 4000+ variables as potential independent variables. We used Least Absolute Shrinkage and Selection Operator (lasso) or L-1 regularized logistic regression models as well as L-2 regularized logistic regression or ridge models; we conducted an iterative thematic analysis (ITA) of variables generated from a series of regularized models. Findings Thematic analysis of regularized models highlight that past exposure to violence was most predictive of NMSV, followed by geography, sexual behavior, and poor sexual and reproductive health knowledge. After these, indicators largely related to resources and autonomy (e.g., access to health services, and income generating) were associated with NMSV. Exploratory analysis with the subsample of never married adolescents 15–19 years old, a population with higher representation of recent NMSV, further emphasized the role of wealth and mobility as key correlates of NMSV, along with poor HIV knowledge, tobacco use, higher fertility preferences, and attitudes accepting of marital violence. Interpretation Findings indicate the validity of machine learning with iterative theme analysis (ITA) to identify factors associated with violence. Findings were consistent with prior work demonstrating associations between NMSV and other violence experiences, but also showed novel correlates such as lower SRH knowledge and service utilization and, for girls, norms and preferences suggesting more restrictive gender norms. Sexual and reproductive health, gender equity and safety focused interventions are important for addressing NMSV in India, particularly for adolescents. Funding This work was funded by the Bill and Melinda Gates Foundation, Grant OPP1179208 (PI: Raj).

Background Survival following liver transplant (LT) is influenced by a variety of factors, including donor risk factors and recipient disease burden and co-morbidities. It is difficult to separate these effects from those of socioeconomic factors, such as income or insurance. The United Network for Organ Sharing (UNOS) created equitable access policies, such as Share 35, to ensure that organs are distributed to individuals with greatest medical need; however, the effect of Share 35 on disparities in post-LT survival is not clear. This study aimed to (1) characterize associations between post-transplant survival and race and ethnicity, income, insurance, and citizenship status, when adjusted for other clinical and demographic factors that may influence survival, and (2) determine if the direction of associations changed after Share 35. Methods A retrospective, cohort study of adult LT recipients (n = 83,254) from the UNOS database from 2005 to 2019 was conducted. Kaplan-Meier survival graphs and stepwise multivariate cox-regression analyses were performed to characterize the effects of socioeconomic status on post-LT survival, adjusted for recipient and donor characteristics, across the time period and after Share 35. Findings Male sex (HR: 0.93 (95% CI: 0.90-0.96)), private insurance (0.91 (0.88-0.94)), income (0.82 (0.79-0.85)), U.S. citizenship, and Asian (0.81 (0.75-0.88)) or Hispanic (0.82 (0.79-0.86)) race and ethnicity were associated with higher post-transplant survival, after adjustment for clinical and demographic factors (Table 3). These associations were found across the entire time period studied and many persisted after the implementation of Share 35 in 2013 (Table 3; male sex (0.84 (0.79-0.90)), private insurance (0.94 (0.89-1.00)), income (0.82 (0.77-0.89)), and Asian (0.87 (0.73-1.02)) or Hispanic (0.88 (0.81-0.96)) race and ethnicity). Interpretation Recipients' socioeconomic factors at time of transplant may impact long-term post-transplant survival, and a single policy may not significantly alter these structural health inequalities. Funding None.

Background: South Africa is disproportionately impacted by non-communicable diseases (NCDs) and HIV/AIDS. We investigated the prevalence of known/unknown NCD risk factors, HIV, and NCD risk factor-HIV comorbidity; and treatment status on known diseases to determine the prevalence of controlled/uncontrolled disease. Methods: This cross-sectional study (June 2018-March 2019) within an integrated testing centre in Soweto, South Africa, screened adults (aged ≥18 years) for body mass index (BMI), hypertension (HT), rapid glucose and cholesterol, and HIV. Results were stratified by age group, sex, HIV-status, and self-reported ART use. Analysis included Fisher's exact, chi-squared, Kruskal Wallis, and Student's T-tests. Findings: Of 780 enrolled participants, 19.2% were HIV-positive, 37.5% were overweight/obese, 18.0% hypertensive, 10.8% hyperglycaemic, and 8.1% had hypercholesterolaemia. Significantly more women had overweight/obese BMI than men (46.8% vs 19.7%; p

Background: We examined whether an increased risk of cancer incidence and death is associated with kidney function and albuminuria and whether the risk is more readily identified when kidney function is estimated using cystatin C. Methods: Participants were from UK Biobank (recruitment spanning 2007–2010), excluding those with a prior diagnosis of cancer. Estimated glomerular filtration rate (ml/min/1.73m2) was calculated using creatinine (eGFRcr), cystatin C (eGFRcys) and creatinine-cystatin C (eGFRcr-cys). Cox proportional hazards models tested associations between eGFR, urinary albumin:creatinine ratio (uACR) and cancer incidence and death. Findings: In 431,263 participants over median follow-up of 11.3 (IQR 10.6–12.0) years, there were 41,745 incident cancers and 11,764 cancer deaths. eGFRcys was most strongly associated with cancer incidence and death (HR 1.04 (95% CI 1.03–1.04) and 1.06 (1.05–1.07) per 10 ml/min/1.73m2 decline, respectively). eGFRcr was not associated with either outcome (incidence: HR 1.00 (1.00–1.01); death: HR 0.99 (0.98–1.01) per 10 ml/min/1.73m2 decline). Relative to eGFRcys>90 or uACR

Background The impact febrile neutropenia (FN) has on the health-related quality of life (HRQoL) of children with cancer and their families is poorly understood. We sought to characterize the course of child and parent HRQoL during and following FN episodes. Method Data on HRQoL were collected in the multisite Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study. Participants were enrolled between November 2016 to January 2018. The Child Health Utility (CHU9D) was used to assess HRQoL in children (N = 167 FN events) and the Assessment of Quality of Life (AQoL-8D) was used to assess HRQoL parents (N = 218 FN events) at three time points: 0–3 days, 7-days and 30-days following the onset of FN. Group-based trajectory modeling (GBTM) was used to characterize the course of HRQoL. Findings For children, three distinct groups were identified: persistently low HRQoL over the 30-day course of follow-up (chronic: N = 78/167; 47%), increasing HRQoL after the onset of FN to 30 days follow-up (recovering: N = 36/167; 22%), and persistently high HRQoL at all three timepoints (resilient: N = 53/167; 32%). Applying these definitions, parents were classified into two distinct groups: chronic (N = 107/218, 49%) and resilient (N = 111/218, 51%). The child being male, having solid cancer, the presence of financial stress, and relationship difficulties between the parent and child were significant predictors of chronic group membership for both parents and children. Children classified as high-risk FN were significantly more likely to belong to the recovery group. Being female, having blood cancers and the absence of financial or relationship difficulties were predictive of both parents and children being in the resilient group. Interpretation Approximately half the children and parents had chronically low HRQoL scores, which did not improve following resolution of the FN episode. The child's sex, cancer type, and presence of financial and relationship stress were predictive of chronic group membership for both parents and children. These families may benefit from increased financial and psychosocial support during anti-cancer treatment. Funding National Health and Medical Research Council Grant (APP1104527).

Background Anxiety and alcohol use disorders are common and disabling conditions that people typically endure for many years before accessing treatment. The link between anxiety and alcohol use is well-established, with these issues commonly emerging and/or escalating during emerging adulthood. This randomized controlled trial evaluated a psychologist-supported, web-based intervention, designed with and for emerging adults, that aims to promote adaptive coping strategies, and prevent anxiety and alcohol use from progressing to chronic, mutually-reinforcing disorders. Methods Between December 2017 and September 2018, 123 emerging adults (aged 17–24) reporting anxiety symptoms and hazardous alcohol use were randomized to receive the Inroads or control (assessment plus alcohol information) intervention. The Inroads program combined five web-based cognitive behavioral therapy modules with weekly psychologist support via email/phone. Primary outcomes were alcohol consumption, severity of alcohol-related consequences, and general anxiety symptoms, assessed at baseline, 2 and 6-months post-baseline. Secondary outcomes included hazardous alcohol use and social anxiety. Trial Registration: Prospectively registered in the Australian New Zealand Clinical Trials Registry, ACTRN12617001609347. Findings Alcohol consumption and associated consequences reduced in both groups, with the Inroads group reporting greater alcohol reductions by 6-month follow-up (mean difference -0.74, 95% CI: -1.47 to -0.01, d = 0.24). Relative to controls, hazardous alcohol use reduced among Inroads participants at both follow-ups (2-month mean difference -2.14, 95% CI: -4.06 to -0.22). Inroads participants also reported reduced symptoms of general (mean difference -3.06, 95% CI: -4.97 to -1.15, d = 0.88) and social anxiety (mean difference -3.21, 95% CI: -6.34 to -0.07, d = 0.32) at 2-month follow-up, with improvements in social anxiety sustained at 6-months. Interpretation The Inroads program demonstrated beneficial effects on alcohol consumption, hazardous alcohol use, and anxiety symptoms. The web-based format is aligned with youth treatment preferences and can be delivered at scale to achieve wide dissemination and reduce the significant burden associated with these chronic, mutually reinforcing conditions. Funding Australian Rotary Health, Australian National Health and Medical Research Council.

Background The effects of omega-3 fatty acids (FAs), such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, on cardiovascular outcomes are uncertain. We aimed to determine the effectiveness of omega-3 FAs on fatal and non-fatal cardiovascular outcomes and examine the potential variability in EPA vs. EPA+DHA treatment effects. Methods We searched EMBASE, PubMed, ClinicalTrials.gov, and Cochrane library databases through June 7, 2021. We performed a meta-analysis of 38 randomized controlled trials of omega-3 FAs, stratified by EPA monotherapy and EPA+DHA therapy. We estimated random-effects rate ratios (RRs) with (95% confidence intervals) and rated the certainty of evidence using GRADE. The key outcomes of interest were cardiovascular mortality, non-fatal cardiovascular outcomes, bleeding, and atrial fibrillation (AF). The protocol was registered in PROSPERO (CRD42021227580). Findings In 149,051 participants, omega-3 FA was associated with reducing cardiovascular mortality (RR, 0.93 [0.88-0.98]; p = 0.01), non-fatal myocardial infarction (MI) (RR, 0.87 [0.81–0.93]; p = 0.0001), coronary heart disease events (CHD) (RR, 0.91 [0.87–0.96]; p = 0.0002), major adverse cardiovascular events (MACE) (RR, 0.95 [0.92–0.98]; p = 0.002), and revascularization (RR, 0.91 [0.87–0.95]; p = 0.0001). The meta-analysis showed higher RR reductions with EPA monotherapy (0.82 [0.68–0.99]) than with EPA + DHA (0.94 [0.89–0.99]) for cardiovascular mortality, non-fatal MI (EPA: 0.72 [0.62–0.84]; EPA+DHA: 0.92 [0.85–1.00]), CHD events (EPA: 0.73 [0.62–0.85]; EPA+DHA: 0.94 [0.89–0.99]), as well for MACE and revascularization. Omega-3 FA increased incident AF (RR, 1.26 [1.08–1.48]). EPA monotherapy vs. control was associated with a higher risk of total bleeding (RR: 1.49 [1.20–1.84]) and AF (RR, 1.35 [1.10–1.66]). Interpretation Omega-3 FAs reduced cardiovascular mortality and improved cardiovascular outcomes. The cardiovascular risk reduction was more prominent with EPA monotherapy than with EPA+DHA. Funding None.

Background: HIV self-testing (HIVST) is recommended by the WHO as an innovative strategy to reach UNAIDS targets to end HIV by 2030. HIVST with digital supports is defined as the use of digital interventions (e.g., website-based, social media, mobile HIVST applications (apps), text messaging (SMS), digital vending machines (digital VMs)) to improve the efficiency and impact of HIVST. HIVST deployment and integration in health services is an emerging priority. We conducted a systematic review aiming to close the gap in evidence that summarizes the impact of digitally supported HIVST and to inform policy recommendations. Methods: We searched PubMed and Embase for articles and abstracts on HIVST with digital supports published during the period February 1st, 2010 to June 15th, 2021, following Cochrane guidelines and PRISMA methodology. We assessed feasibility, acceptability, preference, and impact outcomes across all populations and study designs. Metrics reported were willingness to use HIVST, preferences for HIVST delivery, proportion of first-time testers, HIVST uptake, HIVST kit return rate, and linkage to care. Heterogeneity of the interventions and reported metrics precluded us from conducting a meta-analysis. Findings: 46 studies were narratively synthesized, of which 72% were observational and 28% were RCTs. Half of all studies (54%, 25/46) assessed web-based innovations (e.g., study websites, videos, chatbots), followed by social media (26%, 12/46), HIVST-specific apps (7%, 3/46), SMS (9%, 4/46), and digital VMs (4%, 2/46). Web based innovations were found to be acceptable (77-97%), preferred over in-person and hybrid options by more first-time testers (47-48%), highly feasible (93-95%), and were overall effective in supporting linkage to care (53-100%). Social media and app-based innovations also had high acceptability (87-95%) and linkage to care proportions (80-100%). SMS innovations increased kit return rates (54-94%) and HIVST uptake among hard-to-reach groups. Finally, digital VMs were highly acceptable (54-93%), and HIVST uptake was six times greater when using digital VMs compared to distribution by community workers. Interpretation: HIVST with digital supports was deemed feasible, acceptable, preferable, and was shown to increase uptake, engage first-time testers and hard-to-reach populations, and successfully link participants to treatment. Findings pave the way for greater use of HIVST interventions with digital supports globally. Funding: This work was funded by the Foundation for Innovative New Diagnostics. The agency had no role in the decision to submit it for publication, however the funders contributing to the writing of the manuscript. NPP also acknowledges support from the Fonds de recherche du Quebec Sante (Senior scientist scholar award), The Canadian Institutes of Health Research (PJT 153149 and HBR 422155), Grand Challenges Canada (Transition to Scale award, 071005), the India-Canada centre for Innovative Multidisciplinary Partnerships to Accelerate Community Transformation and Sustainability (IC-IMPACTS), and the MUHC Foundation. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Background Multi-month dispensing (MMD) for antiretroviral therapy (ART) is a promising care strategy to improve HIV treatment adherence. The effectiveness of MMD in routine settings has not yet been evaluated within a causal inference framework. We analyzed data from a robust clinical data system to evaluate MMD in Haiti. Methods We assessed 1-year retention in care among 21,880 ART-naive HIV-positive persons who started ART on or after January 1, 2017, up until November 1, 2018. We used an instrumental variable analysis to estimate the causal impact of MMD. This approach was used to address potential selection into specific dispensing intervals because MMD is not randomly applied to individuals. Findings We found that extending ART dispensing intervals increased the probability of retention at 12 months after ART initiation, with up to a 24·2%-point increase (95%CI: 21·9, 26·5) in the likelihood of retention with extending dispenses by 30 days for those receiving one-month dispenses. We observed statistically significant gains to retention with MMD with up to an approximately 4-month supply of ART; +5·1%-points (95%CI: 2·4,7·8). Increasing dispensing lengths for those already receiving ≥5-month supply of ART had a potentially negative effect on retention. Interpretation MMD for ART is an effective service delivery strategy that improves care retention for new ART recipients. There is a potentially negative effect of increasing prescription lengths for those new ART recipients already receiving longer ART supplies, though more research is needed to characterize this effect given medication supplies of this length are not common for newer ART recipients. Funding This research has been supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the US Centers for Disease Control and Prevention (https://www.cdc.gov/), under award number NU2GGH002226-02, made to the center Haitien de Renforcement du Systeme Sanitaire (CHARESS).