eClinicalMedicine

BackgroundDrug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design. MethodsWe conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results52 participants were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% of participants had microbiologically-confirmed TBM; vs 41% possible or 25% probable. AESI or death occurred in 10/16 (arm 3) vs 4/14 (arm 2) vs 6/20 (arm 1) (p=0.083). The cumulative proportion of AESI or death (Kaplan-Meier method) demonstrated worse outcomes in arm 3 vs arm 1 (p=0.04), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (Modified Rankin Scale) at day 56 between the three arms. ConclusionsHigh-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly aspirin, is outweighed by mortality or morbidity benefit. SUMMARYIn this phase 2a randomised control trial we demonstrate that high-doserifampicin and adjunctive linezolid is safe in adult HIV-associated tuberculous meningitis. Larger studies are required to evaluate potential toxicity with aspirin, in relation to benefit on morbidity and mortality.

ImportancePredictive models can help identify SARS-CoV-2 patients at greatest risk of post-COVID sequelae and direct them towards appropriate care. ObjectiveTo develop and internally validate a model to predict children and young people most likely to experience at least one impairing physical symptom 3 months after a SARS-CoV-2 PCR-test and to determine whether the impact of these predictors differed by SARS-CoV-2 infection status. DesignPotential pre-specified predictors included: SARS-CoV-2 status, sex, age, ethnicity, deprivation, quality of life/functioning (5 EQ-5D-Y items), physical and mental health, and loneliness (all prior to SARS-CoV-2 testing), and number of physical symptoms at testing. Logistic regression was used to develop the model. Model performance was assessed using calibration and discrimination measures; internal validation was performed via bootstrapping; the final model was adjusted for overfitting. SettingNational cohort study of SARS-CoV-2 PCR-positive and PCR-negative participants matched according to age, sex, and geographical area. ParticipantsChildren and young people aged 11-17 years who were tested for SARS-CoV-2 infection in England, January to March 2021. Main outcome measureone or more physical symptom 3 months after initial PCR-testing which affected physical, mental or social well-being and interfered with daily living. ResultsA total of 50,836 children and young people were approached; 7,096 (3,227 test-positives, 3,869 test-negatives) who completed a questionnaire 3 months after their PCR-test were included. 39.6% (1,279/3,227) of SAR-CoV-2 PCR-positives and 30.6% (1,184/3,869) of SAR-CoV-2 PCR-negatives had at least one impairing physical symptom 3 months post-test. The final model contained predictors: SARS-COV-2 status, number of symptoms at testing, sex, age, ethnicity, self-rated physical and mental health, feelings of loneliness and four EQ-5D-Y items before testing. Internal validation showed minimal overfitting with excellent calibration and discrimination measures (optimism adjusted calibration slope:0.97527; C-statistic:0.83640). Conclusions and relevanceWe developed a risk prediction equation to identify those most at risk of experiencing at least one impairing physical symptom 3 months after a SARS-CoV-2 PCR-test which could serve as a useful triage and management tool for children and young people during the ongoing pandemic. External validation is required before large-scale implementation. Key PointsO_ST_ABSQuestionC_ST_ABSWhich children have impairing physical symptoms during the COVID-19 pandemic? FindingsUsing data from a large national matched cohort study in children and young people (CYP) aged 11-17 years (N=7,096), we developed a prediction model for experiencing at least one impairing physical symptom 3 months after testing for SARS-COV-2. Our model had excellent predictive ability, calibration and discrimination; we used it to produce a risk estimation calculator. MeaningOur developed risk calculator could serve as a useful tool in the early identification and management of CYP at risk of persisting physical symptoms in the context of the COVID-19 pandemic.

ImportanceSeasonal variation in adverse drug reactions has clinical and mechanistic implications for understanding disease mechanisms and risk mitigation strategies. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a life-threatening mucocutaneous reaction with high morbidity and mortality, which may have a seasonal component. ObjectiveTo determine whether the reporting of SJS/TEN to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) follows a seasonal pattern, incorporating both traditional seasonal analyses and time-series modeling. DesignCross-sectional, population-based analysis of FAERS reports from January 2010 to December 2019. Seasonal differences were assessed using Kruskal-Wallis tests and Seasonal-Trend Decomposition using Loess (STL). Seasonal autoregressive integrated moving average (SARIMA) models were used to counterfactually forecast SJS/TEN and comparator conditions during the COVID-19 pandemic, assessing changes in reporting. SettingPopulation-based analysis of spontaneous adverse event reports submitted to FAERS. ParticipantsAll deduplicated FAERS reports with complete event dates from 2010 to 2019 were included. SJS/TEN cases were identified using standardized MedDRA terms. Comparator analyses of known seasonal conditions - photosensitivity reactions, influenza, and respiratory syncytial virus (RSV) - served as positive controls. ExposuresDrug exposures as recorded in FAERS. Main Outcomes and MeasuresThe primary outcome was the monthly and seasonal proportion of unique SJS/TEN reports, normalized using all FAERS reports during a particular interval as the denominator. Seasonality strength was quantified from STL decomposition (range 0-1). SARIMA models were applied to pre-COVID data to counterfactually forecast trends from March 2020 to December 2023. Forecast accuracy was evaluated using mean squared error (MSE), root mean squared error (RMSE), and residual diagnostics. ResultsAmong 5,900 SJS/TEN cases reported from 2010-2019, no significant monthly or seasonal variation was detected (p > 0.05), and seasonality strength was low (0.163). Positive controls (influenza, RSV, photosensitivity) showed expected strong seasonality. SARIMA forecasts indicated a mild increase in SJS/TEN reporting during the pandemic, compared to its previous declining trend. Influenza and RSV dropped below predictions during the pandemic, while photosensitivity remained relatively consistent. Conclusions and RelevanceSJS/TEN reporting to FAERS does not exhibit apparent seasonality, in contrast to positive controls. Time-series modeling confirmed these findings and highlighted the relative stability of SJS/TEN reporting during the pandemic compared to respiratory viruses.

ImportanceSevere cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE), are rare but life-threatening drug hypersensitivity syndromes. Due to their low incidence and diagnostic complexity, large-scale characterization of SCAR is challenging. ObjectiveTo characterize the demographics, causative agents, trends, latency, and phenotypic overlap of SCAR using a large-scale, sanitized pharmacovigilance dataset from FAERS (FDA Adverse Event Reporting System). DesignCross-sectional study of spontaneous adverse event reports. Cases were drawn from the U.S. Food and Drug Administration Adverse Event Reporting System (FDA FAERS) from January 2004 to December 2023 and subjected to sanitization and deduplication. Disproportionality analysis was used to characterize causative agents. Machine learning (random forest classifiers) was used to analyze predictors of drug latency and mortality. SettingGlobal pharmacovigilance reports submitted to FAERS. ParticipantsA total of 56,683 deduplicated SCAR reports were identified, representing 0.33% of reports during the study period. ExposuresSuspected causative drugs, including both small molecules and biologics. Main Outcomes and MeasuresMain outcomes included the frequency and distribution of SCAR syndromes, reporting trends over time, latency from drug start to reaction onset, drug-specific disproportionality (PRR, ROR, IC), and co-reporting between SCAR types and related conditions. ResultsA total of 56,683 unique SCAR reports were identified, including SJS-TEN (28,871), DRESS (22,444), AGEP (6,183), and GBFDE (150). We identified 237 drugs with significant disproportionality for SCAR overall. Co-reporting between SCARs was significantly enriched (p < 10-200), suggesting overlapping phenotypes. Latency varied by drug and syndrome (median: GBFDE 3 days, AGEP 4 days, SJS-TEN 15 days, DRESS 24 days). Conclusions and RelevanceSCAR syndromes display distinct but overlapping phenotypes, with variable latency and diverse causative agents. These findings, based on the largest SCAR dataset to date, highlight the need for improved classification frameworks and molecular validation. Large-scale pharmacovigilance, integrated with genomic and histopathologic data, will be critical to improving diagnosis, mechanistic understanding, and clinical management of SCAR.

BackgroundCryptococcal meningitis is a leading cause of adult community-acquired meningitis in sub-Saharan Africa with high mortality rates in the first 10 weeks post diagnosis. Practical tools to stratify mortality risk may help to tailor effective treatment strategies. MethodsWe pooled individual-level data from two randomised-controlled trials of HIV-associated cryptococcal meningitis across eight sub-Saharan African countries (ACTA, ISRCTN45035509; Ambition-cm, ISRCTN72509687). We used this pooled dataset to develop and validate multivariable logistic regression models for 2-week and 10-week mortality. Candidate predictor variables were specified a priori. Basic models were developed using only predictors available in resource-limited settings; Research models were developed from all available predictors. We used internal-external cross-validation to evaluate performance across countries within the development cohort, before validation of discrimination, calibration and net benefit in held-out data from Malawi (Ambition-cm trial). We also evaluated whether treatment effects in the trials were heterogenous by predicted mortality risk. FindingsWe included 1488 participants, of whom 236 (15.9%) and 469 (31.5%) met the 2-week and 10-week mortality outcomes, respectively. In the development cohort (n=1263), five variables were selected into the basic model (haemoglobin, neutrophil count, Eastern Cooperative Oncology Group performance status, Glasgow coma scale and treatment regimen), with two additional variables in the research model (cerebrospinal fluid quantitative culture and opening pressure) for 2-week mortality. During internal-external cross-validation, both models showed consistent discrimination across countries (pooled areas under the receiver operating characteristic curves (AUROCs) 0.75 (95% CI 0.68-0.82) and 0.78 (0.75-0.82) for the Basic and Research 2-week mortality models, respectively), with some variation in calibration between sites. Performance was similar in held-out validation (n=225), with the models demonstrating higher net benefit to inform decision-making than alternative approaches including a pre-existing comparator model. In exploratory analyses, treatment effects varied by predicted mortality risk, with a trend towards lower absolute and relative mortality for a single high-dose liposomal Amphotericin B-based regimen (in comparison to 1-week Amphotericin B deoxycholate plus flucytosine) among lower risk participants in the Ambition-cm trial. InterpretationBoth models accurately predict mortality, were generalisable across African trial settings, and have potential to be incorporated into future treatment stratification approaches in low and middle-income settings. FundingMRC, United Kingdom (100504); ANRS, France (ANRS12275); SIDA, Sweden (TRIA2015-1092); Wellcome/MRC/UKAID Joint Global Health Trials (MR/P006922/1); European DCCT Partnership; NIHR, United Kingdom through a Global Health Research Professorship to JNJ (RP-2017-08-ST2-012) and a personal Fellowship to RKG (NIHR302829). RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSThere is an urgent need to improve clinical management for HIV-associated cryptococcal meningitis in resource limited settings across Africa. Cryptococcal meningitis accounts for [~]112,000 AIDS-related deaths per year globally, with over 75% in Africa, despite widespread antiretroviral therapy roll-out. The development of practical tools to identify patients at highest risk of death could help to tailor management strategies and stratify therapy. We searched PubMed for studies published between database inception and Jan 12, 2024, using the terms "cryptococcal meningitis", "HIV", "human immunodeficiency virus", "immunocompromised", "predict*", and "model*", with no language restrictions. Three previous studies, all conducted in China, have developed prognostic models for cryptococcal meningitis mortality. Of these, two used statistical methods while the third used machine learning but focused on persons without HIV only. No studies conducted in Africa, specifically targeting people living with HIV, or using both statistical and machine learning approaches in parallel, were identified. Well-developed and validated tools to predict risk of cryptococcal meningitis mortality and guide treatment stratification are thus lacking for resource limited settings in Africa. Added value of this studyTo our knowledge, this is the largest study to date to develop and validate prediction models for HIV-associated cryptococcal meningitis mortality. We combined high-quality data from the two largest randomised-controlled clinical trials conducted to date for cryptococcal meningitis treatment, with a total sample size of 1488 participants of whom 236 (15.9%) and 469 (31.5%) met the 2-week and 10-week mortality outcomes, respectively. We developed two models, basic and research, to enable use in both resource-limited and research settings (where additional prognostic markers such as measurements of cerebrospinal fluid (CSF) opening pressure and CSF fungal burden may also be available). In the 2-week mortality models, five variables were included in the basic model, with two additional variables included in the research model. Both models predicted risk of mortality with consistent discrimination and calibration across sub-Saharan African settings. Head-to-head statistical (logistic regression) and machine learning (XGBoost) methods revealed no added value of the machine learning approach. In exploratory analyses, treatment effects varied by predicted 2-week mortality risk, thus providing proof-of-concept for future treatment stratification approaches. Specifically, there was a trend towards lower mortality for a single high-dose liposomal Amphotericin B-based regimen (in comparison to 1-week Amphotericin B deoxycholate plus flucytosine) among lower risk participants in the Ambition-cm trial. Implications of all the available evidenceThe personalised risk predictor for cryptococcal meningitis (PERISKOPE-CM) models accurately predicted mortality risk among patients with HIV-associated cryptococcal meningitis and demonstrated generalisable performance across trial settings in Africa. Predictions from the models could be utilised to direct treatment stratification approaches in future clinical trials, with patients at lowest predicted risk receiving less intensive and less toxic therapy. The models have been made available for future research use on an open access online interface.

ObjectiveTo assess the cost-effectiveness of two COVID-19 oral antivirals (COAVs) Paxlovid and Molnupiravir compared to the standard of care, in Ghana, Rwanda and Zambia. MethodsWe modelled costs (2022 US$) and health outcomes in the acute phase of the COVID-19 disease from a public payers perspective in three unvaccinated target populations - (1) patients aged 65 years and above (elderly); (2) adult patients with at least one other underlying risk factors for disease severity; and (3) all adult patients. In addition, we conducted a series of sensitivity and scenario analyses. ResultsIn elderly patients, Paxlovid was less costly and more effective (i.e., dominated) than standard of care in all three study countries. Molnupiravir dominated standard of care in Rwanda and Zambia and an incremental cost-effectiveness ratio (ICER) was estimated at US$1023.58 per disability-adjusted life year (DALY) averted in Ghana. In adults with other underlying risk factors, Paxlovid dominated in Rwanda and Zambia while Molnupiravir dominated in Rwanda. Neither Paxlovid nor Molnupiravir were cost-effective in the all-adult group in any country context. Incremental net monetary benefit for Paxlovid was consistently higher than for Molnupiravir. In COVID-19 vaccinated patients, Paxlovid was cost-effective for elderly patients in Zambia and Rwanda but not in Ghana. Key determinants of cost-effectiveness were COAV price, likelihood of early treatment initiation, and hospitalization rates. ConclusionIn African settings similar to Zambia, Ghana or Rwanda, COAVs could be cost-effective in populations who are unvaccinated, and at high risk of progression to severe COVID-19. More evidence is needed to determine cost-effectiveness for patients that are unvaccinated but have previously been infected with COVID-19 and may have developed some immune protection. Key messagesO_LIWhat is already known on this topic - Two COVID-19 oral antivirals (COAVs), Molnupiravir and Paxlovid have been shown to represent good value for money in high-income countries. However, there is a dearth of evidence on the cost-effectiveness of these drugs in African countries. C_LIO_LIWhat this study adds-This study finds that COAVs are likely to be cost-effective in populations who are unvaccinated and at high risk of progression to severe COVID-19. However, the probability of Molnupiravir being cost-effective was consistently lower than the probability of Paxlovid being cost-effective. Early treatment initiation, COAV price and baseline hospitalization rates had the largest impact on the cost-effectiveness of both COAVs in unvaccinated patients. More evidence is needed on the cost-effectiveness for patients who have previously been infected with COVID-19. C_LIO_LIHow this study might affect research, practice, or policy - This study broadly supports African governments decisions to not procure substantial quantities of either COAV but is evidence that Paxlovid could be good value for money when treating very specific populations. C_LI

ObjectiveTo assess the evidence on the presence of antibodies cross-reactive with SARS-CoV-2 antigens in pre-pandemic samples from African populations. MethodsWe performed a systematic review and meta-analysis of studies evaluating pre-pandemic African samples using pre-set assay-specific thresholds for SARS-CoV-2 seropositivity. Results26 articles with 156 datasets were eligible, including 3,437 positives among 29,923 measurements (11.5%) with large between-dataset heterogeneity. Positivity was similar for anti-N (14%) and anti-S antibodies (11%), higher for anti-S1 (23%) and lower for anti-RBD antibodies (7%). Positivity was similar, on average, for IgM and IgG. Positivity was seen prominently in countries where malaria transmission occurs throughout and in datasets enriched in malaria cases (14%, 95% CI, 12-15% versus 2%, 95% CI 1-2% in other datasets). Substantial SARS-CoV-2 reactivity was seen in high malaria burden with or without high dengue burden (14% and 12%, respectively), and not without high malaria burden (2% and 0%, respectively). Lower SARS-CoV-2 cross-reactivity was seen in countries and cohorts of high HIV seroprevalence. More sparse individual-level data showed associations of higher SARS-CoV-2 cross-reactivity with Plasmodium parasitemia and lower SARS-CoV-2 cross-reactivity with HIV seropositivity. ConclusionsPre-pandemic samples from Africa show high levels of anti-SARS-CoV-2 seropositivity. Levels of cross-reactivity tracks especially with malaria prevalence.

BackgroundInfections by SARS-CoV-2 variants of concern (VOCs) might affect children and adolescents differently than earlier viral lineages. We aimed to address five questions about SARS-CoV-2 VOC infections in children and adolescents: i) symptoms and severity, ii) risk factors for severe disease, iii) the risk of becoming infected, iv) the risk of transmission and v) long-term consequences following a VOC infection. MethodsWe carried out a systematic review. We searched the COVID-19 Open Access Project database up to 1 March 2022 and PubMed up to 9 May 2022 for observational epidemiological studies about alpha, beta, gamma, delta and omicron VOCs among 0 to 18 year olds. We synthesised data for each question descriptively and assessed the risks of bias at the outcome level. ResultsWe included 53 articles, of which 47% were from high-income countries and none were from low-income countries, according to World Bank categories. Most children with any VOC infection presented with mild disease, with more severe disease being described with the delta or the gamma VOC. Diabetes and obesity were reported as risk factors for severe disease during the whole pandemic period. The risk of becoming infected with a SARS-CoV-2 VOC seemed to increase with age, while in daycare settings the risk of onward transmission of VOCs was higher for younger than older children or at least partially vaccinated adults. Long-term symptoms or signs following an infection with a VOC were described in <5% of children and adolescents. ConclusionOverall patterns of SARS-CoV-2 VOC infections in children and adolescents are similar to those of earlier lineages. Comparisons between different pandemic periods, countries and age groups should be improved with complete reporting of relevant contextual factors, including VOCs, vaccination status of study participants and the risk of exposure of the population to SARS-CoV-2. PROSPERO registration numberCRD42022295207 Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSSARS-CoV-2 variants of concern (VOCs) might affect children and adolescents differently from earlier viral lineages. What this study addsChildren and adolescents are susceptible to SARS-CoV-2 VOC infection, though they mostly experience mild disease, and can transmit the VOCs. More severe disease was described with the delta or the gamma VOC but comparison within paediatric age groups as well as to adults is hindered by the lack of reporting of contextual factors such as the vaccination status of these groups. How this study might affect research practice or policyThe applicability of our findings about clinical presentations, susceptibility and transmissibility of SARS-CoV-2 VOCs is limited by an absence of research from low-and middle-income settings. As new VOCs continue to emerge, new studies are needed globally, with methods and results reported in ways that allow comparison between different VOCs and age groups.

BackgroundSevere COVID-19 infection is associated with dysregulated immune response which, in a substantial minority of patients, results in cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS). Inhibition of cytokines or cytokine-associated signal transduction is a promising strategy to ameliorate ARDS associated with CRS. We and others have previously shown that serum free LIGHT (TNFSF14) levels are markedly elevated in patients with COVID-19 pneumonia/ARDS10,11, suggesting that LIGHT neutralization may offer therapeutic benefit to COVID-19 ARDS patients. MethodsWe conducted a randomized, double-blind, placebo-controlled, multi-center, proof-of-concept clinical trial of CERC-002 in adults with mild to moderate ARDS associated with COVID-19 (n=83). Enrolled patients received a single dose of CERC-002 or placebo, in addition to standard of care that included high dose corticosteroids. The primary efficacy endpoint was alive and free of respiratory failure status through Day 28. Secondary outcomes included alive status at Day 28, free of invasive ventilation through Day 28, and serum free LIGHT levels. ResultsIn patients hospitalized with COVID-19 associated pneumonia and mild to moderate (ARDS), CERC-002 increased the rate of alive and free of respiratory failure status through Day 28 as compared to placebo (83.9% vs 64.5%; p=0.044). Efficacy was highest in the prespecified subgroup of patients 60 years old and older (76.5% vs 47.1%; p=0.042), the population most vulnerable to severe complications and death with COVID-19 infection. Through both the initial 28-day and 60-day follow-up periods, reductions of approximately 50% in mortality were observed for CERC-002 compared to placebo (7.7% vs 14.3% at Day 28 and 10.8% vs 22.5% at Day 60). Importantly, this improvement was incremental to standard of care including high dose steroids and remdesivir 88.0% and 57.8%, respectively). In addition, serum LIGHT levels but not IL-6 levels were markedly reduced in patients treated with CERC-002. ConclusionsThe data presented herein demonstrate that CERC-002 markedly reduces the risk of respiratory failure and death incremental to standard of care including high dose corticosteroids and reduces LIGHT levels in patients with COVID-19 ARDS. (ClinicalTrials.gov number NCT04412057).

BackgroundHomelessness might increase the risk of premature mortality, but evidence is scarce, imprecise, and is mostly limited to rough sleepers as opposed to more common types of homelessness. MethodsPublished studies were retrieved through a systematic search of MEDLINE, Embase PsycINFO and Scopus from inception to December 2024. Unpublished data were identified from open-access data archives. We used random-effects meta-analysis to combine effect estimates from published and unpublished data. This review is registered at PROSPERO (CRD42023430984). FindingsWe included 116 studies from Europe, the USA, South America, Africa, Asia, and Australia. The meta-analysis of all-cause mortality comprised 110,892,271 people (1,618,049 exposed to homelessness). The risk of all-cause mortality was significantly increased in people exposed to homelessness (Relative risk [RR] 2{middle dot}12 [95% CI 1{middle dot}91-2{middle dot}57], p<0{middle dot}001, I2=99{middle dot}7%), with risks similar in men (3{middle dot}88, 2{middle dot}69-5{middle dot}06) and women (3{middle dot}46, 2{middle dot}17-4{middle dot}70). This risk was most elevated in people who had slept rough (7{middle dot}63, 3{middle dot}29-11{middle dot}97), followed by those who used low-cost hotels (5{middle dot}18, 1{middle dot}14-9{middle dot}23), then hostels (3{middle dot}44, 2{middle dot}10-4{middle dot}77). In analyses of cause-specific mortality (26,291,900 people, 1,202,205 homeless), summary RR estimates were elevated for 33 of the 36 (92%) causes of death and highest for deaths due to psychoactive substance use disorder (21{middle dot}36, 14{middle dot}44-31{middle dot}67), accidental injuries (13{middle dot}15, 5{middle dot}46-31{middle dot}69), drug-overdose (10{middle dot}80, 6{middle dot}37-18{middle dot}31), and those that are alcohol-related (5{middle dot}93, 1{middle dot}10-22{middle dot}04). No evidence of publication bias was detected. InterpretationHomeless people experience an increased risk of premature mortality across an array of health outcomes. That the most extreme inequities have an interrelated aetiology suggests a cross-sectoral medical, housing, and social care response is required. FundingThe Centre for Homelessness Impact, Health and Care Research Wales, UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhile existing systematic reviews have found that homelessness is associated with an increased risk of all-cause mortality, there remains substantial gaps in knowledge. Currently there is no meta-analysis of the risk of death from all-causes and specific disorders, comparison of mortality risk across the spectrum of homelessness experience (e.g., rough sleeping, hostels, single-occupancy low-cost hotels), whether differences exist in the impact on men and women, or in high, or low and middle income countries (LMICs). Accordingly, we searched MEDLINE, Embase, PsycINFO and Scopus from inception to December 2024 for studies reporting mortality outcomes among people with a history of homelessness. Additionally, we searched the grey literature and obtained unpublished individual-participant data for two cohort studies from open-access data archives. Added value of this studyOur systematic review and meta-analysis provides the first comprehensive examination to date of mortality among people who have experienced homelessness. Drawing on 116 studies, there was, in aggregate, a doubling in risk of all-cause mortality in the 1,618,049 people who had experienced homelessness relative to the 109,274,222 population controls (relative risk [RR] 2{middle dot}12, [95% CI 1{middle dot}91-2{middle dot}57], p<0{middle dot}001, I2=99{middle dot}7%). This association was strongest in people who had slept rough (7{middle dot}63, 95% CI 3{middle dot}29-11{middle dot}97) than in a hostel (3{middle dot}44, 95% CI 2{middle dot}10-4{middle dot}77) and was of equal magnitude in men (3{middle dot}88, 95% CI 2{middle dot}69-5{middle dot}06) and women (3{middle dot}43, 95% CI 2{middle dot}10-4{middle dot}70). Summary RRs were extremely high for some causes of death, including RRs of >20 for psychoactive substance use disorder, 10-19 for drug-overdose, accidents, and accidental injuries, and 5-10 for alcohol-related causes - none of which have been previously summarised. No evidence of publication bias was found. Implications of all the available evidenceHomelessness is associated with an increased risk of all-cause mortality. Our analysis suggests these a large proportion of these excess deaths are caused by substance use, drug-overdose, accidents and harmful alcohol consumption. The extreme inequalities in mortality we identified points to the need a cross-sectoral response to improve both health and housing conditions for people who have experienced homelessness.

IMPORTANCENicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking. OBJECTIVETo determine whether nicotinamide use results in an increase of MACE. DESIGN, SETTING, PARTICIPANTSRetrospective cohort study of two patient cohorts, Vanderbilt University Medical Center (VUMC) and Military Veteran Program (MVP). The risk of MACE in patients exposed to nicotinamide was compared to the risk of MACE in unexposed patients. In the VUMC cohort, 1228 patients were exposed to nicotinamide based on keyword entry for "nicotinamide" or "niacinamide" and hand-review of charts, while 253 were unexposed but had documented recommendation for use. In the MVP cohort, there were 1594 with exposure to nicotinamide propensity score matched to 2694 without exposure. EXPOSURESThe primary exposure for the VUMC cohort was a confirmed exposure to nicotinamide in chart review. The primary exposure for the MVP cohort was medication entry for "nicotinamide" or "niacinamide". MAIN OUTCOME(S) AND MEASURE(S)The primary outcome was development of MACE based on a validated phenotype. RESULTSBetween both cohorts, 6039 patients were included, of whom 5125 were male with a mean age of 63.2 years. Neither cohort had significant differences in mean age, sex, race and ethnicity between the nicotinamide exposed and unexposed groups. In the VUMC cohort, there was no significant association between nicotinamide exposure and the primary outcome of MACE (HR 0.76, 95% CI 0.46 - 1.25, p = 0.28). MACE prior to nicotinamide exposure was strongly associated with subsequent MACE (HR 9.01, 95% CI 5.90 - 13.70, p < 0.001). In the MVP cohort, we adjusted for MACE risk factors as potential confounding variables and saw no significant association between nicotinamide exposure and MACE (HR 1.00 95% CI 0.75 - 1.32), while history of prior MACE remained strongly associated with subsequent MACE (HR 9.50, 95% CI 6.38 - 14.1). CONCLUSIONS AND RELEVANCEIn this retrospective cohort study of 6039 adults from two different patient populations, we found no increased risk of MACE in patients with nicotinamide exposure.

Background: Roma, the largest ethnic minority in Europe,, are almost absent from movement-disorder research despite living in environments with biomass combustion, poor sanitation, and unprotected water, creating a high-risk neurological exposome. Objective: To describe baseline exposome profiles in a nationwide Roma screening cohort and compare exposures between marginalized and integrated communities, and between screen-positive and screen-negative participants. Methods: A nationwide community-based program combined door-to-door recruitment of marginalized Roma with recruitment of integrated Roma through neurological services. Participants completed standardized exposome questionnaires and a brief, non-diagnostic motor symptom screen. Results: Among 541 Roma (350 marginalized; 191 integrated), marginalized participants showed greater environmental and socioeconomic disadvantage, and screen-positive individuals tended to cluster at the more adverse end of this exposome spectrum. Conclusion: This nationwide Roma movement-disorder screening cohort with exposome assessment reveals substantial disparities relevant for future clinical and genetic research.

BackgroundMultidrug-resistant (MDR) tuberculosis (TB) in children remains a major public health challenge. Although treatment is provided free of direct charge in many countries, it can impose substantial indirect and non-medical costs on affected households. Evidence on the economic burden of childhood MDR-TB on families, remains limited. MethodsA cross-sectional household survey was conducted in the Western Cape, South Africa, among 45 households with a child <15 years who initiated MDR-TB treatment between 2018 and 2021. Socioeconomic status, costs of accessing care, and health-related quality of life (HRQoL) were assessed and linked to health service utilisation data to estimate household-level costs. ResultsThe median total cost per household was ZAR 7,443 (US$504) per episode of care (IQR: ZAR 4,119- 13,207), with indirect costs accounting for the largest share of household costs. Twenty-three (51.1%) of the households incurred catastrophic health expenditure, defined as >20% of annual household income. Costs increased with hospital-based care, longer treatment duration, and more frequent caregiver visits. The HRQoL of children was generally high, though not uniformly distributed. ConclusionsChildhood MDR-TB places a substantial financial burden on already vulnerable households. Economic evaluations and care models should incorporate household costs and consider strategies to reduce the indirect burden of treatment on families.

BackgroundHow post-COVID-19 condition (PCC) differs from post-acute infection syndromes (PAIS) caused by other respiratory viruses remains uncertain. Comparing these conditions may clarify whether post-acute symptoms reflect specific consequences of SARS-CoV-2 infection or broader post-viral mechanisms. MethodsWe conducted a systematic review and meta-analysis of cohort studies comparing persistent symptoms or conditions in adults after SARS-CoV-2 infection with those following other acute respiratory viral infections. PubMed, Embase, and Scopus were searched. Random-effects models were used to estimate pooled risks. ResultsAmong 9,371 records screened, 22 studies were included and 14 contributed to the meta-analysis. Increased risk after SARS-CoV-2 infection was observed for pulmonary embolism, abnormal breathing, fatigue, hemorrhagic stroke, memory loss/brain fog, and palpitations; heart rate abnormalities showed borderline significance. For most other outcomes pooled estimates were inconclusive. ConclusionsOnly a subset of outcomes appears more frequent after SARS-CoV-2 infection, suggesting many symptoms attributed to PCC may reflect broader post-viral syndromes.

1.1BackgroundNusinersen has substantially increased survival and improved disease progression in Spinal Muscular Atrophy (SMA) patients. However, treatment response is heterogeneous, with some patients gaining the ability to sit and walk whilst others display less obvious changes. MethodFrom the SMA Reach UK and the Italian Telethon Network, 124 non-sitter SMA patients treated with nusinersen under 4 years were included and randomly allocated to training and testing (80/20%). Tree and regression-based machine learning for survival outcomes were compared, and oblique random forests were selected, with a testing C-Index of 0.74. The features were selected from items of the CHOP-INTEND and HINE-2 motor function assessments, respiratory and swallowing status using mutual information. FindingsSixty-two patients (50%) achieved sitting, at a median age of 2.4 years. The predicted median time-to-sitting in those requiring tube feeding at treatment initiation was 4-months later than those without, and this was the most influential factor. Specific motor function features, including the ability to kick in supine, were strongly associated with a higher likelihood of sitting. InterpretationThis work provides a framework for predicting nusinersen-response and represents the first stage in personalised counselling on treatment plans for SMA. FundingSupport for SMA Reach is provided by Biogen, Roche and Novartis, and historically NIHR BRC, SMA Trust, the MRC Translational Research Centre and MD UK. Support for the Italian network is provided by Famiglie SMA, Telethon (GSP 13002), and ASAMSI. 1.2 Research Into ContextO_ST_ABSEvidence before this studyC_ST_ABSA literature search on PubMed up to January 1st 2025 with the term "("Spinal Muscular Atrophy" OR "SMA") AND ("Nusinersen" OR "Spinraza" OR "ISIS-SMNRx" OR "ISIS 396443") AND ("predict*")" across all fields was performed. Achievement of sitting after nusinersen treatment in SMA 1 has been linked to the age of treatment, symptom onset and general motor function severity (CHOP-INTEND and HINE-2 score), but no multivariable analysis or prediction of outcomes after treatment was found. Added value of this studyOur study identifies key patient features that are linked to nusinersen treatment response in non-sitter SMA 1 patients. This work provides a higher level of granularity beyond previous univariate models, yielding a framework for predicting personalised patient sitting. Crucially, we highlight that bulbar impairment as a proxy for disease severity is very influential in predicting a patients likelihood of sitting, along with specific motor function abilities at baseline. Implications of all the available evidenceDespite considerable evidence of efficacy, this work provides insights into the homogenous gross motor function response observed in SMA patients treated with nusinersen, which has been under researched. The results of this study provide individualised predictions of the likelihood of patients outcomes after treatment with nusinersen. Crucially, this work can inform clinicians in their discussions on treatment-response with parents and carers of babies with SMA.

BackgroundAnthropometric deficits persist in sub-Saharan Africa (SSA) despite sustained improvements in nutrition, disease burden and living conditions. The UN Sustainable Development Goals advocate for disaggregation of health indicators by ethnic group. However, few studies have assessed how ethnicity is associated with anthropometric deficits across SSA. MethodsData were extracted from 37 georeferenced Demographic and Health Surveys carried out during 2006-2019 across SSA that recorded anthropometric data for children aged <5 years. In a cross-sectional analysis, the odds of stunting (low height-for-age), wasting (low weight-for-height) and underweight (low weight-for-age) were modelled in relation to ethnic group using a generalised linear hierarchical mixed-effects model, controlling for survey design and environmental, socioeconomic, and clinical variables. FindingsThe study population comprised 138,312 children spanning 45 ethnic groups across 18 countries. In pairwise comparisons between ethnic groups, height-for-age Z scores differed by at least 0.5 standard deviations in 56% of comparisons, weight-for-height Z scores in 39% of comparisons and weight-for-age Z scores in 34% of comparisons. Compared to a reference group of Fula children (the largest ethnic group), ethnic group membership was associated with both increases and decreases in growth faltering, ranging from a 69% reduction to a 32% increase in odds of stunting (Igbo: adjusted odds ratio (aOR) 0.31, 95% confidence intervals (CI) 0.27-0.35, p<0.0001; Hausa: aOR 1.32, 95% CI 1.21-1.44, p<0.0001); a 13% to 87% reduction in odds of wasting (Mandinka: aOR 0.87, 95% CI 0.76-0.99, p=0.034; Bamileke: aOR 0.13, 95% CI 0.05-0.32, p<0.0001) and an 85% reduction to 13% increase in odds of underweight (Bamileke: aOR 0.15, 95% CI 0.08-0.29, p<0.0001; Hausa: aOR 1.13, 95% CI 1.03-1.24, p=0.010). InterpretationMajor ethnic disparities in stunting, wasting and underweight were observed across 18 countries in SSA. Understanding and accounting for these differences is essential to support progress monitoring and targeting of nutrition interventions in children. FundingUK Medical Research Council, Novo Nordisk Foundation Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed with no date restrictions for studies published in English, using the following search terms: ("child*", "five" OR "infant") AND ("child growth", "stunting", "stunted", "growth failure", "growth faltering", "height" OR "anthropometric") AND ("ethnic*"). We identified 288 studies (196 from the database search and 92 from reference lists). Of 93 studies full text studies screened, 37 were relevant. Two multi-country studies measured the association between ethnicity and growth outcomes. An analysis of 13 national surveys from Latin America during 2006-2020 found a 97% higher prevalence of stunting among indigenous than European or mixed ancestry participants. In a 2014 systematic review, 20% of height means in 55 countries or ethnic groups differed by [&ge;]0.5 standard deviations (SD) from the WHO Multicentre Growth Reference Study mean, suggesting some differences. A further 35 local studies measured ethnicity as a potential risk factor for child growth outcomes in Australia, Brazil, China, Guatemala, Hawaii, India, Iran, Lithuania, Malaysia, Nepal, Peru, South Africa, Thailand, Trinidad and Tobago, the UK and the USA, with a range of associations observed. We identified additional multi-country, population-based cohorts designed to support the development of international growth standards, but these did not specifically measure inequalities between ethnic groups. Added value of this studyTo our knowledge, this is the first systematic, multi-country analysis of ethnicity and anthropometric deficits in sub-Saharan Africa. By analysing data for 138,312 children spanning 45 ethnic groups in 18 countries, measured in 37 Demographic and Health Surveys, we found ethnicity to be a primary risk factor for anthropometric deficits after adjusting for socioeconomic, environmental and child-level characteristics. The strength of this association exceeded that for other factors known to affect childrens growth, such as household wealth, history of diarrhoea and access to improved water and sanitation. Anthropometric z-scores differed by [&ge;]0.5 SD (a clinically relevant threshold) in 34%-56% of pairwise comparisons between ethnic groups. Implications of all the available evidenceChild growth faltering persists as a major cause of morbidity and mortality in sub-Saharan Africa1 but our study shows that this burden is unequally distributed among ethnic groups. Research is needed to understand these differences, in order to target interventions and effectively track progress towards Sustainable Development Goal 2.

Background Risk stratification tools for childhood pneumonia have been proposed to improve identification of children at highest risk of death, particularly in low-resource settings. However, their added value over the WHO Integrated Management of Childhood Illness (IMCI) criteria and danger signs remains uncertain. Methods We conducted a secondary analysis of a multi-country randomised controlled trial of children without HIV hospitalised with pneumonia in Mozambique, South Africa, Uganda, Zambia, and Zimbabwe. We evaluated the performance of five published risk scores alongside WHO IMCI severity classification and danger signs. Discrimination for (1) in-hospital mortality, (2) 28-day mortality, and (3) 28-day readmission or death was assessed using area under the receiver operating characteristic curve (AUC). Comparative performance and clinical utility were examined. Results Of the 1010 participants, 18 (1.8%) died in hospital, 22 (2.2%) died in hospital or in the 7 days post-discharge, and 63 (6.2%) died or were readmitted by day 28. Univariate case-fatality rates were highest for variables associated with malnutrition, convulsions, and hypoxaemia. All risk scores demonstrated moderate discrimination for in-hospital and in-hospital+7-day mortality (AUC range approximately 0.75-0.84), with no meaningful differences between models, and performed similarly to the WHO danger signs and IMCI severity classification. In contrast, all approaches performed poorly in predicting 28-day readmission or death (AUC approximately 0.54-0.58). No risk score consistently outperformed simple clinical criteria. Conclusions In this multi-country dataset, we found no evidence that published paediatric pneumonia risk scores meaningfully outperform WHO IMCI-based clinical assessment for predicting mortality. The relatively small number of mortality events limits precision, and modest differences cannot be excluded. These findings suggest that, in low-resource settings, strengthening implementation of existing WHO clinical criteria may be more effective than adopting more complex prediction tools.

BackgroundSevere acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection has disproportionately affected older individuals and those with underlying medical conditions. Research has focused on short-term outcomes in hospital, and single organ involvement. Consequently, impact of long COVID (persistent symptoms three months post-infection) across multiple organs in low-risk individuals is yet to be assessed. MethodsAn ongoing prospective, longitudinal, two-centre, observational study was performed in individuals symptomatic after recovery from acute SARS-CoV-2 infection. Symptoms and organ function (heart, lungs, kidneys, liver, pancreas, spleen) were assessed by standardised questionnaires (EQ-5D-5L, Dyspnoea-12), blood investigations and quantitative magnetic resonance imaging, defining single and multi-organ impairment by consensus definitions. FindingsBetween April and September 2020, 201 individuals (mean age 44 (SD 11.0) years, 70% female, 87% white, 31% healthcare workers) completed assessments following SARS-CoV-2 infection (median 140, IQR 105-160 days after initial symptoms). The prevalence of pre-existing conditions (obesity: 20%, hypertension: 6%; diabetes: 2%; heart disease: 4%) was low, and only 18% of individuals had been hospitalised with COVID-19. Fatigue (98%), muscle aches (88%), breathlessness (87%), and headaches (83%) were the most frequently reported symptoms. Ongoing cardiorespiratory (92%) and gastrointestinal (73%) symptoms were common, and 42% of individuals had ten or more symptoms. There was evidence of mild organ impairment in heart (32%), lungs (33%), kidneys (12%), liver (10%), pancreas (17%), and spleen (6%). Single (66%) and multi-organ (25%) impairment was observed, and was significantly associated with risk of prior COVID-19 hospitalisation (p<0.05). InterpretationIn a young, low-risk population with ongoing symptoms, almost 70% of individuals have impairment in one or more organs four months after initial symptoms of SARS-CoV-2 infection. There are implications not only for burden of long COVID but also public health approaches which have assumed low risk in young people with no comorbidities. FundingThis work was supported by the UKs National Consortium of Intelligent Medical Imaging through the Industry Strategy Challenge Fund, Innovate UK Grant 104688, and also through the European Unions Horizon 2020 research and innovation programme under grant agreement No 719445.

BackgroundSkin disease affects 4.7-4.9 billion individuals globally; however, little is known about access to dermatological care. MethodsWe conducted a multinational, cross-sectional survey of dermatological care across 194 WHO member states and three additional geographic areas in 2024-2025. Primary outcomes included dermatologist density per 100,000 population and number of dermatologists globally. Secondary outcomes included training programme density, workforce distribution, perceived access to care, and health system characteristics. Descriptive statistics and nonparametric tests compared outcomes across World Bank Income (WBI) levels and WHO regions. FindingsResponses were obtained from 158 countries. Mean dermatologist density was 2.66 per 100,000, ranging from 0.37 in low-income (LICs) to 5.05 in high-income countries (HICs). There are estimated 175,633 dermatologists globally (95% CI: 173,598-177,668). Forty-two percent of countries reported inadequate or extremely poor access to dermatological care. There was significant variation (p < 0.001) in access to all types of subspecialty care (paediatric, surgical, dermatopathology) across WBI levels, with consistently worse access in lower-income countries. Dermatologists are primarily based in urban centres (79%). Twenty-one percent of countries lack dermatology training programs, with training varying by WBI level (p < 0.001). Non-dermatologist healthcare workers bear a substantial responsibility for management of skin disease. InterpretationSignificant global disparities exist in access to dermatological care, particularly in lower resource settings. Achieving skin health equity will require global commitment to expanding/funding training programmes, incentivizing decentralization of dermatology practice, and optimizing alternative care delivery including upskilling front-line healthcare workers. FundingInternational League of Dermatological Societies and LOreal Dermatological Beauty.

BackgroundMental health risks are high in conflict settings, but mental health research mostly focuses on non-conflict settings. Survey data from active conflict settings often suffer from low response rates, unrepresentative samples, and a lack of detailed information on the roots and implications of poor mental health. We overcome these challenges by analyzing nationally representative evidence on the prevalence, sources, and socio-economic correlates of depression, a highly disabling and costly public health issue, in an active conflict setting. MethodsWe analyze nationally and sub-nationally representative geocoded survey data from the Palestinians Psychological Conditions Survey, collected from 5,877 Palestinian individuals in West Bank and Gaza in 2022. We calculate representative depression statistics, disaggregate by sub-areas and across socio-demographic groups, and estimate the associations with geocoded violent conflict event data as well as survey-based trauma exposure across conflict types and socio-economic outcomes. Findings58 percent (SE=2{middle dot}21) of adults in Palestine exhibit depressive symptoms. Prevalence is highest in Gaza (71 percent, SE=2{middle dot}70), increases with exposure to violent conflict and traumatic events, and is associated with worse socio-economic outcomes. The associated losses for 2022 are equivalent to 732,555 Years Lost in Disability, representing 8{middle dot}9 percent of Palestines GDP. InterpretationThose exposed to violence and traumatic events are disproportionately affected by depression in conflict settings, which may fuel poverty and instability. Scalable investments in mental health in conflict settings promise to not only support well-being but also strengthen productivity and social cohesion for a given level of violence. FundingThe study received funding by the World Banks State and Peace Building Trust Fund.