Accurate rapid diagnostic tests for SARS-CoV-2 infection could help manage the COVID-19 pandemic by potentially increasing access to testing and speed detection of infection, as well as informing clinical and public health management decisions to reduce transmission. Previous iterations of this review provided clear and conclusive evidence of superior test performance in those experiencing possible signs and symptoms of Covid-19. However, test performance in asymptomatic individuals and sensitivity by setting and indication for testing remains unclear. This is the fourth iteration of this review, first published in 2020. To assess the diagnostic accuracy of rapid, point-of-care antigen tests (Ag-RDTs) for diagnosis of SARS-CoV-2 infection in asymptomatic population groups. We searched the COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from MEDLINE and Embase and preprints from medRxiv and bioRxiv) on 17 February 2022. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen tests in asymptomatic people tested because of known or suspected contact with SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included evaluations of single applications of a test (one test result reported per person). Reference standards for presence or absence of infection were any laboratory-based molecular test (primarily reverse transcription polymerase chain reaction (RT-PCR)). We used standard screening procedures with three reviewers. Two reviewers independently carried out quality assessment (using the QUADAS-2 tool) and extracted study results. Other study characteristics were extracted by one review author and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test, and pooled data using the bivariate model. We investigated heterogeneity by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. We included 146 study cohorts (described in 130 study reports). The main results relate to 164 evaluations of single test applications including 144,250 unique samples (7104 with confirmed SARS-CoV-2) obtained from asymptomatic or mainly asymptomatic populations. Studies were mainly conducted in Europe (85/146, 58%), and evaluated 41 different commercial antigen assays (test kit). Only six studies compared two or more brands of test. Nearly all studies (96%) used RT-PCR alone to define presence or absence of infection. Risk of bias was high because of participant selection (13, 9%); interpretation of the index test (3, 2%); weaknesses in the reference standard for absence of infection (3, 2%); and participant flow and timing (46, 32%). Characteristics of participants (11, 8%) and index test delivery (117, 80%) differed from the way in which and in whom the test was intended to be used. Estimates of sensitivity varied considerably between studies, with consistently high specificities. Average sensitivity was 55.0% (95% CI 50.9%, 59.0%) and average specificity was 99.5% (95% CI 99.5%, 99.6%) across the 147 evaluations of Ag-RDTs reporting both sensitivity and specificity (149,251 samples, 7636 cases). Average sensitivity was higher when epidemiological exposure to SARS-CoV-2 was suspected (58.6%, 95% CI 51.4% to 65.5%; 43 evaluations; 15,516 samples, 1483 cases) compared to where COVID-19 testing was reported to be widely available to anyone on presentation for testing (53.0%, 95% CI 48.4% to 57.5%; 103 evaluations; 129,032 samples, 5660 cases); however CIs overlapped, limiting the inference that can be drawn from these data. Average specificity was similarly high for both groups (99.4% and 99.6%). Sensitivity was generally lower when used in a screening context (summary values from 40.6% to 42.1% for three of four screening settings) compared to testing asymptomatic individuals at Covid-19 test centres (56.7%) or emergency departments (54.7%). We observed a decline in summary sensitivities as measures of sample viral load decreased. Sensitivity varied between brands. When tests were used according to manufacturer instructions, average sensitivities by brand ranged from 36.3% to 78.8% in asymptomatic participants (14 assays with sufficient data for pooling). None of the assays met the WHO acceptable performance standard for sensitivity (of 80%) based on meta-analysis; however, sensitivities from individual studies (where meta-analysis was not possible) exceeded 80% for three assays. The WHO acceptable performance criterion of 97% specificity was met by all but four assays (based on individual studies or meta-analysis) when tests were used according to manufacturer instructions. At 0.5% prevalence using summary data for asymptomatic people, where testing was widely available and where epidemiological exposure to COVID-19 was suspected, resulting PPVs would be 40% and 33%, meaning that 3 in 5 or 2 in 3 positive results will be false positives, and between 1 in 2 and 2 in 5 cases will be missed. Evidence for antigen testing in asymptomatic cohorts has increased considerably since the publication of the previous update of this review. Average sensitivities remain lower for testing of asymptomatic when compared to symptomatic individuals; however, there is an indication that sensitivities may be higher where epidemiological exposure to SARS-CoV-2 is suspected compared to testing any asymptomatic individual regardless of indication. Sensitivities were particularly low when antigen tests were used in screening settings. Assays from different manufacturers also vary in sensitivity, indicating the need for appropriate clinical validation of a particular antigen test in a given intended use setting prior to more widespread deployment. Further research is needed to evaluate the effectiveness of screening programmes at reducing transmission of infection, whether mass screening or targeted approaches, including schools, healthcare setting and traveller screening. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Protocol (2020) doi: 10.1002/14651858.CD013596.
Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. Gates Foundation.
To assess the effects of and related evidence certainty of interventions for attention deficit/hyperactivity disorder (ADHD) across an individual's lifespan, and to develop a continuously updated web platform for people with lived experience of ADHD as a method to disseminate living evidence synthesis for shared decision making. Umbrella review and platform for shared decision making. Six databases from inception to 19 January 2025. Study authors were contacted for additional information when necessary. Systematic reviews that used meta-analyses of randomised controlled trials were eligible if they compared a drug or non-drug intervention with a passive control in individuals with a diagnosis of ADHD. Primary outcomes were severity of ADHD symptoms, analysed by rater type (clinician-rated, parent-rated, teacher-rated, or self-rated) and time point (short term (12 weeks, or study endpoint), medium term (26 weeks), and long term (52 weeks)),acceptability (participants dropping out for any reason), and tolerability (participants dropping out owing to any side effects). Secondary outcomes included daily functioning, quality of life, comorbid symptoms, and key side effects (decreased sleep and appetite). Eligible meta-analyses were re-estimated with a standardised statistical approach. Methodological quality was assessed using AMSTAR-2. Evidence certainty was evaluated using an algorithmic version of the GRADE framework, adapted for drug and non-drug interventions. 115 of 414 full text articles were deemed eligible and 299 were excluded; the eligible articles comprised 221 unique combinations of participants, interventions, comparators, and outcomes. For each combination, the most recent and methodologically robust meta-analysis was selected for re-estimation, which gave 221 re-estimated meta-analyses in total, derived from 47 meta-analytic reports. In the short term, alpha-2 agonists, amphetamines, atomoxetine, methylphenidate, and viloxazine showed medium to large effect sizes in reducing the severity of ADHD symptoms in children and adolescents, with moderate to high certainty evidence. Methylphenidate showed consistent benefits across raters (standardised mean difference >0.75, 95% confidence interval (CI) 0.56 to 1.03; moderate or high certainty evidence). These interventions showed lower tolerability than the placebo, but this effect was not significant for methylphenidate and atomoxetine. In adults, atomoxetine, cognitive behavioural therapy, methylphenidate (and, when restricting analyses to high quality trials, amphetamines) showed at least moderate certainty evidence of efficacy on ADHD symptoms, with medium effect sizes. Methylphenidate, amphetamines, and atomoxetine had worse tolerability than placebo (methylphenidate, risk ratio 0.50, 95% CI 0.36 to 0.69; amphetamines, 0.40, 0.22 to 0.72; atomoxetine, 0.45, 0.35 to 0.58). Some non-drug interventions (acupuncture and cognitive behavioural therapy in children and adolescents, and mindfulness in adults) showed large effect sizes for ADHD symptoms, but with low certainty evidence. No high certainty, long term evidence was found for any intervention. An online platform showing effects and evidence certainty of each intervention across age groups, time points, and outcomes (https://ebiadhd-database.org/) was developed. This review provides updated evidence to inform patients, practitioners, and guideline developers how best to manage ADHD symptoms. The online platform should facilitate the implementation of shared decision making in daily practice. Open Science Framework https://osf.io/ugqy6/.
Lower respiratory infections (LRIs) remain the world's leading infectious cause of death. This analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides global, regional, and national estimates of LRI incidence, mortality, and disability-adjusted life-years (DALYs), with attribution to 26 pathogens, including 11 newly modelled pathogens, across 204 countries and territories from 1990 to 2023. With new data and revised modelling techniques, these estimates serve as an update and expansion to GBD 2021. Through these estimates, we also aimed to assess progress towards the 2025 Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) target for pneumonia mortality in children younger than 5 years. Mortality from LRIs, defined as physician-diagnosed pneumonia or bronchiolitis, was estimated using the Cause of Death Ensemble model with data from vital registration, verbal autopsy, surveillance, and minimally invasive tissue sampling. The Bayesian meta-regression tool DisMod-MR 2.1 was used to model overall morbidity due to LRIs. DALYs were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs) for all locations, years, age groups, and sexes. We modelled pathogen-specific case-fatality ratios (CFRs) for each age group and location using splined binomial regression to create internally consistent estimates of incidence and mortality proportions attributable to viral, fungal, parasitic, and bacterial pathogens. Progress was assessed towards the GAPPD target of less than three deaths from pneumonia per 1000 livebirths, which is roughly equivalent to a mortality rate of less than 60 deaths per 100 000 children younger than 5 years. In 2023, LRIs were responsible for 2·50 million (95% uncertainty interval [UI] 2·24-2·81) deaths and 98·7 million (87·7-112) DALYs, with children younger than 5 years and adults aged 70 years and older carrying the highest burden. LRI mortality in children younger than 5 years fell by 33·4% (10·4-47·4) since 2010, with a global mortality rate of 94·8 (75·6-116·4) per 100 000 person-years in 2023. Among adults aged 70 years and older, the burden remained substantial with only marginal declines since 2010. A mortality rate of less than 60 deaths per 100 000 for children younger than 5 years was met by 129 of the 204 modelled countries in 2023. At a super-regional level, sub-Saharan Africa had an aggregate mortality rate in children younger than 5 years (hereafter referred to as under-5 mortality rate) furthest from the GAPPD target. Streptococcus pneumoniae continued to account for the largest number of LRI deaths globally (634 000 [95% UI 565 000-721 000] deaths or 25·3% [24·5-26·1] of all LRI deaths), followed by Staphylococcus aureus (271 000 [243 000-298 000] deaths or 10·9% [10·3-11·3]), and Klebsiella pneumoniae (228 000 [204 000-261 000] deaths or 9·1% [8·8-9·5]). Among pathogens newly modelled in this study, non-tuberculous mycobacteria (responsible for 177 000 [95% UI 155 000-201 000] deaths) and Aspergillus spp (responsible for 67 800 [59 900-75 900] deaths) emerged as important contributors. Altogether, the 11 newly modelled pathogens accounted for approximately 22% of LRI deaths. This comprehensive analysis underscores both the gains achieved through vaccination and the challenges that remain in controlling the LRI burden globally. Furthermore, it demonstrates persistent disparities in disease burden, with the highest mortality rates concentrated in countries in sub-Saharan Africa. Globally, as well as in these high-burden locations, the under-5 LRI mortality rate remains well above the GAPPD target. Progress towards this target requires equitable access to vaccines and preventive therapies-including newer interventions such as respiratory syncytial virus monoclonal antibodies-and health systems capable of early diagnosis and treatment. Expanding surveillance of emerging pathogens, strengthening adult immunisation programmes, and combating vaccine hesitancy are also crucial. As the global population ages, the dual challenge of sustaining gains in child survival while addressing the rising vulnerability in older adults will shape future pneumonia control strategies. Gates Foundation.
Chagas disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, primarily transmitted by infected bugs, but also through contaminated food, transfusions, congenital transmission, and organ transplantation. Chagas disease has acute and chronic phases; the chronic phase can occur decades after infection, leading to complications such as heart failure, arrhythmias, and megaviscera. Accurate mortality and morbidity estimates are hindered by under-reporting and misclassification. Comprehensive and updated estimates are needed to improve global assessments of Chagas disease burden. We aim to provide a comprehensive description of global and regional burden of Chagas disease and its trends from 1990 to 2023. In this systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we produced estimates of Chagas disease deaths, years of life lost (YLLs), prevalence, incidence, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 204 countries and territories from 1990 to 2023 by age and sex. The GBD 2023 estimates supersede previous estimates for all years. For mortality estimates, we fit a cause of death ensemble model to vital registration data. For non-fatal estimates in endemic locations, we did a systematic review of seroprevalence data, defining a confirmed case as a confirmed diagnosis of T cruzi infection by two different positive tests (or a single ELISA or immunochromatographic test). After adjustment for the population at risk, we used a Bayesian compartmental model (DisMod-MR) to produce estimates. For non-endemic locations, we estimated prevalence on the basis of migration patterns and estimated prevalence from endemic countries. Prevalence of acute and chronic sequelae and corresponding disability weights were used to calculate YLDs. We estimated 10·5 million (95% uncertainty interval 9·4-11·7) Chagas disease prevalent cases in 2023 globally, a 16·1% (12·6-19·2) decrease compared with 1990. The global age-standardised Chagas disease prevalence rate declined by 55·0% (53·8-56·1) from 1990 to 2023, with rates decreasing across all endemic regions. The highest age-standardised Chagas disease prevalence rates in 2023 were in southern Latin America (2485·9 [2249·6-2707·7] per 100 000) and Andean Latin America (2313·8 [2093·7-2570·1] per 100 000). Non-endemic regions experienced notable increases in prevalence due to migration from endemic countries. The age distribution of cases shifted over time, peaking at older ages in 2023 (between age 45 years and 65 years) compared with 1990 (30-45 years). In 2023, there were 352 000 (308 000-398 000) new cases of Chagas disease globally, with the age-standardised rate decreasing by 55·1% (53·4-56·6) since 1990. There were 8420 (7480-9360) deaths globally in 2023. Age-standardised mortality decreased by 72·5% (68·9-75·4) globally from 1990 to 2023. In 2023, the highest age-standardised mortality rates were in tropical Latin America (2·2 [1·9-2·4] per 100 000) and Andean Latin America (0·92 [0·70-1·2] per 100 000). The GBD 2023 Chagas disease estimates are notably higher than previous GBD estimates, reflecting additional data and methodological improvements, and those published by the Pan American Health Organization. Nevertheless, these updated estimates show decreasing prevalence and incidence in endemic countries, highlighting the importance of socioeconomic development, housing conditions, and vector-control policies. Conversely, the increase in prevalence in non-endemic countries, mainly due to migration, requires new strategies for screening, early recognition, and access to care. Although the marked decrease in mortality and YLLs might be due to better access to care at different levels, the shift in age distribution highlights the importance of preparing and funding health systems for caring for older populations with advanced sequelae. Finally, the continuous refinement of data-source quality, including adequate coding and classification, is crucial for the accuracy of global estimates, which can ultimately drive health and social policies. The Gates Foundation, the World Heart Federation, and Novartis Pharma.
Capillary blood microsampling enables the sampling of small blood volumes, making it suitable for vulnerable populations, remote collection, and repeated sampling. Owing to its minimal invasiveness, blood microsampling has emerged as an alternative to venipuncture in many fields. However, as capillary blood differs from venous blood in composition and analytes vary in their distribution between the blood cell and plasma fractions, plasma and capillary blood concentrations may differ. Because plasma is often the standard matrix for routine analyses, this discrepancy can compromise the clinicians' interpretation of capillary blood results. Hence, to ensure comparability with results obtained through plasma-based assays and reference ranges, accurate conversion to plasma concentrations may be required, which may improve the reliability and validity of microsampling-based outcomes. Despite its relevance, guidance on whether conversion is appropriate or desired and on how to translate and validate the translation of capillary blood microsampling results to plasma concentrations is lacking. To address this gap, members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) expert committees have prepared this guideline to discuss the "what, when, and how" of converting capillary to plasma concentrations and provide guidance on the decision of fit-for-purpose conversion. In addition, guidance to assess capillary blood results when the reference matrix is whole blood and to assess liquid capillary plasma results is provided. The included topics, as well as considerations and recommendations presented in this guideline, were based on a previously published dried blood spot-based IATDMCT guideline, literature review and expert opinions of the authors. Key points include the importance of conducting a comprehensive clinical validation study to fully understand capillary blood microsampling results. In addition, the performance of the conversion method should be evaluated case by case, as it depends on both the microsampling-based method and analyte of interest. Furthermore, an independent set of paired capillary and venous samples should be used to validate an established conversion formula. Finally, a key point for future studies is to focus on the clinical impact of (converted) capillary blood concentrations in comparison with decisions based on results in the reference matrix to guarantee any microsampling-based outcome.
Molecular diagnostics in Low- and Middle-Income Countries (LMICs) face significant barriers: limited expertise, geographical access, and infrastructure. These impede effective disease management and public health. Traditional workflows lack scalability and objectivity. This review explores how Digital Pathology (DP) and Artificial Intelligence (AI) can enhance LMIC molecular diagnostics. DP, via whole slide imaging, enables remote expert consultation and quality control. AI integration automates quantitative analysis (e.g. cell counting, biomarker scoring), facilitating rapid interpretation and extending specialized diagnostic reach. We discuss successful telepathology pilots and their cost-effectiveness. The manuscript highlights DP/AI's capacity to bolster molecular screening and accelerate research, while addressing implementation barriers: infrastructure, cost, training, and regulation. Strategic integration of Digital Pathology (DP) and Artificial Intelligence (AI) offers an unparalleled opportunity to transform molecular diagnostics in LMICs. By providing scalable, objective, and accessible capabilities, these technologies can significantly improve public health outcomes and medical research. However, successful adoption demands targeted investment in digital infrastructure, capacity building, robust ethics, and public-private partnerships. Prioritizing direct clinical utility and molecular diagnostic applications is key to sustainable implementation and equitable access to advanced diagnostics.
People with mental disorders have an increased risk of diabetes, yet conflicting evidence exists regarding the quality of diabetes care they receive. To address this evidence gap, we conducted a systematic review and meta-analysis to assess and compare diabetes quality of care in people with diabetes with mental disorders versus people with diabetes without mental disorders. In this systematic review and random-effects meta-analysis, we searched Scopus, Embase, MEDLINE, and PsycINFO for cohort and case-control studies published between database inception and Feb 8, 2025. We estimated summary odds ratios (ORs) for diabetes quality of care indicators in individuals with any mental disorder versus without mental disorders to investigate the association between the presence of a mental disorder and diabetes quality of care indicators, including overall diabetes monitoring and treatment. Studies were excluded if it was not possible to generate pooled quantitative data. The primary outcome was a binary composite measure of diabetes quality of care, meaning the percentage of people receiving any diabetes monitoring and treatment (ie, urine albumin-creatinine ratio test, HbA1c test, blood pressure measured, foot surveillance, serum creatinine test, serum cholesterol test, BMI recorded, smoking status recorded, retinal monitoring). Secondary outcomes were study-specific diabetes quality of care individual indicators matched to the nine NICE diabetes monitoring indicators and specific diabetes interventions and anti-diabetes medications. We analysed primary and secondary outcomes according to any mental disorder and to specific diagnostic subgroups. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS). Data from 49 studies (42 cohort and seven case-control) were included, comprising 5 503 712 individuals with diabetes, of whom 838 366 (15·2%) had a diagnosed mental disorder (defined using ICD-9 or ICD-10 criteria in 40 studies). Sex was reported in 35 of 49 studies, comprising 4 250 666 individuals, 1 956 506 (46·0%) of whom were female and 2 294 160 (54·0%) were male. The mean age was 61·4 years (SD 8·7; range 47-82 years). 38 studies reported on various mental disorders, 21 on mood disorders spectrum, 21 on major depressive disorder, 20 on schizophrenia, 11 on bipolar disorder, 11 on substance use disorder spectrum, including alcohol use disorder, six on dementia, five on anxiety disorder spectrum, and one on personality disorder spectrum. Most studies were high quality and spanned Asia, North America, Europe, and Australasia. Significant negative associations were observed between having any mental disorder and the likelihood of receiving any recommended diabetes monitoring (29 studies, OR=0·81 [95% CI 0·70-0·94], p=0·0049). Negative associations were also observed for HbA1c measurement (24 studies, 0·81 [0·68-0·97], p=0·024), retinal screening (21 studies, 0·77 [0·63-0·95], p=0·013), lipid and cholesterol measurement (20 studies, 0·83 [0·69-0·99], p=0·043), foot examination (11 studies, 0·85 [0·76-0·95], p=0·0044), and renal investigation (16 studies, 0·78 [0·63-0·96], p=0·022). A significant positive association was found between any mental disorder and recorded smoking status (two studies, 1·09 [1·02-1·17]; p=0·0076). Any mental disorder was significantly associated with higher odds of receiving insulin (ten studies, 1·52 [95% CI 1·16-1·99]; p=0·0022), but negatively associated with treatment with a GLP-1 receptor agonist (two studies, 0·26 [0·13-0·49]; p<0·0001). There was no evidence of publication bias. Mental disorders are negatively associated with receiving adequate diabetes monitoring and GLP-1 agonist therapy. Addressing these disparities has the potential to address the increased mortality associated with mental disorders. None.
Infections caused by different Leishmania species are considered as neglected diseases and are prevalent in many tropical and temperate regions worldwide. Extracellular vehicles (EVs) transport different nanoparticles for extracellular medium as enzymes, proteins, lipids, nucleic acids and others for cellular metabolic activities. However, the precise role of EVs in infections caused by Leishmania species is not totally established. This article revised the significance of EVs in pathogenesis, diagnosis and treatment strategies for the different forms of leishmaniasis. EVs of Leishmania spp. may be considered as potential drug targets in treatment, as they can encapsulate small molecules or drugs for more effective delivery to specific cells or tissues. The perspectives on EVs research in Leishmania facilitate the understanding of the role of these nanoparticles in parasite-host interactions and the development of diagnostic and therapeutic strategies, as vaccine development, and enhancing drug delivery systems. The knowledge of the participation of EVs in Leishmania species offers opportunities to further our understanding in pathogenesis and in the development of innovative diagnostic tools and treatments and to explore new approaches to disease.
Since 1993, when a polymorphic CAG trinucleotide repeat was established as the cause of Huntington's disease (HD), fragment analysis has been the first-tier test in genetic diagnosis of HD. However, in recent years it has become increasingly clear that, in addition to the repeat length itself, sequence variations within the HTT repeat and elsewhere in the genome also play a crucial role in the onset and clinical presentation of the disease. Sequence interruptions or non-canonical repeat motifs have historically been difficult to identify, as PCR cannot distinguish an interrupted repeat tract when assessed by capillary electrophoresis. However, these non-canonical interruptions may directly affect the phenotype or result in an underestimation of the uninterrupted CAG repeat length. While next-generation sequencing (NGS) with short read lengths has revolutionized genetic diagnostics, it faces limitations in diagnosing repeat expansion diseases. The literature search methodology involved a review of relevant studies and clinical data. In contrast, long-read sequencing (LRS) generates read lengths of over 10 kb and can thus overcome the limitations associated with short reads. This enables detailed investigation of repeat sequences and the identification of complex patterns of alternating sequence motifs, potentially providing additional clinically relevant information.
Despite a combined approach to manage malignant brain tumors (including glioblastoma), which includes surgical removal of the tumor followed by cycles of radiotherapy and chemotherapy, patient survival remains extremely low. Advances in nanotechnology in recent decades offer hope for the use of nanoscale agents for the successful diagnosis and treatment of brain tumors. This review analyzes the results of preclinical and clinical studies of nanoparticles of various physico-chemical compositions (e.g. SPIONs, AuNPs, QDs, etc) in the diagnosis and therapy (theranostics) of brain tumors. Particular attention is paid to the challenges of targeted drug delivery, antitumor activity, and future development strategies in this field. Nanoscale agents of diverse physicochemical compositions have demonstrated transformative potential in the diagnosis and treatment of brain tumors, bridging the gap between bench research and clinical application. By enabling precise imaging, targeted delivery, and real-time therapeutic monitoring, nanotechnology offers a multifaceted platform for advancing personalized neuro-oncology. Further interdisciplinary research, standardization of preclinical protocols, and carefully designed clinical trials will be vital in translating these advances into tangible clinical benefits. Nanoparticle-based theranostics are poised to redefine the therapeutic landscape of brain tumors moving from broad cytotoxicity toward targeted, adaptive, and patient-centered treatment paradigms.
Prostate cancer diagnosis and treatment planning depend on accurate histopathological assessment of needle biopsies, particularly through the Gleason scoring system. The inherently subjective nature of the grading creates variability between pathologists, potentially resulting in suboptimal patient management decisions. These reproducibility challenges extend beyond Gleason scoring to encompass other critical diagnostic and prognostic markers, including cancer volume quantification and detection of cribriform morphology patterns and perineural invasion. Artificial intelligence (AI) applications in digital pathology have emerged as promising solutions for enhancing diagnostic consistency and accuracy, with recent research demonstrating that automated systems can match expert-level performance in prostate biopsy evaluation. Nevertheless, comprehensive validation studies have revealed concerning limitations in model generalisability when deployed across different clinical environments and patient populations. Recent systematic reviews revealed widespread risk-of-bias limitations and insufficient external validation in AI diagnostic studies, highlighting critical needs for accumulated evidence supporting generalisability before clinical implementation. Rigorous external validation with preregistered protocols using independent datasets from diverse clinical settings remains essential to establish the reliability and safety of AI-assisted prostate pathology systems. This study protocol establishes a framework for the retrospective external validation of an AI system developed for prostate biopsy assessment, to be conducted on the case-control samples of the National Prostate Cancer Register of Sweden, ProMort study (1998-2015). The primary aim is to evaluate the AI model's diagnostic accuracy and Gleason grading performance using completely independent datasets separate from any model development or previously used validation cohorts. The diversity of the validation samples, spanning multiple geographic regions, temporal collection periods and reference standards, allows evaluation of model robustness across varied clinical contexts. Secondary aims encompass evaluating AI performance in cancer length estimation and detection of cribriform patterns and perineural invasion. This protocol delineates procedures for data collection, reference standard clarification and prespecified statistical analyses, ensuring comprehensive validation and reliable performance assessment. The study design conforms to established reporting guidelines Checklist for Artificial Intelligence in Medical Imaging (CLAIM) and Standards for Reporting Diagnostic Accuracy Studies using Artificial Intelligence (STARD-AI), and recognised best practices for AI validation in medical imaging. Data collection and usage were approved by the Swedish Regional Ethics Review Board and the Swedish Ethical Review Authority (permits 2012/1586-31/1, 2016/613-31/2, 2019-01395, 2019-05220). The study adheres to the Declaration of Helsinki principles, and findings will be made available in open access peer-reviewed publications.
Pythium insidiosum keratitis (PIK) is a rapidly progressive, aggressive corneal infection that closely mimics fungal keratitis but fails to respond to conventional antifungal therapy. Misdiagnosis and delayed intervention frequently result in poor outcomes, including high rates of therapeutic keratoplasty and irreversible vision loss. Timely and accurate identification is therefore vital, yet conventional microbiological methods are slow, and histopathology is invasive and often inconclusive. Recent advances in imaging, molecular diagnostics, and biosensor technology are revolutionizing diagnostic possibilities. Modern tools such as anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy(IVCM) permit rapid, noninvasive visualization of characteristic stromal patterns. Molecular platforms, including PCR, loop-mediated isothermal amplification (LAMP), recombinase polymerase amplification (RPA), and multiplex panels, provide precise results within hours. Innovative lateral flow immunoassays (LFIA), aptamer-based electrochemical biosensors, and artificial intelligence (AI)-assisted image interpretation expand point-of-care capabilities, while metagenomic sequencing aids in culture-negative cases. The integration of imaging, molecular, and biosensor modalities marks a paradigm shift in PIK diagnostics. PortableAS-OCT, handheld IVCM, and rapid multiplex panels promise to reduce diagnostic delay, minimize unnecessary antifungal use, lower keratoplasty rates, and improve visual prognosis. Collaborative validation and affordable access remain essential for global impact.
Sepsis, a life-threatening condition characterized by dysregulated host immune and metabolic responses to infection, is associated with high mortality, making accurate diagnosis and targeted treatment crucial. Sepsis often induces a notable reduction in serum high-density lipoprotein (HDL) levels. As the fundamental structural and functional components of HDL, apolipoproteins play pivotal roles in mediating the function of HDL. Therefore, these apolipoproteins can serve as potential biomarkers in sepsis. This review systematically synthesizes current evidence on the dynamic expression profiles of these apolipoproteins in sepsis, highlighting the relation of their single nucleotide polymorphisms (SNPs) with sepsis and clinical relevance in diagnosis and prognosis. Furthermore, it also summarizes the underlying mechanisms by which these apolipoproteins are involved in the progression of sepsis. The changes in the levels of HDL-associated apolipoproteins can characterize the progression of sepsis and the type of infecting bacteria, and provide therapeutic targets for the treatment of sepsis. Therefore, the comprehensive understanding of their integrated effects holds promise for developing precision interventions to improve clinical outcomes of sepsis.
Lung cancer is the most frequently diagnosed cancer worldwide and the leading cause of cancer-related mortality. Cell-free DNA (cfDNA) has emerged as a powerful biomarker in cancer detection. Early diagnostics efforts often leverage cancer-associated mutations present in cfDNA, but beyond such mutation-based assays, recent advances have shed light on other non-mutational features. The analysis of cfDNA epigenetic profiles and fragmentation patterns, known as 'fragmentomics,' has revealed a wealth of data to explore in noninvasive lung cancer diagnosis. This review will explore this new narrative, summarizing the current understanding and use of cfDNA epigenetic modifications and fragmentomic patterns, while integrating findings to illustrate their vast potential in early-stage detection and therapeutics. By considering a range of epigenetic and fragmentomic features, cfDNA methylation (5mC, 5hmC), histone modifications, size profiles, and end signatures, this review highlights how the multidimensional integration of such signals shows promise in refining early-stage lung cancer and guiding therapeutic decisions. cfDNA epigenetic and fragmentomic analyses represent a transformative frontier in lung cancer diagnostics and monitoring. While these approaches demonstrate significant potential, most studies are limited by modest cohort sizes and reports of survival benefits, underscoring the need for large-scale validation and deeper mechanistic understanding.
Child growth failure (CGF), which includes underweight, wasting, and stunting, is among the factors most strongly associated with mortality and morbidity in children younger than 5 years worldwide. Poor height and bodyweight gain arise from a variety of biological and sociodemographic factors and are associated with increased vulnerability to infectious diseases. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 to estimate CGF prevalence, the risk of infectious diseases associated with CGF, and the disease mortality, morbidity, and overall burden associated with CGF. In this analysis we estimated the all-cause and cause-specific (diarrhoea, lower respiratory tract infections, malaria, and measles) disability-adjusted life-years (DALYs) lost and mortality associated with stunting, wasting, underweight, and CGF in aggregate. We combined the burden associated with mild, moderate, and severe forms of CGF: stunting was defined as height-for-age Z scores (HAZ) less than -1, underweight was defined as weight-for-age Z scores (WAZ) less than -1, and wasting was defined as weight-for-height Z scores (WHZ) less than -1, according to WHO Child Growth Standards. Population-level continuous distributions of HAZ, WAZ, and WHZ were estimated for 2000 to 2023 using data from surveys, literature, and individual-level study data. The risk of incidence of, and mortality due to, diarrhoea, lower respiratory infections, malaria, and measles was separately estimated in a meta-regression framework from longitudinal cohort data for Z scores less than -1. Finally, fatal outcomes associated with these diseases were estimated with vital registration, verbal autopsy, and case-fatality data, while non-fatal outcomes were estimated with surveys as well as health-care utilisation and case reporting data. The exposure prevalence and relative risk estimates were from continuous distributions, allowing for direct assessment of the attributable fractions for mild, moderate, and severe stunting, underweight, wasting, and the combined impact of child growth failure within populations. All estimates were age-specific, sex-specific, geography-specific, and year-specific. We estimated that, in children younger than 5 years in 2023, CGF was associated with 79·4 million (95% uncertainty interval [UI] 47·0-106) DALYs lost and 880 000 (517 000-1 170 000) deaths. This represented 17·9% (10·6-23·8) of 444 million (434-457) total under-5 DALYs and 18·8% (11·1-25·0) of all 4·67 million (4·59-4·75) under-5 deaths. Compared to stunting (33·0 million [24·1-42·2] DALYs, 373 000 [272 000-477 000] deaths) and wasting (39·2 million [23·8-53·0] DALYs, 428 000 [256 000-583 000] deaths), childhood underweight was associated with the largest share of CGF-related disease burden: 52·2 million (21·9-75·1) DALYs and 573 000 (236 000-824 000) deaths in children younger than 5 years in 2023. CGF remains a leading factor associated with death and disability in children younger than 5 years, despite global attention and focused interventions to reduce the prevalence of associated CGF indicators. Our findings underscore the need for policies, strategies, and interventions that focus on all indicators of CGF to reduce its associated health burden. Gates Foundation.
Early diagnosis and treatment initiation are essential to prevent ongoing tuberculosis (TB) transmission and reduce the disease burden. Smear microscopy, which is widely used test for diagnosis, has limited sensitivity and does not detect rifampicin resistance. Truenat is a portable, battery-operated, chip-based test that can be placed in peripheral laboratories, serving as a point-of-care test. It also detects rifampicin resistance, which is crucial in the management of TB. Our review comprehensively covers the functionality and workflow of the Truenat MTB assay, in addition to its cost-effectiveness and diagnostic accuracy, based on recent evidence. We also discuss the merits and drawbacks of alternative diagnostic tests available for detecting TB and rifampicin resistance. Truenat assays are rapid molecular tests that revolutionized TB diagnosis, moving toward peripheral testing. Evidence indicates that the Truenat MTB Plus performs better than the original Truenat MTB, with an approximate LOD of 30 CFU/ml. The 2025 WHO guidelines rely exclusively on data from Truenat MTB Plus. We need larger studies on the newer Truenat MTB Ultima to evaluate its performance on tongue swabs. Additionally, data on the accuracy of Truenat MTB in children remains scarce, emphasizing the importance of further research in this group. Evidence regarding its accuracy in detecting rifampicin resistance is also limited, requiring larger studies and technological advancements. Truenat MTB will remain crucial in the fight to eliminate TB in the future. Early diagnosis of tuberculosis (TB) is essential to stop its spread, prevent drug resistance, and reduce deaths and disabilities due to TB. Truenat assays are molecular tests that can detect the bacterial DNA and resistance to rifampicin – a key first-line TB drug within few hours. Truenat devices are portable and battery-operated. They use chip-based PCR technology to amplify the bacterial DNA into million folds and target specific genes like nrdB (MTB assay), nrdz, and IS6110 (MTB Plus assay), IS1081 (Truenat MTB Ultima assay) to detect TB and rpoB (MTB-RIF Dx reflex assay) to detect rifampicin resistance. Unlike other molecular tests like Xpert, Truenat can operate in environments up to 40°C and 80% humidity. This makes it ideal for use in rural or resource-limited settings, eliminating the need for transport of samples to air-conditioned labs. Among 100 adults tested with Truenat MTB, it accurately rules out 87 people without TB and detects 86 people with TB. Truenat MTB Plus performs better than Truenat MTB. More research is needed on its use in children and for detecting drug resistance. The World Health Organization (WHO) recommends Truenat as an initial test for TB, expanding its utility to improve TB diagnosis worldwide.
The global burden of sepsis, a life-threatening dysregulated host response to infection leading to organ dysfunction, remains challenging to quantify. We aimed to comprehensively estimate the global, regional, and national burden of sepsis, including the impact of the COVID-19 pandemic and underlying causes of sepsis-related deaths with co-occurring infectious syndromes. We used multiple cause-of-death, hospital, minimally invasive tissue sampling, and linked death certificate and hospital record data representing 149 million deaths, covering 4290 location-years with mortality estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 to capture explicit and implicit sepsis cases and deaths. We estimated age-location-sex-specific fractions of sepsis-related deaths from 195 underlying causes of death and 22 infectious syndromes from 1990 to 2021 using binomial logistic regression models, and estimated sepsis-related deaths using GBD cause-specific mortality estimates. Using 250 million hospital admissions and 7·82 million deaths from hospital data, representing 1310 location-years, we modelled case fatality rates by use of binomial logistic regression, applied to sepsis death estimates to estimate sepsis incidence by age, location, and year. In 2021, we estimated 166 million (95% uncertainty interval 135-201) sepsis cases and 21·4 million (20·3-22·5) all-cause sepsis-related deaths globally, representing 31·5% of total global deaths. Sepsis-related deaths decreased between 1990 and 2019, followed by a surge in 2020 and 2021. As of 2021, individuals aged 15 years and older experienced increases across incidence (230%) and mortality (26·3%) since 1990. Those aged 70 years and older had the highest sepsis-related mortality in 2021 (9·28 million [8·74-9·86] deaths). Sepsis-related deaths from infectious underlying causes decreased from 11·8 million (11·1-12·5) in 1990 to 8·34 million (7·72-9·01) in 2019, then increased by 86·4% to 15·5 million (14·7-16·4) in 2021. Sepsis-related mortality due to non-infectious underlying causes of death increased from 4·69 million (4·35-5·05) in 1990 to 5·81 million (5·40-6·25) in 2021; the leading non-infectious underlying causes of death with sepsis were stroke, chronic obstructive pulmonary disease, and cirrhosis. In 2021, bloodstream infections inclusive of HIV and malaria (3·08 million [2·83-3·35]) and lower respiratory infections inclusive of COVID-19 (11·33 million [1·20-1·47]) were the most prominent infectious syndromes complicating sepsis-related deaths from non-infectious underlying causes, representing a consistent trend since 1990. The global burden of sepsis increased in 2020 and 2021, reversing progress from 1990. Sepsis incidence and mortality increased in people aged 15 years and older, especially those aged 70 years and older, and as a complication of non-infectious underlying causes of death such as stroke, primarily through bloodstream infections and lower respiratory infections. The global burden of sepsis is substantial, and sepsis is increasingly a complication of non-infectious causes of death. Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.
The CRISPR/Cas system has emerged as a highly versatile platform for diagnosing infectious diseases, particularly viral pathogens. Human papillomavirus (HPV) comprises of more than 200 types, with persistent infection by 14 high-risk genotypes recognized as the primary cause of cervical cancer worldwide. Early and accurate detection of these High-Risk HPV (HR-HPV) types is essential for effective clinical management and prevention of disease progression. This narrative review was based on literature searches in PubMed, Scopus, and Google Scholar covering studies published between 2015 and 2024. This review summarizes recent advances in CRISPR/Cas based diagnostics for HR-HPV, including both pre-amplification and amplification-free strategies. Integration of CRISPR systems with diverse readout modalities such as colorimetric, fluorescent, electrochemical, and lateral-flow biosensors has enabled rapid, sensitive, and user-friendly detection suitable for point-of-care testing (POCT), particularly in low-resource settings. CRISPR/Cas assays demonstrate high sensitivity, specificity, and speed, offering a promising alternative to conventional molecular techniques for HR-HPV detection and genotyping. The convergence of CRISPR diagnostics with artificial intelligence, microfluidics, and affordable biosensors holds significant potential to transform community-level HPV screening. With continued innovation and regulatory support, CRISPR/Cas systems are poised to become indispensable tools for early HR-HPV detection and cervical cancer prevention.
Chronic kidney disease (CKD) is common and ranks among the leading causes of mortality and morbidity. This analysis aimed to present global CKD estimates using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 to inform evidence-based policies for CKD identification and treatment. This analysis focused on adults aged 20 years and older over the period 1990 to 2023, from 204 countries and territories. Data sources used were published literature, vital registration systems, kidney failure treatment registries, and household surveys. Estimates of CKD burden, including deaths, incidence, prevalence, and disability-adjusted life-years (DALYs), were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool. A comparative risk assessment approach estimated the proportion of cardiovascular deaths attributable to impaired kidney function and estimated risk factors for CKD. Globally, in 2023, 788 million (95% uncertainty interval 743-843) people aged 20 years and older were estimated to have CKD, up from 378 million (354-407) in 1990. The global age-standardised prevalence of CKD in adults was 14·2% (13·4-15·2), a relative rise of 3·5% (2·7-4·1) from 1990. The region with the highest age-standardised prevalence was north Africa and the Middle East (18·0%; 16·9-19·4). Most people had stage 1-3 CKD, with a combined prevalence of 13·9% (13·1-15·0). In 2023, CKD was the ninth leading cause of death globally, accounting for 1·48 million (1·30-1·65) deaths, and the 12th leading cause of DALYs, with an age-standardised DALY rate of 769·2 (691·8-857·4) per 100 000. Impaired kidney function as a risk factor accounted for 11·5% (8·4-14·5) of cardiovascular deaths. High fasting plasma glucose, body-mass index, and systolic blood pressure were all leading risk factors for CKD DALYs. CKD is a major global health issue, with rising prevalence and increasing importance as a cause of death and as a risk factor for cardiovascular death. A better understating of aetiology, appropriate screening, and implementation programmes are needed to translate advances in CKD treatment into improved patient outcomes. Gates Foundation, Wellcome, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.