A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders.

The emergence of adeno-associated virus (AAV)-based gene therapy has brought hope to patients with severe monogenic disorders. However, immune responses to AAV vectors and transgene products present challenges that require effective immunosuppressive strategies. This systematic review focuses on the immunosuppressive protocols used in 38 clinical trials and 35 real-world studies, considering a range of monogenic diseases, AAV serotypes, and administration routes. The review underscores the need for a deeper understanding of immunosuppressive regimens to enhance the safety and effectiveness of AAV-based gene therapy. Characterizing the immunological responses associated with various gene therapy treatments is crucial for optimizing treatment protocols and ensuring the safety and efficacy of forthcoming gene therapy interventions. Further research and understanding of the impact of immunosuppression on disease, therapy, and route of administration will contribute to the development of more effective and safer gene therapy approaches in the future.

ERS Statement on Benign Pleural Effusions in Adults.

The incidence of non-malignant pleural effusions (NMPE) far outweighs that of malignant pleural effusions (MPE) and is estimated to be at least 3-fold higher. These so called "benign" effusions do not follow a "benign course" in many cases, with mortality rates matching and sometimes exceeding that of MPEs. In addition to the impact on patients, healthcare systems are significantly affected, with recent US epidemiological data demonstrating that 75% of resource allocation for pleural effusion management is spent on NMPEs (excluding empyema). Despite this significant burden of disease, and by existing at the junction of multiple medical specialties, reflecting a heterogenous constellation of medical conditions, NMPEs are rarely the focus of research or the subject of management guidelines. With this ERS Taskforce, we assembled a multi-specialty collaborative across eleven countries and three continents to provide a Statement based on systematic searches of the medical literature to highlight evidence in the management of the following clinical areas: a diagnostic approach to transudative effusions, heart failure, hepatic hydrothorax, end stage renal failure, benign asbestos related pleural effusion, post-surgical effusion and non-specific pleuritis.

Effect of mindfulness-based programmes on elite athlete mental health: a systematic review and meta-analysis.

OBJECTIVE: To determine the effectiveness of mindfulness-based programmes (MBPs) on the mental health of elite athletes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Eight online databases (Embase, PsycINFO, SPORTDiscus, MEDLINE, Scopus, Cochrane CENTRAL, ProQuest Dissertations & Theses and Google Scholar), plus forward and backward searching from included studies and previous systematic reviews. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they were randomised controlled trials (RCTs) that compared an MBP against a control, in current or former elite athletes. RESULTS: Of 2386 articles identified, 12 RCTs were included in this systematic review and meta-analysis, comprising a total of 614 elite athletes (314 MBPs and 300 controls). Overall, MBPs improved mental health, with large significant pooled effect sizes for reducing symptoms of anxiety (hedges g=-0.87, number of studies (n)=6, p=0.017, I 2=90) and stress (g=-0.91, n=5, p=0.012, I 2=74) and increasing psychological well-being (g=0.96, n=5, p=0.039., I 2=89). Overall, the risk of bias and certainty of evidence was moderate, and all findings were subject to high estimated levels of heterogeneity. CONCLUSION: MBPs improved several mental health outcomes. Given the moderate degree of evidence, high-quality, adequately powered trials are required in the future. These studies should emphasise intervention fidelity, teacher competence and scalability within elite sport. PROSPERO REGISTRATION NUMBER: CRD42020176654.

Preparing for pandemics: a systematic review of pandemic influenza clinical management guidelines.

BACKGROUND: The COVID-19 pandemic has highlighted the importance of evidence-based clinical decision-making. Clinical management guidelines (CMGs) may help reduce morbidity and mortality by improving the quality of clinical decisions. This systematic review aims to evaluate the availability, inclusivity, and quality of pandemic influenza CMGs, to identify gaps that can be addressed to strengthen pandemic preparedness in this area. METHODS: Ovid Medline, Ovid Embase, TRIP (Turning Research Into Practice), and Guideline Central were searched systematically from January 2008 to 23rd June 2022, complemented by a grey literature search till 16th June 2022. Pandemic influenza CMGs including supportive care or empirical treatment recommendations were included. Two reviewers independently extracted data from the included studies and assessed their quality using AGREE II (Appraisal of Guidelines for Research & Evaluation). The findings are presented narratively. RESULTS: Forty-eight CMGs were included. They were produced in high- (42%, 20/48), upper-middle- (40%, 19/48), and lower-middle (8%, 4/48) income countries, or by international organisations (10%, 5/48). Most CMGs (81%, 39/48) were over 5 years old. Guidelines included treatment recommendations for children (75%, 36/48), pregnant women (54%, 26/48), people with immunosuppression (33%, 16/48), and older adults (29%, 14/48). Many CMGs were of low quality (median overall score: 3 out of 7 (range 1-7). All recommended oseltamivir; recommendations for other neuraminidase inhibitors and supportive care were limited and at times contradictory. Only 56% (27/48) and 27% (13/48) addressed oxygen and fluid therapy, respectively. CONCLUSIONS: Our data highlights the limited availability of up-to-date pandemic influenza CMGs globally. Of those identified, many were limited in scope and quality and several lacked recommendations for specific at-risk populations. Recommendations on supportive care, the mainstay of treatment, were limited and heterogeneous. The most recent guideline highlighted that the evidence-base to support antiviral treatment recommendations is still limited. There is an urgent need for trials into treatment and supportive care strategies including for different risk populations. New evidence should be incorporated into globally accessible guidelines, to benefit patient outcomes. A 'living guideline' framework is recommended and further research into guideline implementation in different resourced settings, particularly low- and middle-income countries.

Bipolar disorder: Trimodal age-at-onset distribution.

OBJECTIVE: Bipolar disorder (BD) is a chronic mental health disorder with significant morbidity and mortality. Age at onset (AAO) may be a key variable in delineating more homogeneous subgroups of BD patients. However, no known research has systematically assessed how BD age-at-onset subgroups should be defined. METHODS: We systematically searched the following databases: Cochrane Central Register of Controlled Trials, PsycINFO, MEDLINE, Embase, CINAHL, Scopus, Proquest Dissertations and Theses, Google Scholar and BIOSIS Previews. Original quantitative English language studies investigating AAO in BD were sought. RESULTS: A total of 9454 unique publications were identified. Twenty-one of these were included in data analysis (n = 22981 BD participants). Fourteen of these studies (67%, n = 13626 participants) found a trimodal AAO distribution: early-onset (µ = 17.3, σ = 1.19, 45% of sample), mid-onset (µ = 26.0, σ = 1.72, 35%), and late-onset (µ = 41.9, σ = 6.16, 20%). Five studies (24%, n = 1422 participants) described a bimodal AAO distribution: early-onset (µ = 24.3, σ = 6.57, 66% of sample) and late-onset (µ = 46.3, σ = 14.15, 34%). Two studies investigated cohort effects on BD AAO and found that when the sample was not split by cohort, a trimodal AAO was the winning model, but when separated by cohort a bimodal distribution fit the data better. CONCLUSIONS: We propose that the field conceptualises bipolar disorder age-at-onset subgroups as referring broadly to life stages. Demarcating BD AAO groups can inform treatment and provide a framework for future research to continue to investigate potential mechanisms of disease onset.

Pharmacological strategies used to manage symptoms of patients dying of COVID-19: A rapid systematic review.

BACKGROUND: COVID-19 has tragically resulted in over 2.5 million deaths globally. Despite this, there is a lack of research on how to care for patients dying of COVID-19, specifically pharmacological management of symptoms. AIM: The aim was to determine the dose ranges of pharmacological interventions commonly used to manage symptoms in adult patients dying of COVID-19, establish how effectiveness of these interventions was measured, and whether the pharmacological interventions were effective. DESIGN: This was a rapid systematic review with narrative synthesis of evidence, prospectively registered on PROSPERO (ID: CRD42020210892). DATA SOURCES: We searched MEDLINE, EMBASE, CINAHL via the NICE Evidence Health Databases Advanced Search interface; medRxiv; the Cochrane COVID-19 Study Register; and Google Scholar with no date limits. We included primary studies which documented care of patients dying of COVID-19 under the care of a specialist palliative care team. RESULTS: Seven studies, documenting the care of 493 patients met the inclusion criteria. Approximately two thirds of patients required a continuous subcutaneous infusion with median doses of 15 mg morphine and 10 mg midazolam in the last 24 h of life. Four studies described effectiveness by retrospective review of documentation. One study detailed the effectiveness of individual medications. CONCLUSIONS: A higher proportion of patients required continuous subcutaneous infusion than is typically encountered in palliative care. Doses of medications required to manage symptoms were generally modest. There was no evidence of a standardised yet holistic approach to measure effectiveness of these medications and this needs to be urgently addressed.

Addressing challenges for clinical research responses to emerging epidemics and pandemics: a scoping review.

BACKGROUND: Major infectious disease outbreaks are a constant threat to human health. Clinical research responses to outbreaks generate evidence to improve outcomes and outbreak control. Experiences from previous epidemics have identified multiple challenges to undertaking timely clinical research responses. This scoping review is a systematic appraisal of political, economic, administrative, regulatory, logistical, ethical and social (PEARLES) challenges to clinical research responses to emergency epidemics and solutions identified to address these. METHODS: A scoping review. We searched six databases (MEDLINE, Embase, Global Health, PsycINFO, Scopus and Epistemonikos) for articles published from 2008 to July 2018. We included publications reporting PEARLES challenges to clinical research responses to emerging epidemics and pandemics and solutions identified to address these. Two reviewers screened articles for inclusion, extracted and analysed the data. RESULTS: Of 2678 articles screened, 76 were included. Most presented data relating to the 2014-2016 Ebola virus outbreak or the H1N1 outbreak in 2009. The articles related to clinical research responses in Africa (n = 37), Europe (n = 8), North America (n = 5), Latin America and the Caribbean (n = 3) and Asia (n = 1) and/or globally (n = 22). A wide range of solutions to PEARLES challenges was presented, including a need to strengthen global collaborations and coordination at all levels and develop pre-approved protocols and equitable frameworks, protocols and standards for emergencies. Clinical trial networks and expedited funding and approvals were some solutions implemented. National ownership and community engagement from the outset were a key enabler for delivery. Despite the wide range of recommended solutions, none had been formally evaluated. CONCLUSIONS: To strengthen global preparedness and response to the COVID-19 pandemic and future epidemics, identified solutions for rapid clinical research deployment, delivery, and dissemination must be implemented. Improvements are urgently needed to strengthen collaborations, funding mechanisms, global and national research capacity and capability, targeting regions vulnerable to epidemics and pandemics. Solutions need to be flexible to allow timely adaptations to context, and research led by governments of affected regions. Research communities globally need to evaluate their activities and incorporate lessons learnt to refine and rehearse collaborative outbreak response plans in between epidemics.

Drug-resistant enteric fever worldwide, 1990 to 2018: a systematic review and meta-analysis.

BACKGROUND: Antimicrobial resistance (AMR) is an increasing threat to global health. There are > 14 million cases of enteric fever every year and > 135,000 deaths. The disease is primarily controlled by antimicrobial treatment, but this is becoming increasingly difficult due to AMR. Our objectives were to assess the prevalence and geographic distribution of AMR in Salmonella enterica serovars Typhi and Paratyphi A infections globally, to evaluate the extent of the problem, and to facilitate the creation of geospatial maps of AMR prevalence to help targeted public health intervention. METHODS: We performed a systematic review of the literature by searching seven databases for studies published between 1990 and 2018. We recategorised isolates to allow the analysis of fluoroquinolone resistance trends over the study period. The prevalence of multidrug resistance (MDR) and fluoroquinolone non-susceptibility (FQNS) in individual studies was illustrated by forest plots, and a random effects meta-analysis was performed, stratified by Global Burden of Disease (GBD) region and 5-year time period. Heterogeneity was assessed using the I2 statistics. We present a descriptive analysis of ceftriaxone and azithromycin resistance. FINDINGS: We identified 4557 articles, of which 384, comprising 124,347 isolates (94,616 S. Typhi and 29,731 S. Paratyphi A) met the pre-specified inclusion criteria. The majority (276/384; 72%) of studies were from South Asia; 40 (10%) articles were identified from Sub-Saharan Africa. With the exception of MDR S. Typhi in South Asia, which declined between 1990 and 2018, and MDR S. Paratyphi A, which remained at low levels, resistance trends worsened for all antimicrobials in all regions. We identified several data gaps in Africa and the Middle East. Incomplete reporting of antimicrobial susceptibility testing (AST) and lack of quality assurance were identified. INTERPRETATION: Drug-resistant enteric fever is widespread in low- and middle-income countries, and the situation is worsening. It is essential that public health and clinical measures, which include improvements in water quality and sanitation, the deployment of S. Typhi vaccination, and an informed choice of treatment are implemented. However, there is no licenced vaccine for S. Paratyphi A. The standardised reporting of AST data and rollout of external quality control assessment are urgently needed to facilitate evidence-based policy and practice. TRIAL REGISTRATION: PROSPERO CRD42018029432.

A systematic review of clinical guidelines on the management of acute, community-acquired CNS infections.

BACKGROUND: The epidemiology of CNS infections in Europe is dynamic, requiring that clinicians have access to up-to-date clinical management guidelines (CMGs) to aid identification of emerging infections and for improving quality and a degree of standardisation in diagnostic and clinical management practices. This paper presents a systematic review of CMGs for community-acquired CNS infections in Europe. METHODS: A systematic review. Databases were searched from October 2004 to January 2019, supplemented by an electronic survey distributed to 115 clinicians in 33 European countries through the CLIN-Net clinical network of the COMBACTE-Net Innovative Medicines Initiative. Two reviewers screened records for inclusion, extracted data and assessed the quality using the AGREE II tool. RESULTS: Twenty-six CMGs were identified, 14 addressing bacterial, ten viral and two both bacterial and viral CNS infections. Ten CMGs were rated high quality, 12 medium and four low. Variations were identified in the definition of clinical case definitions, risk groups, recommendations for differential diagnostics and antimicrobial therapy, particularly for paediatric and elderly populations. CONCLUSION: We identified variations in the quality and recommendations of CMGs for community-acquired CNS infections in use across Europe. A harmonised European "framework-CMG" with adaptation to local epidemiology and risks may improve access to up-to-date CMGs and the early identification and management of (re-)emerging CNS infections with epidemic potential.

Prostatic capsular incision during radical prostatectomy has important oncological implications: a systematic review and meta-analysis.

INTRODUCTION: Prostatic capsular incision (CapI) is an iatrogenic breach of the prostatic capsule during radical prostatectomy (RP) that can cause positive surgical margins (PSMs) in organ-confined (pT2) prostate cancer, or the retention of benign prostatic tissue. We systematically interrogated the literature in order to clarify the definition of CapI, and the implications of this event for rates of PSM and biochemical recurrence (BCR). METHODS: A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria using the search terms 'capsular incision' AND 'prostatectomy', and variations of each. In all, 18 studies were eligible for inclusion. RESULTS: A total of 51 057 RP specimens were included. The incidence of CapI ranged from 1.3% to 54.3%. CapI definitions varied and included a breach of the prostatic capsule 'exposing both benign or malignant prostate cancer cells', 'malignant tissue only', or 'benign tissue only'. The incidence of PSMs due to CapI ranged from 2.8% to 71.7%. Our meta-analysis results found that when CapI was defined as 'exposing malignant tissue only in organ-confined prostate cancer' there was an increased risk of BCR compared to patients with pT2 disease and no CapI (relative risk 3.53, 95% confidence interval 2.82-4.41; P < 0.001). CONCLUSIONS: The absolute impact of CapI on oncological outcomes is currently unclear due to inconsistent definitions. However, the data imply an association between CapI and PSMs and BCR. Reporting of possible areas of CapI on the operation note, or marking areas of concern on the specimen, are critical to assist CapI recognition by the pathologist.

The prevalence of depression in general hospital inpatients: a systematic review and meta-analysis of interview-based studies.

BACKGROUND: Comorbid depression in the medically ill is clinically important. Admission to a general hospital offers an opportunity to identify and initiate treatment for depression. However, we first need to know how common depression is in general hospital inpatients. We aimed to address this question by systematically reviewing the relevant literature. METHODS: We reviewed published prevalence studies in any language which had used diagnostic interviews of general hospital inpatients and met basic methodological quality criteria. We focussed on interview-based studies in order to estimate the proportion of patients with a diagnosis of depressive illness. RESULTS: Of 158 relevant articles, 65 (41%) describing 60 separate studies met our inclusion criteria. The 31 studies that focussed on general medical and surgical inpatients reported prevalence estimates ranging from 5% to 34%. There was substantial, highly statistically significant, heterogeneity between studies which was not materially explained by the covariates we were able to consider. The average of the reported prevalences was 12% (95% CI 10-15), with a 95% prediction interval of 4-32%. The remaining 29 studies, of a variety of specific clinical populations, are described. CONCLUSIONS: The available evidence suggests a likely prevalence high enough to make it worthwhile screening hospital inpatients for depression and initiating treatment where appropriate. Further, higher quality, research is needed to clarify the prevalence of depression in specific settings and to further explore the reasons for the observed heterogeneity in estimates.

A systematic review of co-responder models of police mental health 'street' triage.

BACKGROUND: Police mental health street triage is an increasingly common intervention when dealing with police incidents in which there is a suspected mental health component. We conducted a systematic review of street triage interventions with three aims. First, to identify papers reporting on models of co-response police mental health street triage. Second, to identify the characteristics of service users who come in to contact with these triage services. Third, to evaluate the effectiveness of co-response triage services. METHODS: We conducted a systematic review. We searched the following databases: Ovid MEDLINE, Embase, PsycINFO, EBSCO CINAHL, Scopus, Thompson Reuters Web of Science Core Collection, The Cochrane Library, ProQuest National Criminal Justice Reference Service Abstracts, ProQuest Dissertations & Theses, EThoS, and OpenGrey. We searched reference and citation lists. We also searched for other grey literature through Google, screening the first 100 PDFs of each of our search terms. We performed a narrative synthesis of our results. RESULTS: Our search identified 11,553 studies. After screening, 26 were eligible. Over two-thirds (69%) had been published within the last 3 years. We did not identify any randomised control trials. Results indicated that street triage might reduce the number of people taken to a place of safety under S136 of the Mental Health Act where that power exists, or reduce the use of police custody in other jurisdictions. CONCLUSIONS: There remains a lack of evidence to evaluate the effectiveness of street triage and the characteristics, experience, and outcomes of service users. There is also wide variation in the implementation of the co-response model, with differences in hours of operation, staffing, and incident response.

Nocturnal oxygen therapy in obstructive sleep apnoea: a systematic review and meta-analysis.

Obstructive sleep apnoea is characterised by recurrent reduction of airflow during sleep leading to intermittent hypoxia. Continuous positive airway pressure is the first-line treatment but is limited by poor adherence. Nocturnal oxygen therapy may be an alternative treatment for obstructive sleep apnoea but its effects remain unclear. This meta-analysis evaluates the effects of nocturnal oxygen therapy on both obstructive sleep apnoea severity and blood pressure.A literature search was performed based on the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Peer-reviewed, randomised studies that compared the effect of nocturnal oxygen therapy to sham in obstructive sleep apnoea patients were included. The main outcomes were the apnoea-hypopnoea index and systolic and diastolic blood pressure.The search strategy yielded 1295 citations. Nine studies with 502 participants were included. When nocturnal oxygen therapy was compared to sham/air, it significantly reduced the apnoea-hypopnoea index (mean difference (MD) -15.17 events·h-1, 95% CI -19.95- -10.38 events·h-1, p<0.00001). Nocturnal oxygen therapy had no significant effect on blood pressure at follow-up without adjustment for baseline values, but did, where available, significantly attenuate the change in blood pressure from baseline to follow-up for both systolic blood pressure (MD -2.79 mmHg, 95% CI -5.45- -0.14 mmHg, p=0.040) and diastolic blood pressure (MD -2.20 mmHg, 95% CI -3.83- -0.57 mmHg, p=0.008).Nocturnal oxygen therapy reduced the apnoea-hypopnoea index severity and the change in (but not absolute) systolic and diastolic blood pressure, compared to sham. This suggests that nocturnal oxygen therapy may be a treatment option for obstructive sleep apnoea. Further studies with longer-term follow-up and standardised measurements are needed.

Development and application of the direct mycobacterial growth inhibition assay: a systematic review.

Introduction: First described by Wallis et al. in 2001 for the assessment of TB drugs, the direct mycobacterial growth inhibition assay (MGIA) offers a tractable ex vivo tool measuring the combined influences of host immunity, strain virulence and intervention effects. Over the past 13 years, we have led efforts to adapt the direct MGIA for the assessment of TB vaccines including optimisation, harmonisation and validation of BCG vaccine-induced responses as a benchmark, as well as assay transfer to institutes worldwide. Methods: We have performed a systematic review on the primary published literature describing the development and applications of the direct MGIA from 2001 to June 2023 in accordance with the PRISMA reporting guidelines. Results: We describe 63 studies in which the direct MGIA has been applied across species for the evaluation of TB drugs and novel TB vaccine candidates, the study of clinical cohorts including those with comorbidities, and to further understanding of potential immune correlates of protection from TB. We provide a comprehensive update on progress of the assay since its conception and critically evaluate current findings and evidence supporting its utility, highlighting priorities for future directions. Discussion: While further standardisation and validation work is required, significant advancements have been made in the past two decades. The direct MGIA provides a potentially valuable tool for the early evaluation of TB drug and vaccine candidates, clinical cohorts, and immune mechanisms of mycobacterial control. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023423491.

Stakeholder perspectives towards diagnostic artificial intelligence: a co-produced qualitative evidence synthesis.

Background: Diagnosis is a cornerstone of medical practice. Worldwide, there is increased demand for diagnostic services, exacerbating workforce shortages. Artificial intelligence (AI) technologies may improve diagnostic efficiency, accuracy, and access. Understanding stakeholder perspectives is key to informing implementation of complex interventions. We systematically reviewed the literature on stakeholder perspectives on diagnostic AI, including all English-language peer-reviewed primary qualitative or mixed-methods research. Methods: We searched PubMed, Ovid MEDLINE/Embase, Scopus, CINAHL and Web of Science (22/2/2023 and updated 8/2/2024). The Critical Appraisal Skills Programme Checklist informed critical appraisal. We used a 'best-fit' framework approach for analysis, using the Non-adoption, Abandonment, Scale-up, Spread, Sustainability (NASSS) framework. This study was pre-registered (PROSPERO CRD42022313782). Findings: We screened 16,577 articles and included 44. 689 participants were interviewed, and 402 participated in focus groups. Four stakeholder groups were described: patients, clinicians, researchers and healthcare leaders. We found an under-representation of patients, researchers and leaders across articles. We summarise the differences and relationships between each group in a conceptual model, hinging on the establishment of trust, engagement and collaboration. We present a modification of the NASSS framework, tailored to diagnostic AI. Interpretation: We provide guidance for future research and implementation of diagnostic AI, highlighting the importance of representing all stakeholder groups. We suggest that implementation strategies consider how any proposed software fits within the extended NASSS-AI framework, and how stakeholder priorities and concerns have been addressed. Funding: RK is supported by an NIHR Doctoral Research Fellowship grant (NIHR302562), which funded patient and public involvement activities, and access to Covidence.

Understanding psychosis complexity through a syndemic framework: A systematic review.

Psychotic conditions pose significant challenges due to their complex aetiology and impact on individuals and communities. Syndemic theory offers a promising framework to understand the interconnectedness of various health and social problems in the context of psychosis. This systematic review aims to examine existing literature on testing whether psychosis is better understood as a component of a syndemic. We conducted a systematic search of 7 databases, resulting in the inclusion of five original articles. Findings from these studies indicate a syndemic characterized by the coexistence of various health and social conditions, are associated with a greater risk of psychosis, adverse health outcomes, and disparities, especially among ethnic minorities and deprived populations. This review underscores the compelling need for a new paradigm and datasets that can investigate how psychosis emerges in the context of a syndemic, ultimately guiding more effective preventive and care interventions as well as policies to improve the health of marginalised communities living in precarity.

Systematic Review and Geospatial Modeling of Molecular Markers of Resistance to Artemisinins and Sulfadoxine-Pyrimethamine in Plasmodium falciparum in India.

Surveillance for genetic markers of resistance can provide valuable information on the likely efficacy of antimalarials but needs to be targeted to ensure optimal use of resources. We conducted a systematic search and review of publications in seven databases to compile resistance marker data from studies in India. The sample collection from the studies identified from this search was conducted between 1994 and 2020, and these studies were published between 1994 and 2022. In all, Plasmodium falciparum Kelch13 (PfK13), P. falciparum dihydropteroate synthase, and P. falciparum dihydrofolate reductase (PfDHPS) genotype data from 2,953, 4,148, and 4,222 blood samples from patients with laboratory-confirmed malaria, respectively, were extracted from these publications and uploaded onto the WorldWide Antimalarial Resistance Network molecular surveyors. These data were fed into hierarchical geostatistical models to produce maps with a predicted prevalence of the PfK13 and PfDHPS markers, and of the associated uncertainty. Zones with a predicted PfDHPS 540E prevalence of >15% were identified in central, eastern, and northeastern India. The predicted prevalence of PfK13 mutants was nonzero at only a few locations, but were within or adjacent to the zones with >15% prevalence of PfDHPS 540E. There may be a greater probability of artesunate-sulfadoxine-pyrimethamine failures in these regions, but these predictions need confirmation. This work can be applied in India and elsewhere to help identify the treatments most likely to be effective for malaria elimination.

A systematic review and meta-analysis of the risk of hepatitis B virus (HBV) resistance in people treated with entecavir or tenofovir.

BACKGROUND: As nucleos/tide analogue (NA) therapy (e.g. entecavir and tenofovir) for chronic Hepatitis B virus (HBV) infection becomes more widely indicated and available, understanding drug resistance is essential. A systematic review to quantify resistance to these agents has not previously been undertaken. METHODS: We performed a systematic review and random-effects meta-analysis to estimate the risk of HBV resistance to entecavir and tenofovir. We searched nine databases up to 29-Aug-23. We included studies of HBV infection featuring >10 individuals, written in English, reporting treatment ≥48 weeks, with assessment of HBV resistance based on viral sequence data. Data were analysed according to prior exposure history to NA, and choice of NA agent. Analyses were performed in R. FINDINGS: 62 studies involving a total of 12,358 participants were included. For entecavir, in treatment-naive individuals (22 studies; 4326 individuals), resistance increased over time to 0.9 % at ≥5 years (95 %CI 0.1-2.3 %), and resistance was increased in NA-experienced individuals (18 studies; 1112 individuals), to 20.1 % (95 %CI 1.6-50.1 %) at ≥5 years. For tenofovir, pooled resistance risk was 0.0 % at all time points, whether previously NA naive (11 studies; 3778 individuals) or experienced (19 studies; 2059 individuals). There was a lack of consistent definitions, poor global representation and insufficient metadata to support subgroup analysis. INTERPRETATION: We have generated the first pooled estimates of HBV entecavir and tenofovir resistance over time. HBV resistance to entecavir in treatment-experienced groups in particular may represent a clinical and public health challenge. To date, tenofovir appears to have an excellent resistance profile, but due to data gaps, we caution that existing studies under-estimate the true real-world risk of resistance. Robust prospective data collection is crucial to reduce health inequities and reduce blind-spots in surveillance as treatment is rolled out more widely.

The lymphatic filariasis treatment study landscape: A systematic review of study characteristics and the case for an individual participant data platform.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease (NTD) targeted by the World Health Organization for elimination as a public health problem (EPHP). Since 2000, more than 9 billion treatments of antifilarial medicines have been distributed through mass drug administration (MDA) programmes in 72 endemic countries and 17 countries have reached EPHP. Yet in 2021, nearly 900 million people still required MDA with combinations of albendazole, diethylcarbamazine and/or ivermectin. Despite the reliance on these drugs, there remain gaps in understanding of variation in responses to treatment. As demonstrated for other infectious diseases, some urgent questions could be addressed by conducting individual participant data (IPD) meta-analyses. Here, we present the results of a systematic literature review to estimate the abundance of IPD on pre- and post-intervention indicators of infection and/or morbidity and assess the feasibility of building a global data repository. METHODOLOGY: We searched literature published between 1st January 2000 and 5th May 2023 in 15 databases to identify prospective studies assessing LF treatment and/or morbidity management and disease prevention (MMDP) approaches. We considered only studies where individual participants were diagnosed with LF infection or disease and were followed up on at least one occasion after receiving an intervention/treatment. PRINCIPAL FINDINGS: We identified 138 eligible studies from 23 countries, having followed up an estimated 29,842 participants after intervention. We estimate 14,800 (49.6%) IPD on pre- and post-intervention infection indicators including microfilaraemia, circulating filarial antigen and/or ultrasound indicators measured before and after intervention using 8 drugs administered in various combinations. We identified 33 studies on MMDP, estimating 6,102 (20.4%) IPD on pre- and post-intervention clinical morbidity indicators only. A further 8,940 IPD cover a mixture of infection and morbidity outcomes measured with other diagnostics, from participants followed for adverse event outcomes only or recruited after initial intervention. CONCLUSIONS: The LF treatment study landscape is heterogeneous, but the abundance of studies and related IPD suggest that establishing a global data repository to facilitate IPD meta-analyses would be feasible and useful to address unresolved questions on variation in treatment outcomes across geographies, demographics and in underrepresented groups. New studies using more standardized approaches should be initiated to address the scarcity and inconsistency of data on morbidity management.

Post-kala-azar dermal leishmaniasis (PKDL) drug efficacy study landscape: A systematic scoping review of clinical trials and observational studies to assess the feasibility of establishing an individual participant-level data (IPD) platform.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis which can occur after successful treatment of visceral leishmaniasis (VL) and is a public health problem in VL endemic areas. We conducted a systematic scoping review to assess the characteristics of published PKDL clinical studies, understand the scope of research and explore the feasibility and value of developing a PKDL individual patient data (IPD) platform. METHODS: A systematic review of published literature was conducted to identify PKDL clinical studies by searching the following databases: PubMed, Scopus, Ovid Embase, Web of Science Core Collection, WHO Global Index Medicus, PASCAL, Clinicaltrials.gov, Ovid Global Health, Cochrane Database and CENTRAL, and the WHO International Clinical Trials Registry Platform. Only prospective studies in humans with PKDL diagnosis, treatment, and follow-up measurements between January 1973 and March 2023 were included. Extracted data includes variables on patient characteristics, treatment regimens, diagnostic methods, geographical locations, efficacy endpoints, adverse events and statistical methodology. RESULTS: A total of 3,418 records were screened, of which 56 unique studies (n = 2,486 patients) were included in this review. Out of the 56 studies, 36 (64.3%) were from India (1983-2022), 12 (21.4%) from Sudan (1992-2021), 6 (10.7%) were from Bangladesh (1991-2019), and 2 (3.6%) from Nepal (2001-2007). Five (8.9%) studies were published between 1981-1990 (n = 193 patients), 10 (17.9%) between 1991-2000 (n = 230 patients), 10 (17.9%) between 2001-2010 (n = 198 patients), and 31 (55.4%) from 2011 onwards (n = 1,865 patients). Eight (14.3%) were randomised clinical trials, and 48 (85.7%) were non-randomised studies. The median post-treatment follow-up duration was 365 days (range: 90-540 days) in 8 RCTs and 360 days (range: 28-2,373 days) in 48 non-randomised studies. Disease diagnosis was based on clinical criterion in 3 (5.4%) studies, a mixture of clinical and parasitological methods in 47 (83.9%) and was unclear in 6 (10.7%) studies. Major drugs used for treatment were miltefosine (n = 636 patients), liposomal amphotericin B (L-AmB) (n = 508 patients), and antinomy regimens (n = 454 patients). Ten other drug regimens were tested in 270 patients with less than 60 patients per regimen. CONCLUSIONS: Our review identified studies with very limited sample size for the three major drugs (miltefosine, L-AmB, and pentavalent antimony), while the number of patients combined across studies suggest that the IPD platform would be valuable. With the support of relevant stakeholders, the global PKDL community and sufficient financing, a PKDL IPD platform can be realised. This will allow for exploration of different aspects of treatment safety and efficacy, which can potentially guide future healthcare decisions and clinical practices.