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Association Between β-Adrenoreceptor Agonists and Antagonists and Parkinson's Disease: Systematic Review and Meta-Analysis.
Get PDFBACKGROUND: β-agonists and β-antagonists are among the most prescribed drugs worldwide. In 2018, studies suggesting a harmful association between propranolol and Parkinson's disease (PD) prompted a signal procedure by the European Medicines Agency's safety committee, which concluded with no update of product information. Several studies have been published since then. We aimed to systematically review, critically appraise, and meta-analyse all studies on the association between the use of β-antagonists (including propranolol) and β-agonists, and the risk of PD. METHODS: We searched Embase and Medline up to December 2024 for observational and intervention studies that reported relative risk estimates of the association between use of these medicines and PD. Two reviewers screened the records, extracted the data, and assessed the risk of bias. The restricted maximum likelihood method was used to compute pooled effect estimates and 95% confidence intervals (CIs). RESULTS: Twenty-two studies were eligible. Overall, 20 had a high risk of bias in at least one domain. Twelve studies had medium to high risk of outcome misclassification. Of the 14 studies concerning β-antagonists, eleven had an unclear or high risk of protopathic bias, as propranolol is indicated for the treatment of essential tremor. Control for confounding by socio-economic status, area of residence (urban/rural), and smoking (a protective factor against PD) was deficient or lacking in 9/22, 15/22, and 12/22 studies, respectively. Lag times were applied in 9/22 studies. In meta-analysis, the summary relative risk (RR) of PD was 1.41 (95% CI: 1.18-1.68) for the class of β-antagonists (12 studies) and 0.93 (0.84-1.03) for β2-agonists (11 studies). Among specific β-antagonists, the summary RR of PD was 2.36 (1.66-3.36) for propranolol (7 studies), 0.84 (0.80-0.88) for carvedilol (3 studies) and 1.02 (0.87-1.18) for metoprolol (4 studies). For specific β2-agonists, summary RR was 0.88 (0.77-1.01) for salbutamol (7 studies), 0.91 (0.88-0.95) for short-acting β2-agonists (6 studies), and 0.85 (0.76-0.96) for long-acting β2 agonists (5 studies). Restricting to subgroups based on quality criteria resulted in weaker or non-statistically significant associations. CONCLUSION: The quality and quantity of the available evidence do not support a causal association between use of β-adrenoreceptor modulators and PD. Significant associations are most likely explained by protopathic bias and confounding
Scaling-up symptom-agnostic, community-wide screening toward global tuberculosis elimination: opportunities, challenges, and lessons from history.
Get PDFThere has been little change in global tuberculosis (TB) incidence in the 21st century. Although case notification has increased, millions of people with TB each year remain unreached. Recently there has been increased recognition that many people with undiagnosed, potentially infectious TB do not experience or report TB symptoms. Symptom-agnostic screening (e.g., by chest X-ray) can effectively identify such forms of TB. Although this activity is increasing globally and is beneficial to individuals screened, current levels fall far short of what is needed to impact transmission and population-level prevalence. A significant scale-up of symptom-agnostic screening across communities is required to improve treatment coverage and interrupt transmission. Although there are major political, financial, and health system challenges to undertaking such scale-up this is not without precedent. In the mid-20th century, in many countries that now experience a low TB burden, population-level chest X-ray screening was successfully undertaken and contributed to the decline in TB. In this article, we explore the challenges and opportunities that face countries wanting to scale-up symptom-agnostic screening and reflect on important lessons from the past
The Capabilities in Academic Policy Engagement (CAPE) programme in England: a mixed methods evaluation.
Get PDFBACKGROUND: Interventions to support engagement between academics and policy professionals have proliferated, yet little evidence is available to guide what works, how, or for whom. AIMS AND OBJECTIVES: To evaluate the activities, outcomes and impacts of the Capabilities in Academic Policy Engagement (CAPE) programme and identify enabling conditions, using a modified framework for academic-policy engagement. METHODS: Mixed methods evaluation across four intervention types (seed funding, policy fellowships, training, knowledge exchange events), between 2021 and 2024. We interviewed academics, research support staff and policy professionals (n=129), observed 32 activities, and distributed a survey (n=42, 27 per cent response rate). We analysed data using inductive and framework analyses. FINDINGS: CAPE interventions focused at the linear (training) or relational (fellowships, seed funding and knowledge exchange) levels. Interventions led to outcomes in capacity-building, connectivity, conceptual and attitude change, and tacit knowledge development. Interventions were resource-intensive and required responsive intermediary skills, particularly fellowships. We found influencing factors at individual, organisation and system levels. The most experienced participants preferentially benefited from opportunities, potentially perpetuating or even exacerbating inequalities. We did not find evidence of impact on policy processes or outcomes. DISCUSSION AND CONCLUSIONS: CAPE led to an increase in academic-policy engagement activities, mostly as linear and relational interventions. These generated costs as well as benefits and often advantaged individuals with significant prior experience of academic-policy engagement. Future academic-policy engagement interventions should consider motivations, capabilities, goals and resources at the individual and organisation levels, while using strategic planning and coordination to maximise their value, and address diversity and inclusion
Evaluation of household coverage with long-lasting insecticidal nets in central Côte d'Ivoire.
Get PDFBACKGROUND: To reduce malaria burden in Côte d'Ivoire, the Ministry of Health aims for 90% of its population to possess one long-lasting insecticidal net (LLIN) for every two persons by 2025. This study evaluated LLIN coverage two years after a mass distribution in central Côte d'Ivoire. METHODS: A census was conducted in 43 villages. Data were collected on household geo-position, composition, number of sleeping units and LLINs owned. LLIN coverage was assessed using: 1/ownership; proportion of household with at least one LLIN; 2/household access; households with sufficient nets for every two persons and for every sleeping unit; and 3/population access; proportion of population with access to LLIN within households and sleeping units. RESULTS: 10,630 households (89.6% response rate) and 46,619 inhabitants were recruited. Household LLIN ownership was 63.8% (95% CI: 58.7-68.8). Household LLIN access was 37.6% (95% CI: 33.2-42.0) based on 1 LLIN per 2 persons and 37.1% (95% CI: 33.0-41.2) based on 1 net per sleeping unit. Population LLIN access based on 1 LLIN per 2 persons and 1 net per sleeping space was 53.3% (95% CI: 48.6-58.1) and 49.4% (95% CI: 45.1-53.6), respectively. Approximately 17% of households with access for every 2 persons did not have access by every sleeping unit and 9.7% of households with access by sleeping unit did not have access for every 2 persons. Households with adequate access by sleeping unit but not for every 2 persons tend to be larger with fewer sleeping units, and have children under 5 years old and female members. The largest households (>7 members) and households with at least one under-five member had the lowest access (20.8 and 27.3%, respectively). CONCLUSION: LLIN access was low in this area of intense indoor malaria transmission, 2 years after the last mass distribution campaign. Strategies are needed to improve LLINs coverage
Risk stratification of childhood infection using host markers of immune and endothelial activation in Asia (Spot Sepsis): a multi-country, prospective, cohort study.
Get PDFBACKGROUND: Prognostic tools for febrile illnesses are urgently required in resource-constrained community contexts. Circulating immune and endothelial activation markers stratify risk in common childhood infections. We aimed to assess their use in children with febrile illness presenting from rural communities across Asia. METHODS: Spot Sepsis was a prospective cohort study across seven hospitals in Bangladesh, Cambodia, Indonesia, Laos, and Viet Nam that serve as a first point of contact with the formal health-care system for rural populations. Children were eligible if aged 1-59 months and presenting with a community-acquired acute febrile illness that had lasted no more than 14 days. Clinical parameters were recorded and biomarker concentrations measured at presentation. The primary outcome measure was severe febrile illness (death or receipt of organ support) within 2 days of enrolment. Weighted area under the receiver operating characteristic curves (AUC) were used to compare prognostic accuracy of endothelial activation markers (ANG-1, ANG-2, and soluble FLT-1), immune activation markers (CHI3L1, CRP, IP-10, IL-1ra, IL-6, IL-8, IL-10, PCT, soluble TNF-R1, soluble TREM1 [sTREM1], and soluble uPAR), WHO danger signs, the Liverpool quick Sequential Organ Failure Assessment (LqSOFA) score, and the systemic inflammatory response syndrome (SIRS) score. Prognostic accuracy of combining WHO danger signs and the best performing biomarker was analysed in a weighted logistic regression model. Weighted measures of classification were used to compare prognostic accuracies of WHO danger signs and the best performing biomarker and to determine the number of children needed to test (NNT) to identify one additional child who would progress to severe febrile illness. The study was prospectively registered on ClinicalTrials.gov, NCT04285021. FINDINGS: 3423 participants were recruited between March 5, 2020, and Nov 4, 2022, 18 (0·5%) of whom were lost to follow-up. 133 (3·9%) of 3405 participants developed severe febrile illness (22 deaths, 111 received organ support; weighted prevalence 0·34% [95% CI 0·28-0·41]). sTREM1 showed the highest prognostic accuracy to identify patients who would progress to severe febrile illness (AUC 0·86 [95% CI 0·82-0·90]), outperforming WHO danger signs (0·75 [0·71-0·80]; p<0·0001), LqSOFA (0·74 [0·69-0·78]; p<0·0001), and SIRS (0·63 [0·58-0·68]; p<0·0001). Combining WHO danger signs with sTREM1 (0·88 [95% CI 0·85-0·91]) did not improve accuracy in identifying progression to severe febrile illness over sTREM1 alone (p=0·24). Sensitivity for identifying progression to severe febrile illness was greater for sTREM1 (0·80 [95% CI 0·73-0·85]) than for WHO danger signs (0·72 [0·66-0·79]; NNT=3000), whereas specificities were comparable (0·81 [0·78-0·83] for sTREM1 vs 0·79 [0·76-0·82] for WHO danger signs). Discrimination of immune and endothelial activation markers was best for children who progressed to meet the outcome more than 48 h after enrolment (sTREM1: AUC 0·94 [95% CI 0·89-0·98]). INTERPRETATION: sTREM1 showed the best prognostic accuracy to discriminate children who would progress to severe febrile illness. In resource-constrained community settings, an sTREM1-based triage strategy might enhance early recognition of risk of poor outcomes in children presenting with febrile illness. FUNDING: Médecins Sans Frontières, Spain, and Wellcome. TRANSLATIONS: For the Arabic and French translations of the abstract see Supplementary Materials section
Identification of training needs in schistosomiasis research to build capacity for schistosomiasis control in Uganda.
Get PDFBACKGROUND: Schistosomiasis is the leading cause of fatal upper gastrointestinal bleeding among adults in East Africa. The prevalence among school-aged children in villages along the Albert-Nile shoreline in North-Western Uganda is estimated at 85%. Efforts to control schistosomiasis in low- and-middle-income countries remain limited due to an incomplete understanding of the pathogenesis, disease manifestations, transmission mechanisms, preventive measures and interventions. In addition, there is insufficient capacity to analyse, model and predict relevant clinical case management systems, biological interventions and disease control efforts. We conducted a needs assessment for schistosomiasis research training at academic and research institutions in Uganda to inform the development of a structured training programme to build capacity to conduct locally relevant research to control the disease.
METHODS: Using an online survey, we collected data on training needs, potential trainees, available resources including local and international collaborations, as well as priority areas for schistosomiasis research and training at academic and research institutions in Uganda. Data were analysed and presented in frequency tables and figures.
RESULTS: Overall, schistosomiasis had the lowest number of studies conducted, based on the studies approved by research ethics committees at the two leading medical schools in Uganda: Makerere University College of Health Sciences (MakCHS) and Mbarara University of Science and Technology (MUST) between 2016 and 2022. The top ranked schistosomiasis focus areas of interest, by scientists at MakCHS, MUST, the Vector Borne and Neglected Tropical Diseases Division of the Ministry of Health and the Uganda Virus Research Institute (UVRI), were schistosomiasis prevention and transmission, vector biology, diagnostics, treatment and clinical trials, respectively. The top ranked training needs were schistosomiasis prevention and control, research ethics, data analysis, epidemiology and research methods (quantitative and qualitative), malacology, infectious diseases modelling, scientific writing and communication skills.
CONCLUSION: Priority areas for schistosomiasis research and training will be utilised to develop a robust, collaborative, multidisciplinary schistosomiasis research training programme, to increase the critical mass of scientists with the competencies required to design, execute and utilise schistosomiasis biology, clinical, laboratory and epidemiology research to advance disease control interventions and minimise/eliminate schistosomiasis-associated morbidity and mortality in sub-Saharan Africa
Safety and Tolerability of a Short Course of Linezolid for the Treatment of Predominantly Moderate to Severe Tuberculous Meningitis in Adults With Human Immunodeficiency Virus.
Get PDFBACKGROUND: Tuberculous meningitis (TBM)-related deaths occur early, often within weeks after treatment initiation. Enhanced treatment early in the disease course with agents that effectively penetrate the central nervous system may improve outcomes in TBM. METHODS: We conducted a phase 2, open-label, randomized trial in Masaka, Uganda, to assess the safety and tolerability of linezolid 1200 mg once daily versus no linezolid with high-dose (35 mg/kg/d) or standard-dose (10 mg/kg/d) rifampin for 4 weeks in participants with definite or suspected TBM. The primary endpoint was any grade ≥3 adverse event during the interventional period. Secondary endpoints included overall survival and functional independence adjusted for TBM disease grade. RESULTS: We randomized 40 participants (98% with human immunodeficiency virus [HIV]). One-fourth had microbiologically confirmed TBM. Nearly 75% had moderate to severe disease (Medical Research Council grades II and III). No significant difference in grade ≥3 adverse event--free survival was observed across the 4 treatment arms (P = .18) or by linezolid (P = .97) or rifampin (P = .46) treatment group. More favorable overall survival at 12 and 24 weeks (odds ratio, 0.28 [P = .10] and 0.43 [P = .24], respectively) and functional outcome at 12 and 24 weeks (OR for lower modified Rankin Scale score [ie, less disability], 2.22 [P = .18] and 2.00 [P = .24]) were observed in the linezolid group. CONCLUSIONS: The addition of a short course of linezolid to treat predominantly moderate to severe TBM in adults with HIV did not introduce excess toxicity. Our findings add to growing evidence that linezolid is a safe and acceptable treatment for TBM that merits further investigation in larger multisite trials
Explanatory models and coping with alcohol misuse among conflict-affected men in Ukraine.
No full textAffecting nearly 10% of men globally, alcohol use disorders (AUDs) represent a significant public health burden. Existing work, including from Ukraine, suggests that living in conflict settings may exacerbate the risk of AUDs. However, there is a dearth of evidence regarding alcohol misuse, as well as knowledge of factors associated with alcohol misuse patterns, in conflict settings. The aim of this qualitative study was to investigate explanatory models of alcohol misuse among conflict-affected men in Ukraine. Purposive and snowball sampling were used to recruit 66 conflict-affected men with alcohol misuse, family members of men who misuse alcohol, community health workers, and mental health and psychosocial support providers from locations across Ukraine. In the group of men who misuse alcohol (n=25), we recruited individuals with diverse experiences of adversity: 1) internally displaced persons from eastern Ukraine and Crimea displaced after 2014; 2) Ukrainian military veterans or territorial defense volunteers from various regions; and 3) men living 5-15 kilometers from the frontline. Semi-structured interviews were conducted in Ukrainian or Russian, and analysed using deductive and inductive analysis. Qualitative data received from each subgroup were analysed separately. The resulting explanatory model represents how Ukrainian conflict-affected men describe causes of alcohol misuse. Participants identified that alcohol misuse among Ukrainian men is often used as "self-treatment" to address mental health symptoms and feelings of demoralization that are exacerbated by a lack of supportive social environments and socio-economic problems; these behaviours also occur in an environment that deems alcohol misuse to be culturally appropriate. Family members and service providers offered a similar understanding of alcohol misuse as the men themselves. Strategies suggested by conflict-affected men to protect against alcohol misuse included engaging in alternative activities, finding supportive social environments, fear of negative consequences from alcohol misuse and increasing self-awareness and self-control. These findings indicate possible implications for interventions that target alcohol misuse among conflict-affected men, as well as demonstrate a need for developing culturally sensitive interventions that can address this unaddressed public health need
Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy.
Get PDFBACKGROUND: Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias.
METHODS: A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n<100), pediatric, or peripartum population. Meta-analysis and metaregression compared the proportion of female participants for an overall DCM cohort and the following subtypes: all genetic DCM, individual selected DCM genes (TTN and LMNA), and gene-elusive DCM. Population DCM sex ratios generated from diagnostic codes were also compared with those from sex-specific means using the UK Biobank imaging cohort; this established ICD coded, novel imaging-first, and genotype first determined sex ratios.
RESULTS: A total of 99 studies, with 37 525 participants, were included. The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28-0.32), corresponding to a male:female ratio (M:F) of 2.38:1. This was similar to patients with an identified DCM variant (0.31 [95% CI, 0.26-0.36]; M:F 2.22:1; P=0.56). There was also no significant difference when compared with patients with gene-elusive DCM (0.30 [95% CI, 0.24-0.37]; M:F 2.29:1; P=0.81). Furthermore, the ratio within autosomal dominant gene variants was not significantly different for TTN (0.28 [95% CI, 0.22-0.36]; M:F 2.51:1; P=0.82) or LMNA (0.35 [95% CI, 0.27-0.44]; M:F 1.84:1; P=0.41). Overall, the sex ratio for DCM in people with disease attributed to autosomal dominant gene variants was similar to the all-cause group (0.34 [95% CI, 0.28-0.40]; M:F 1.98:1; P=0.19). In the UK Biobank (n=47 549), DCM defined by International Classification of Diseases, 10th revision, coding had 4.5:1 M:F. However, implementing sex-specific imaging-first and genotype-first diagnostic approaches changed this to 1.7:1 and 2.3:1, respectively.
CONCLUSIONS: This study demonstrates that DCM is twice as prevalent in male patients. This was partially mitigated by implementing sex-specific DCM diagnostic criteria. The persistent male excess in genotype-positive patients with an equally prevalent genetic risk suggests additional genetic or environmental drivers for sex-biased penetrance.
REGISTRATION: URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42023451944
Impact of increased diagnosis of early HIV infection and immediate antiretroviral treatment initiation on HIV transmission among men who have sex with men in the Netherlands.
Get PDFThe number of new HIV infections among men who have sex with men (MSM) in the Netherlands has been decreasing, but additional efforts are required to bring it further down. This study aims to assess the impact of increased diagnosis of early HIV infection combined with immediate antiretroviral treatment (ART) initiation on reducing HIV transmission among MSM. We developed an agent-based model calibrated to HIV surveillance and sexual behavior data for MSM in the Netherlands in 2017-2022. Starting in 2023, we simulated a 10-year intervention that accelerates HIV diagnosis during the first 3 or 6 months after HIV acquisition across five levels of increased diagnosis rates (2, 4, 8, 16, and 32-fold), followed by immediate ART initiation. The upper limit of the intervention's impact over 10 years is projected to result in the cumulative 298 (95-th QI: 162-451) HIV infections averted. A 32-fold increase in the diagnosis rate within 3 months after HIV acquisition (corresponding to 100% of all new HIV infections diagnosed within 3 months of acquisition) results in 269 (95-th QI: 147-400) infections averted, approaching closely maximum impact. By extending the scope of the intervention to individuals who acquired HIV infection within the previous 6 months, a smaller 8-fold increase in the diagnosis rate (corresponding to 97% of new HIV infections diagnosed within 6 months of acquisition) approaches closely the maximum impact of the intervention by averting 256 (95-th QI: 122-411) HIV infections. Our sensitivity analyses showed that, in an epidemiological context similar to the modern-day the Netherlands, immediate initiation of ART accompanying accelerated diagnosis of individuals with early HIV infection does not significantly affect HIV transmission dynamics. Accelerating early HIV diagnosis through increased awareness, screening, and testing can further reduce transmission among MSM. Meeting this goal necessitates a stakeholder needs assessment