Multidrug-resistant tuberculosis (MDR-TB) is an urgent public health challenge in Namibia, with profound socioeconomic consequences. The high burden of both tuberculosis and HIV complicates treatment and underscores the need for optimised drug therapies. Precision medicine, which leverages patient-specific genetic and molecular information, offers promise for improving MDR-TB outcomes. However, its effective application relies on population-specific data, particularly understanding how individuals metabolise tuberculosis drugs and how genetic diversity drives variability in treatment response. Currently, no pharmacokinetic (PK) or pharmacogenetic (PG) data on TB treatment exist for Namibian populations. This gap is particularly concerning, given the country’s genetic diversity, environmental factors and comorbidities that may uniquely influence drug metabolism. This study aims to generate PK and PG data to inform dose optimisation and support personalised treatment strategies for MDR-TB in Namibia. The findings will contribute to improved patient care and inform health system strengthening based on locally relevant evidence.

This cross-sectional study will consist of 100 Namibian participants with matched human DNA and PK data of MDR-TB cases receiving isoniazid, clofazimine, bedaquiline and the fluoroquinolones (levofloxacin or moxifloxacin). PK sampling will be divided as follows: 30 individuals will undergo intensive PK sampling, while the remaining (n=70) will undergo sparse PK sampling. DNA will be extracted at Stellenbosch University (SU), and samples will be genotyped using the H3Africa microarray. Sequences will be aligned to the human reference genome, hg38 (GRCh38p13), using the freely available Burrows-Wheeler Aligner. A subset of the samples (n=20–30) will undergo whole genome sequencing (WGS) to verify imputation results and identify novel genetic variants potentially affecting PK in this population.

Quality control and variant call format file generation will be performed using the Genome Analysis Toolkit best practices (V.3.5). Intensive and sparse PK data will be pooled for the development of a population PK (popPK) model using a non-linear mixed-effects modelling approach. The popPK model will characterise the relationship between TB drug dose and exposure, including quantifying covariates, including genetic variation, explaining PK variability, providing a foundation for dose optimisation and personalised treatment strategies.

Ethics approval was obtained from the University of Namibia Human Research Ethics Committee for Health (Ref. SOM18/2024), the Ministry of Health and Social Services (Ref. 22/4/2/3), the SU Health Research Ethics Committee (Ref. N21/11/136) and the University of Cape Town Human Research Ethics Committee (Ref. 500/2022).

To explore how well the primary care system in Scotland works for adults with intellectual disabilities (ID), using the rate of unplanned hospital admissions for ambulatory care sensitive conditions (ACSC) as a proxy indicator. As part of this, to investigate those rates and rate ratios among adults with ID and without ID, adjusting for the prevalence of a given ACSC in each population. The secondary aim was to explore deaths due to ACSC among the ID and no-ID populations.

A population-based retrospective cohort data linkage study of adult respondents to Scotland’s 2011 Census. Self-reported or proxy-reported ID status from the Census was linked to hospital admissions data and deaths data. The cohort was followed until the end of 2019. The prevalence of ACSCs in each population was calculated from aggregate-level data published by the National Health Service, as it was not possible to use the linked dataset for this purpose.

Whole population of Scotland.

People aged 18+ on census day (27 March 2011), including all adults with ID (n=16 840) and a 15% randomly selected comparator sample of adults without ID (n=566 074).

Crude and age-sex standardised incidence rates and ratios; cumulative incidence; prevalence ratios. The exposure was ID status, and the outcomes were (1) unplanned ACSC hospital admission, (2) death with an ACSC condition listed as the main cause on the death certificate and (3) death with an ACSC condition listed as one of the causes on the death certificate.

Adults with ID under the age of 55 had only a slightly higher risk of an unplanned ACSC hospitalisation than their general population counterparts (standardised incidence ratio 1.11; 95% CI 1.03 to 1.20). After adjusting for different ACSC prevalence in ID and non-ID cohorts, this difference in risk disappeared. These findings contrast with existing evidence from England, where a much higher unadjusted risk of unplanned ACSC hospitalisations was found among people with ID. Adults with ID had a higher risk of dying due to ACSC than adults without ID (standardised mortality ratio 2.54; 95% CI 2.19 to 2.95).

Our findings on unplanned ACSC hospitalisations suggest that the primary care system in Scotland appears to be similarly effective for adults with ID than for adults without ID. However, the higher risk of dying from ACSC among people with ID suggests that this system is less effective for people with ID. Future research should investigate this tension and aim to understand why the operation of the primary healthcare system seems to be worse with regards to ACSC mortality than with regards to unplanned ACSC hospitalisations.

Sodium-glucose cotransporter (SGLT) inhibitors have shown substantial benefit in reducing cardiovascular and kidney events across diverse clinical populations, but the underlying physiological mechanisms remain unclear. However, existing mechanistic studies on renal and cardiovascular haemodynamics show variability in design, have limited statistical power and yield inconsistent outcomes, thus limiting the ability to draw generalisable conclusions. To address this gap, we conducted a systematic review and proposed the first meta-analysis to aggregate individual participant-level data from mechanistic studies to identify consistent physiological patterns and enhance understanding of the therapeutic effects of SGLT inhibition.

Gold-standard measured glomerular filtration rate (mGFR) was selected as the primary outcome for this systematic review, which aimed to identify all completed mechanistic studies investigating the effects of SGLT inhibition. Electronic databases including Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; and Cochrane Central Register of Controlled Trials were searched using a detailed search strategy. In total, 24 studies (n=1296) were identified. This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key variables including demographics, medical history, concomitant medications, vital signs, mGFR, renal haemodynamics, urine and plasma biochemistry, tubular sodium handling, echocardiography, cardiac output monitoring, arterial stiffness and fluid volume will be extracted. A one-stage individual participant data meta-analysis under a Bayesian framework will be conducted, using hierarchical models to simultaneously analyse data from all eligible studies. The risk of bias due to missing results will be assessed. Sensitivity analyses and subgroup evaluations will be incorporated to explore sources of heterogeneity and assess robustness of findings.

Ethics approval was obtained from University Health Network, Toronto, Canada. Findings from the Mechanisms of SGLT Inhibitor Action and Physiological Mediators (MOSAIC) meta-analysis will be published in peer-reviewed journals and results will be disseminated at scientific conferences.

CRD420251001413.

The mental health impacts of COVID-19 on frontline healthcare workers have been reported globally; however, there is limited evidence from low-income countries such as Ethiopia. We reviewed the literature to understand how COVID-19 impacted the mental health of frontline healthcare workers, including the associated risk and protective factors.

A scoping review of peer-reviewed research was conducted between 2020–2025 to explore the mental health and well-being of frontline healthcare workers in Ethiopia during COVID-19. The process adhered to the guidelines for data extraction outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Our search identified 35 studies, of which 29 studies were included in the final synthesis.

Three online databases, PubMed, Web of Science and PsycInfo, were systematically searched for data.

Studies were considered for inclusion in the review if they focused on mental health conditions and psychosocial well-being among healthcare workers during COVID-19 in Ethiopia. Studies were only included if published in English and excluded if they were conference abstracts, case studies, reviews, commentaries, contained incomplete data or lacked variables of interest.

Data extraction was conducted manually by two reviewers by using a data extraction sheet created in Excel.

Most frontline healthcare workers experienced symptoms of insomnia, psychological distress, stress, anxiety, post-traumatic stress disorder and depression during COVID-19. Female frontline healthcare workers, nurses, midwives and laboratory technicians reported higher rates of adverse mental health outcomes. Our results found that being married, living together with a spouse and having a high educational level were risk factors for adverse mental health outcomes.

The mental health and well-being of frontline healthcare workers is at risk during a global health crisis; however, there is a limited understanding of how to protect the mental health of frontline healthcare workers in low-income countries, such as Ethiopia, at such a critical time. Additional research is needed to better inform mental health preparedness interventions for frontline healthcare workers in these contexts, particularly given predictions of another pandemic occurring within the next decade.

The use of bone-anchored prostheses (BAPs) has greatly increased quality of life for lower limb amputees. However, the long-term frequency of skeletal fractures and the need for arthroplasty surgery in the lower extremities following BAP use is scarce.

The current study aimed to investigate the frequency of fractures and arthroplasties in the lower limb after BAP surgery with the Osseointegrated Prosthesis for the Rehabilitation of Amputees (OPRA) system.

Retrospective cohort study using the OPRA database and medical record review for data collection.

A single-centre study at a tertiary hospital.

All patients with a transfemoral BAP (OPRA system) who underwent surgery between 1999 and 2019, and had completed at least 2 years of follow-up were included in the study. Patients with bilateral transfemoral amputations were excluded. A total of 100 patients were included.

The primary outcome measure was to identify patients who had a fracture or had undergone arthroplasty surgery in the lower extremities after BAP surgery.

Of the 100 patients included, 16 patients (16%) had an event in their lower limb. 11 patients (11%) had a fracture, all of the femur, and six patients (6%) underwent arthroplasty surgery due to osteoarthritis. Long-term prosthetic use was not affected by the occurrence of an event.

Patients with BAP may be at a higher risk for femur fractures and arthroplasty surgery than the general population. Although encouraging that prosthetic usage is not affected after a fracture or arthroplasty surgery, prospective studies on larger cohorts and control groups need to be conducted.

Selective fetal growth restriction (sFGR) is a major cause of perinatal morbidity and mortality in monochorionic diamniotic (MCDA) twin pregnancies. Current management relies on umbilical artery Doppler patterns in the smaller twin. These patterns are, however, inconsistent and do not represent a reliable severity scale, complicating clinical decision-making and parental counselling. This study aims to improve risk stratification by identifying predictors of adverse outcomes, while also evaluating the pathophysiology and multi-organ impact of sFGR in early childhood.

This is a prospective, international, multicentre cohort study conducted in six tertiary fetal medicine centres with expertise in complicated twin pregnancies. Recruitment began in March 2023 and will continue until December 2026, targeting 274 MCDA twin pairs with complete follow-up to develop a prediction model for adverse perinatal outcomes in sFGR at the time of diagnosis. Standardised data collection includes serial ultrasound examinations, advanced fetal imaging (cardiac, cerebral and 3D volumetric), fetal brain MRI and detailed placental phenotyping. Maternal and parental well-being are assessed during pregnancy and after birth. Neurodevelopmental outcome is evaluated up to 2 years after birth using validated tools. The statistical analysis plan includes predictive modelling with internal validation.

The study has been approved by the ethical review boards of all participating centres. Findings will be disseminated through peer-reviewed publications, international conferences and engagement with clinical guideline committees.

NCT05952583.

The prognostic value of left atrial (LA) strain in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully elucidated. Therefore, this study investigated the prognostic value of LA strain in HFrEF patients in relation to all-cause mortality.

A total of 822 echocardiograms from HFrEF patients admitted to a heart failure clinic were analysed offline. To calculate left atrial reservoir strain (LA RS) and left atrial contractile strain (LA CS), LA two-dimensional speckle tracking was performed in the 4-chamber, 2-chamber and 3-chamber view. The end-point was all-cause mortality. The association between LA strain parameters and outcome was examined using Cox regression.

The median follow-up time was 40 months and follow-up was 100% complete. During follow-up, a total of 137 patients (16.7%) died of all causes. In a final multivariable model adjusted for clinical and echocardiographic parameters including global longitudinal strain, LA RS and LA CS were significantly associated with all-cause death during follow-up (LA RS, HR 0.96, 95% CI 0.92 to 0.99, p=0.014, pr. 1% increase) (LA CS, HR 0.95, 95% CI 0.92 to 0.98, p=0.002, pr. 1% increase).

When added to the final multivariable model, both LA RS and LA CS contributed with incremental prognostic value as determined by C-statistic (LA RS: C-stat difference 0.007, 95% CI 0.000 to 0.020, p=0.050) (LA CS: C-stat difference 0.009, 95% CI 0.000 to 0.023, p=0.030).

In HFrEF patients, LA RS and LA CS were associated with all-cause mortality and contributed incremental prognostic value in addition to established prognostic measures.

Optimising post-operative pain management is crucial for recovery in orthopaedic surgery. Methadone has attracted interest due to its long half-life, N-methyl-D-aspartate -receptor antagonism and potential to reduce post-operative opioid consumption. Existing reviews combine multiple surgical populations, limiting applicability to orthopaedic settings. This protocol outlines a systematic review assessing the analgesic efficacy and safety of peri-operative methadone in adult and adolescent orthopaedic patients.

This review will include randomised controlled trials evaluating intravenous peri-operative methadone vs placebo or standard analgesic regimens in orthopaedic surgery. Primary outcomes are post-operative rescue opioid consumption and pain intensity within 72 hours. Secondary outcomes include adverse events, mobility scores and the length of hospital stay. If available data permit, a methadone dose–response pattern may be investigated. Searches will be conducted in MEDLINE (Ovid), Embase (Ovid), CINAHL, CENTRAL, Web of Science and ClinicalTrials.gov without date restrictions. Two reviewers will independently screen studies, extract data and assess risk of bias using the Cochrane risk-of-bias tool for randomised trials. When appropriate, random-effects meta-analysis methods will be performed. Certainty of evidence will be assessed using Grading of recommendations assesment, development and Evaluation (GRADE).

As this study uses previously published data, ethical approval is not required. Findings will be disseminated through a peer-reviewed publication and conference presentations.

CRD42025616291.

International guidelines on breast cancer (BC) screening have differing recommendations leading to uncertainty on best practices for primary care providers. The purpose of this study was to create a Canadian best practices document on BC health and screening for primary healthcare providers through multidisciplinary consensus using Nominal Group Technique and Delphi method.

A 9-member multidisciplinary expert group and a patient advocate participated in the consensus methods and voting. Experts included those involved in BC management and two primary care physicians. Twenty-nine experts across BC disciplines participated in external review.

Two study objectives included (1) building consensus on key ‘best practice’ behaviours related to BC-related health and screening and (2) building consensus on specific definitions related to BC screening.

The final consensus document consists of 65 statements grouped in five categories with companion resources to support uptake of all best practices. Categories include identification and work-up for diagnostic imaging, risk factors and identifying individuals eligible for high-risk screening, shared decision-making, decisions and referrals for BC screening and screening outcomes. Special areas of focus were shared decision-making, age to initiate screening, and BC screening in special populations.

We created a comprehensive consensus document distilling the latest evidence to provide practical Canadian consensus-based advice on specific ‘best practice behaviours’ related to BC health and screening to serve as a resource for providers.

Fibrosing interstitial lung disease (F-ILD) are a heterogeneous group of diseases with multiple subtypes. Both idiopathic pulmonary fibrosis and other ILDs associated with a risk of developing progressive pulmonary fibrosis (PPF) are subtypes of this category. A multidisciplinary team discussion, including a chest high-resolution CT (HRCT), is usually considered the gold standard for diagnosis of F-ILD. Repeated HRCT is one of several established methods to assess progression and thus development of PPF, but it is associated with substantial costs and radiation exposure. Thoracic ultrasound (TUS) and other ultrasound (US) methods have emerged as radiation-free methods for both diagnosing and monitoring disease severity in F-ILD. Yet, consistent knowledge on the use of different TUS- and US methods in patients with F-ILD is limited.

The LORD study is a prospective cohort study conducted in participants with F-ILD at a tertiary ILD centre in Denmark. Physiological testing and patient-related outcome measures, together with TUS- and US examinations, will be performed at inclusion, after 6 and 12 months. The correlations between these assessments will be evaluated. HRCT will be conducted between 3 months prior to and 1 month after baseline, and after 1 year. At least 34 participants will be included.

The protocol was approved by the Danish Data Protection Agency (journal number: 22/45135) and the Science Ethics Committee for the Region of Southern Denmark (journal number: S-20220036). Results will be published in peer-reviewed international journals and will be presented at an international congress.

NCT06844331.

Patients in intensive care units (ICUs) and their families face existential physical, psychosocial and spiritual distress. Integrating palliative care (PC) into ICU care may benefit patients, relatives and ICU clinicians. Prior PC studies have shown a reduction in ICU length of stay (LOS) and distressing symptoms without altering overall mortality. A shorter ICU LOS may alleviate the burden for patients and relatives and help optimise the use of limited intensive care resources. PC in the ICU, however, remains underused, partly due to limited access and knowledge of ICU clinicians. Also, robust data regarding the effectiveness and cost-effectiveness of PC treatment in the ICU are scarce. We established the ‘enhancing palliative care in ICUs’ (EPIC) study to implement a system-based harmonised practice model across European ICUs. The aim is to investigate if early integration of PC via telemedicine, clinician education and bedside tools is effective and cost-effective, ultimately benefiting patients, relatives and ICU clinicians.

This multicentre, controlled, cluster-randomised, non-blinded stepped-wedge design trial with crossover phase aims to recruit around 2,000 patients from five European countries. All adult patients admitted to participating ICUs—with an ICU LOS exceeding 72 hours, where cancer is not the primary cause of critical illness, and who are not expected to die within the next 24 hours—are screened for the need for specialised PC based on the attending physician’s judgement. This judgement is triggered by the presence of one or more of the following: (1) significant disagreement among ICU team members and/or relatives about the appropriateness of current ICU treatment, (2) considerations of limiting life-sustaining therapy or (3) the anticipation that a specialised PC consultation may benefit the patient, their relatives or the ICU team. Patients identified as needing specialised PC and their relatives are then enrolled after obtaining written informed consent.

The complex intervention consists of (a) a blended-learning programme to foster knowledge and attitude about PC among ICU clinicians, (b) bedside tools, including a checklist to identify patients in need of PC and a factsheet and (c) standardised telemedical consultations from trained EPIC interventionists. Patient and relative follow-up is conducted 3 months post-ICU discharge. Outcomes include clinical measures (including ICU LOS (primary outcome), severity of critical illness, invasive treatments and health-related quality of life), economic endpoints (resource use, costs, cost–consequence situation, cost-effectiveness), ICU clinician burnout and distress, and patient and family perception about the quality of symptom management, care and communication. Endpoint analyses will employ generalised linear mixed models, accounting for the clustered data structure and stepped wedge design.

EPIC complies with the Declaration of Helsinki and has been approved by all local ethics committees. A decision-making structure is established to ensure trial procedures are carried out according to Good Clinical Practice. Study findings will be published in peer-reviewed journals and communicated to participants, healthcare professionals and the public. Sets of anonymised study data will be made available following Findable, Accessible, Interoperable, and Reusable principles.

NCT06605079.

The scoping review, which was carried out between January and May 2024 and re-run in May 2025, adhered to the methodology by Arksey and O’Malley, Levac et al and Daudt et al, and the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist. The EGH-WHW Framework was developed by a multidisciplinary Working Group comprising representatives of organisations in the WHW Project consortium.

The review drew upon database searches (Scopus, PubMed) and targeted online hand searches for CA-based frameworks and measures.

All CA-based frameworks and measures of multidimensional well-being were included. CA-based empirical research was considered if it applied a framework or measure; or if it analysed multidimensional well-being across multiple geographies.

Information about each type of CA-based application—its choice of well-being dimensions, methods, focus on inequality, intersectionality and the life course—was recorded in a data charting form. Thematic summative syntheses of publications about each CA-based framework or measure led up to an overall evaluative synthesis of the fit between existing work and our requirements.

The review culminated in 94 publications, including six frameworks and 14 measures that met only some of the WHW Project’s requirements: multidimensionality of well-being; attention to intersectional gender inequality and the life course; as well as demonstrated and intended measurements across multiple geographies.

The review reaffirms the need for the EGH-WHW Framework, which recognises that WHW depend on their freedom ‘to be’ and ‘to do’, and proposes three interconnected clusters of dimensions depicting key capabilities, agency and functionings that are sensitive to intersectional gender inequality and the life course. Each dimension is mapped to specific indicators to support comparative assessments of country performance and drivers of progress across low-income and middle-income countries.

The EGH-WHW Framework distinguishes itself from other CA-based frameworks by incorporating both an intersectional gender lens and a life course perspective. The framework’s conceptualisation of multidimensional well-being allows for a rich and nuanced foundation on which to build policies and programmes that address the complex determinants of health, well-being and human rights of different groups of girls and women.

Cannabis-based medicine may alleviate breathlessness. This study will investigate whether dronabinol, a synthetic form of ⁹-tetrahydrocannabinol (⁹-THC), reduces breathlessness in patients with severe and very severe chronic obstructive pulmonary disease (sCOPD) compared to placebo.

This single-centre, randomised, double-blinded, placebo-controlled, crossover trial will enrol 30 patients with sCOPD and persistent breathlessness despite optimal treatment. Patients will be recruited from a pulmonary outpatient clinic in Denmark over 24 months. Eligible patients (aged ≥18 years) will receive either dronabinol or placebo for 4 weeks, followed by a 2-week washout, before crossing over to the other treatment for 4 weeks. Exclusion criteria include ongoing infection, substance abuse and significant comorbidities. Primary outcome is breathing discomfort or unpleasantness measured using the 0–10 Numerical Rating Scale. Secondary outcomes include lung function (forced expiratory volume in one second), hair cortisol concentrations, functional tests, plasma THC blood concentrations and questionnaires assessing breathlessness, activity, quality of life, anxiety and depression. Continuous monitoring of vital signs, activity and sleep will be performed using a Garmin Venu 3 smartwatch. Data will be entered into electronic case report forms and monitored by the Good Clinical Practice (GCP) unit in Odense.

This will be the largest randomised, double-blinded, crossover trial to investigate dronabinol in patients with COPD and will provide new knowledge on the efficacy and safety.

Written informed consents will be obtained from study patients. The study has been approved by the Danish Medicines Agency (case number: 2023010659) and the medical research ethics committees (case number: 2301456). It is registered in the European Union Clinical Trials Registry (2024-513593-22-00) and ClinicalTrials.gov (NCT06473701). The trial follows the Declaration of Helsinki II and International Council for Harmonisation-GCP guidelines. Findings will be disseminated in peer-reviewed publications.

The European Union Clinical Trials Registry (2024-513593-22-00) and ClinicalTrials.gov (NCT06473701).