Circadian regulation modulates metabolic and hormonal processes throughout the day, yet it remains unclear whether these diurnal fluctuations are reflected in exhaled volatile organic compound (VOC) profiles and whether such temporal patterns differ between individuals with and without diabetes. Previous breath analysis studies in diabetes have shown heterogeneous results, which may reflect differences in analytical approaches and the lack of standardised sampling times.

This prospective, single-centre observational study examines daytime VOC dynamics from 08:00 to 16:00 among adults without diabetes, and individuals with type 1 diabetes or type 2 diabetes. 60 participants will complete one in-person visit with repeated breath measurements using a BreathSpec^® gas chromatography–ion mobility spectrometry system (GC-IMS) device, capillary glucose testing, body composition assessment, questionnaires, and oral and stool microbiota sampling. A standardised breakfast is provided; subsequent meals follow structured timing but are not standardised. The primary outcome is temporal variation in VOC intensities. Secondary outcomes include between-group differences and associations with glucose levels, body composition and microbiota composition. Analyses will use established GC–IMS tools and exploratory multivariate approaches.

Ethics approval was granted by the Ethics Committee of the Canton of Bern (BASEC 2023-01143). Results will be shared via peer-reviewed publications, conferences and lay summaries.

NCT05984979.

To develop and evaluate an explainable machine learning framework enhanced with synthetic data generation to predict unplanned 30-day hospital readmissions among patients with chronic obstructive pulmonary disease (COPD), heart failure (HF) and type 2 diabetes mellitus (T2DM), and to identify key clinical and social predictors of readmission.

A retrospective cohort study using electronic health record data incorporating both structured variables and information extracted from unstructured clinical notes. Synthetic data were generated using advanced resampling and deep learning-based techniques to address outcome imbalance and improve model training.

Intensive care unit and general ward admissions at a single tertiary academic medical centre included in the MIMIC-IV (Medical Information Mart for Intensive Care IV) database.

Adult patients (≥18 years) were admitted with a primary diagnosis of COPD (n=14 050), HF (n=7097) or T2DM (n=12 735) between 2008 and 2019, with complete 30-day follow-up and no in-hospital mortality during the index admission.

The primary outcome was unplanned all-cause hospital readmission within 30-days of discharge. Predictors were drawn from six domains, including demographics, comorbidities, clinical acuity, therapies, behavioural factors and care continuity. Predictive performance was evaluated using multiple machine learning methods and fivefold cross-validation, with model interpretability assessed using established goal and local explanation approaches.

Ensemble-based machine learning models demonstrated the strongest predictive performance across all three disease cohorts. Key predictors of readmission included higher illness severity, greater comorbidity burden, medication non-adherence, gaps in preventive care and limited social support. Models incorporating synthetic data augmentation showed improved discrimination compared with models trained on original data alone.

An explainable synthetic-data driven framework incorporating clinical, behavioural and social data can support prediction of 30-day readmissions among patients with common chronic conditions using routinely available electronic health record data.

Stakeholder involvement in research processes is widely recommended to enhance the relevance, quality and uptake of research findings. However, existing studies highlight persistent challenges in engaging family caregivers in co-design research. This gap may result in research outcomes that fail to reflect family caregivers’ needs and preferences, contradicting the core purpose of co-design. Therefore, the aim of this systematic review is to synthesise the available evidence on family caregivers’ experiences of involvement in co-design research and to generate evidence-based strategies to support effective engagement.

This systematic review will be conducted using a meta-aggregative approach, following the Joanna Briggs Institute’s (JBI’s) Manual for Evidence Synthesis. Systematic searches will be conducted in PubMed, CINAHL, Scopus, Web of Science and PsycINFO, with no date restrictions. Preliminary searches were performed in EMBASE between September and October 2025. Qualitative primary studies that explore family caregivers’ experiences of involvement in co-design research will be included. Study selection and quality appraisal will be performed independently by two researchers using predefined protocols, disagreements will be resolved through discussion with a third reviewer. After calibration, a single reviewer will extract the data using a customised data extraction template with the dataset distributed among the authors. The first author will then review all extractions. Data will be analysed following JBI’s meta-aggregative method, and results will be presented in narrative summaries, tables and diagrams. The findings will inform strategies for stakeholder involvement in future co-design research. Family caregivers and co-design researchers will be involved in reviewing and revising generated recommendations to enhance their relevance and practical utility.

This protocol does not involve human participants. The findings of this review will be submitted for publication in a peer-reviewed journal and presented at relevant scientific conferences and meetings.

CRD420251229190.

To determine the personal, National Health Service and wider societal resource use in relation to caring responsibilities for carers of people living with non-memory led dementias (NMLDs); and to design a resource use measure (RUM) that can be delivered in the Better Living with Non-memory-led Dementia (BELIDE) randomised controlled trial, part of the Rare Dementia (RD) - TALK research programme.

The first stage was to identify and review any existing RUMs that could be used or adapted to the trial population and setting. If no measures were identified, the second stage was initial informal discussions with healthcare professionals (HCPs) and the programme patient and public involvement representatives to inform the perspective, settings of care and main resource items to develop a new RUM. In the third stage, a first draft of the RUM was tested for content and face validity in a modified Delphi study comprising HCPs and carers. The measure was revised and, in the final stage, piloted in the first 3 months of the BELIDE trial to assess acceptability and feasibility of collecting the economic outcomes and the completeness of data collection. The key drivers of resource use and costs were assessed, and appropriate face validity checks were applied to ensure accurate description of the treatment pathways.

Carers and family of people living with NMLD recruited from Rare Dementia Support members in the UK, and a broad range of HCPs with experience of working with people who have NMLD to capture the different dimensions of experience, grade and skill mix.

In total, 20 people participated in the modified Delphi study, 11 HCPs and 9 carers. Rare Dementia Support groups and 1:1 calls were highly rated, as were general practitioner appointments. The greatest consensus was in the productivity and carer tasks; all caring tasks were highly rated. Healthcare practitioners rated healthcare items as higher importance than carers themselves.

Unpaid carers and HCPs are the experts in the resource impact of caring for someone with NMLD and have been underserved in research to date. This research, as part of preparatory stages of the BELIDE trial, has enabled the timely development of a comprehensive and valid RUM for unpaid carers of people with NMLD.

CRD42022356943.

NCT06241287.

To describe disability severity transitions in the ageing population in Switzerland using an overall functioning score to define four disability severity states (no, mild, moderate and severe) and death, and to investigate the association of multimorbidity and further predictors with these transitions.

Secondary analysis of the Swiss version of the Survey of Health, Ageing and Retirement in Europe (SHARE).

Switzerland.

Community-dwelling population aged 50+ with at least two interviews in SHARE (N=3505).

Not applicable.

Primary outcome measures are the disability severity as assessed by a previously developed overall functioning score, and death status as assessed by the SHARE end-of-life interview. Transition analysis between disability severity states and death was conducted using multistate Markov models. The association between predictor variables and transition intensities was quantified using the proportional hazards assumption. Two distinct operationalisations of multimorbidity (count, burden) were used and analysed according to two separate models (A, B).

The findings for both models were similar: Estimated HRs for transition intensities suggest that being multimorbid or having a higher disease burden score increases the risk of transitioning to higher disability severity states and death for most transitions (HRs between 0.90 and 2.34 for model A compared with not being multimorbid; HRs between 0.95 and 1.46 for model B for a one-point increase in the disease burden score). In addition, most transitions to higher disability severity states and death are more likely for higher age (HRs between 1.00 and 1.14 for model A, and between 1.00 and 1.15 for model B for a 1 year increase in age), and transitions to death are less likely for women, compared with men (HRs between 0.34 and 0.88 for model A, and between 0.38 and 0.71 for model B).

This study is a first attempt to understand disability severity transitions in the older population in Switzerland. Although we believe that such an approach is suitable to inform resource allocation to LTC, rehabilitation and prevention, more detailed information on contextual factors will be important to consider for future research. Moreover, our study contributes to the discussion on how to operationalise multimorbidity in healthy ageing research.

To identify predictors of treatment changes and to evaluate the effectiveness and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) initiating tofacitinib in a real-world setting.

The non-interventional study ESCALATE-RA included 1518 patients with RA from Germany. RA treatment, including all changes in therapy, was documented for 24 months starting from the initial intake of tofacitinib.

All patients started with tofacitinib therapy, either as monotherapy or in combination with methotrexate (MTX).

The impact of several factors of interest on the number and timing of treatment changes was assessed as primary outcome using Cox proportional hazards models. Further outcomes were tofacitinib drug survival and the use of follow-up disease-modifying antirheumatic drugs after first treatment change. We also assessed the effectiveness, concomitant glucocorticoid (GC) use, PROs (such as functional ability, patient satisfaction, pain and quality of life) and safety. Analyses were based on observed data.

‘Lack of efficacy’ (HR 3.30) and ‘intolerance’ (HR 4.43) leading to termination of tofacitinib were key factors favouring therapy changes. Higher patient satisfaction was significantly associated with a reduced likelihood of treatment changes (HR 0.82). Increasing GC doses were associated with a higher probability of step-up/switch changes (HR 1.21). The estimated tofacitinib drug survival was 48% at the end of study. Proportions of patients achieving low disease activity (both Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) 62%) and remission (SDAI 25%, CDAI 28%) increased from baseline under tofacitinib and were comparable between monotherapy and combination therapy with MTX. Mean concomitant GC dose decreased (2 mg/day). PROs indicated reduced pain and fatigue, while functional ability and quality of life improved. 63.9% of the patients experienced a treatment-emergent adverse event (AE), 8.8% a treatment-emergent AE of special interest and deaths occurred in 0.5%.

Key factors for therapy changes in patients with RA treated with tofacitinib were lack of efficacy and intolerance. Higher patient satisfaction was associated with a reduced probability of treatment changes, while increased GC doses led to a higher likelihood of step-ups/switches. Patients demonstrated a marked reduction in disease activity for up to 24 months, along with improvements in functional ability, pain and quality of life. Observed AEs were consistent with the known safety profile of tofacitinib.

NCT03387423.

Childhood overweight and obesity pose a growing public health problem with increasing prevalence both in Europe and globally. Reasons can be found in behavioural factors such as a sedentary lifestyle, eating habits or low exercise levels and to a lesser extent in a genetic predisposition or a metabolic disorder. Preventing children with obesity and overweight to grow into obese teenagers is therefore of high importance. However, there are currently no established care and prevention programmes in Germany for the early reduction of overweight and prevention of obesity in children aged 3–6 years. fruehstArt aims to close this gap with a cross-sector outreach and family-centred personal counselling approach, where parents receive support from paediatricians and trained coaches who conduct consultations in the home of the family. The main research question is whether the fruehstArt programme reduces overweight and obesity in children aged 3–6 years within 12 months, as measured by the body mass index-standard deviation score (BMI-SDS).

fruehstArt has been developed as a new form of care, which includes a family intervention with motivational interviews provided by paediatricians and individual home-based counselling provided by a trained coach on eating behaviour, exercising, sleeping behaviour and age-appropriate use of electronic devices. fruehstArt will be accompanied by an efficacy study (summative evaluation of change in BMI-SDS). In addition to German, the project is also offered in Turkish in order to reach families with a migration background and language barriers. 812 children with overweight or obesity and their families in the region North Rhine will be included and observed over 12 months. Recruitment of children occurred from December 2023 to April 2025 with the final visits scheduled for April 2026. The study is conducted as a randomised controlled trial with a social-ecological intervention approach, considering children in their living environment and conditions. Moreover, a formative evaluation at the process level, and the system level will be carried out and complemented by a health economic analysis. Those are carried out to provide information about the intervention’s success and relevant costs. Thus, fruehstArt is realised in the form of an effectiveness–implementation hybrid design that combines the analysis of effectiveness with an evaluation of the implementation process.

The study received ethics approval in a coordinated procedure from the ethics committee of the Medical Faculty University hospital of Cologne and the ethics committee of the North Rhine Medical Association. For all collected data, the relevant national and European data protection regulations will be considered. All personal data (contact details) will be removed for the data analysis in order to ensure pseudonymisation. Dissemination strategies include reports and quality workshops for organisations, peer-reviewed publications and the presentation of results at conferences.

The aim of the unique form of care fruehstArt is to improve the care of preschool children with overweight or obesity through innovative home-based counselling, cross-sectoral service integration and to address the cultural needs of Turkish families.

DRKS00030749 (29-09-2023)

The analgesic and antipyretic paracetamol (acetaminophen) is generally considered safe in therapeutic doses. The most important toxic effect is hepatotoxicity after supratherapeutic doses or in the presence of risk factors (eg, malnutrition, alcoholism). According to the WHO analgesic ladder, a combination of a non-opioid analgesic such as paracetamol with a strong opioid is recommended as step III treatment of patients with chronic pain, despite limited evidence for this approach. The main aim of this study is to test the hypothesis that paracetamol does not provide clinically relevant benefits when added to strong opioids in patients with chronic pain.

Investigator-initiated, randomised, double-blind, placebo-controlled, non-inferiority trial at two Swiss hospitals. A total of 140 patients with chronic pain requiring strong opioids and paracetamol ≥1.5 g/day for at least 7 days will be enrolled and randomised to either continued combination treatment or strong opioid plus placebo. In the first study phase (days 1–7), patients receive identically looking capsules containing either paracetamol at the exact dose previously used or a placebo. During a second study phase (days 7–14), all patients stop the blinded study medication (paracetamol and placebo) with follow-up to day 14. Adherence will be assessed by pill count and measurement of paracetamol and opioid serum concentrations. Patients are instructed to use a pain diary daily during the whole study. The primary outcome is the average pain score on day 7 using a 10 cm visual analogue scale (VAS). A difference between groups of ≤8 mm will be considered clinically irrelevant. Secondary outcomes will include VAS pain score on day 14, number of opioid rescue doses used, subjective ratings of overall feeling of well-being, quality of life, nausea/vomiting, drowsiness and constipation, and other adverse events, and potential effects of study drug concentrations and opioid receptor and cytochrome P450 (CYP) genotypes on the observed differences.

The study was approved by the Ethics Committee (Ethikkommission Bern, reference number 2021-01518) and the Swiss Agency for Therapeutic Products (Swissmedic, reference number 701286). Results will be published in open-access policy peer-reviewed journals. The study is funded by the Swiss National Science Foundation (grant number 32 003B_201072).

NCT05088876.

Although multiple studies have offered self-collection for human papillomavirus (HPV)-based cervical screening in community settings, there are no randomised controlled trials (RCTs) that have compared implementation outcomes of programme approaches for self-collection. This trial will compare two such approaches in low-resource settings in the states of Tamil Nadu and Mizoram, India.

A cluster RCT will be conducted over a year, offering self-collection to 3000 women aged 30–49 from 28 clusters (average size 101) in selected districts. Clusters in tribal, rural and urban low-income settings will be randomised to two arms. The intervention arm, co-designed with multiple stakeholders, will involve campaigns to offer self-collection in the community. The comparison arm will be offered self-collection at the nearest health facilities.

HPV-based cervical screening will be performed at central laboratories using clinically validated screening assays that can identify the highest risk carcinogenic HPV types (Group 1a–c - HPV16/18/31/33/45/52/58, ±35). Ablative treatment will be based on positivity with this extended genotyping triage, while those with any of the lower carcinogenic HPV types (Group 1d - 39, 51, 56, 59, ±35, Groups 2a/b - 66, 68) will undergo further assessment with visual inspection with acetic acid. Outcomes will be evaluated quantitatively and qualitatively using RE-AIM and the Theoretical Framework of Acceptability.

The primary outcome will be percentage of women well-managed (screened and appropriately treated) in both arms, with secondary outcomes including proportion screened, proportion treated, acceptability (willingness to screen, rescreen, and/or recommend to others) to women, community and healthcare providers, adoption (by providers), implementation fidelity, costs, sustainability assessment and systematically identified implementation barriers and facilitators. The reach, effectiveness and acceptability of community-based self-collection and the use of extended genotyping for triage in resource-constrained, hard-to-reach populations will be assessed, with lessons that can inform future statewide and national programmes.

Ethics approval has been obtained from the Institutional Review Board (IRB) and Ethics Committee of the Christian Medical College Vellore, Tamil Nadu, India (IRB Min. No 14314; INTERVEN), the Alfred Hospital Ethics Committee (HREC Ref 80134, Local Reference: project 601/21), Melbourne, Australia, the IARC Ethics Committee (IEC 21-32), Lyon, France, the Salem Polyclinic Institutional Ethics Committee (SPCIEC/2022/June/01/02), Tamil Nadu, India and the Institutional Ethics Committee, Civil Hospital, Aizawl, Mizoram, India (No.B.12018/1/13-CHA(A)/IEC/115). The study is also approved by the State Scientific Advisory Committee, Directorate of Public Health and Preventive Medicine, Chennai, Tamil Nadu (R. No. 011575/HEB/A2/2023). The Alfred Hospital Approval, as an authorised Australian ethics committee for national mutual recognition, is recognised and registered with the University of Melbourne Human Research Ethics Committee (2024-25255-57650-1). Written informed consent will be obtained from participants. The results of the trial will be disseminated through a peer-reviewed medical journal, and also through workshops, reports and conferences.

The trial has been registered with the Clinical Trials Registry - India: CTRI/2022/04/042327.

Venous thromboembolism (VTE) contributes to hospitalisation-associated morbidity. Although guidelines recommend limiting VTE prophylaxis to high-risk patients, some physicians prescribe it broadly. We compared beliefs of low and high prescribing physicians.

We surveyed hospitalists and medical residents who had the opportunity to prescribe prophylaxis ≥50 times. Best-worst scaling was used to assess their beliefs. Using a balanced incomplete block design, we created seven choice tasks with seven statements regarding prophylaxis beliefs each presented four times. For each task, physicians selected the statement that most and least reflected their beliefs. We used a count method to calculate best-worst scores and a conditional logistic regression choice model to compare low and high prescribers.

Of 434 invitees, 172 (40%) completed all survey questions between June and November 2023. Low (n=86, ≤62.5% prescribing rate) and high (n=86, >62.5 prescribing rate) prescribers endorsed similar beliefs with differing levels of agreement. All felt confident to prescribe prophylaxis appropriately (low: +1.13, high: +1.10, p=0.81). High prescribers expressed more concern about VTE without prophylaxis (+1.02 vs +0.65, p=0.002). Low prescribers disagreed more that prophylaxis had no downside (–1.03 vs –0.73, p=0.01). High prescribers worried less about prophylaxis risks (–0.49 vs –0.22, p=0.01), and overuse (–0.61 vs –0.34, p=0.02).

Compared with low prescribers, high prescribers were more concerned about VTE without prophylaxis and less about harms. These differences in beliefs may underlie physician behaviour and could be targets for interventions to reduce inappropriate prophylaxis.

Exercise-based interventions are well-established in reducing falls and fall-related injuries, but adherence and accessibility remain key challenges, particularly in rural areas. While conventional in-person training is widely used, digital interventions may offer scalable solutions to enhance engagement and reach. However, pragmatic trials evaluating the real-world effectiveness of conventional and digitally supported fall prevention interventions are lacking, limiting the evidence base for their implementation in routine healthcare settings. The SURE-Footed into the Future Fall Intervention Trial (SURE-FIT) aims to compare the effectiveness of two structured fall prevention interventions—a conventional centre-based exercise programme and a hybrid telemedical programme combining in-person and tablet-supported training—against a wait-list control group in reducing falls and fall-related injuries among community-dwelling older adults.

This study is a pragmatic three-arm, parallel-group, randomised controlled superiority trial with a 1:1:1 allocation ratio. Participants (≥65 years, community-dwelling, planned n=2778) will be randomly assigned to (1) conventional centre-based training supplemented with printed materials for home-based continuation (conventional group), (2) a hybrid model integrating centre-based and tablet-supported training for continuation (tablet group) or (3) a wait-list control group. The intervention includes a 9-week supervised phase followed by 43 weeks of independent home-based training. The primary outcomes are the incidence rate of falls and fall-related injuries over 12 months. Secondary outcomes include physical functioning, physical activity, concerns about falling, loneliness and the risk of low protein intake. A process evaluation will assess intervention feasibility and implementation. Additionally, qualitative interviews will be conducted with participants, course instructors and municipal stakeholders to explore experiences, facilitators and challenges related to programme participation and implementation. A health-economic evaluation will be conducted to assess the cost-effectiveness of the structured fall prevention interventions. Data collection will take place at baseline and every 3 months via standardised questionnaires, with a subgroup undergoing physical performance testing and sensor-based activity monitoring. Analyses will follow an intention-to-treat approach.

Ethical approval has been granted by the Ethics Committee of Ulm University (271/23). Written informed consent will be obtained from all participants before enrolment. Study findings will be disseminated through peer-reviewed publications, scientific conferences and national fall prevention initiatives. Additionally, results will be shared with key municipal representatives, and the German National Association of Senior Citizens’ Organisations (BAGSO). A publicly accessible website will provide ongoing access to study information and findings in plain language.

DRKS00032878, German Clinical Trials Register