Longitudinal observational research study: establishing the Australasian Congenital Cytomegalovirus Register (ACMVR)

Purpose
Congenital cytomegalovirus (cCMV) is an important cause of long-term childhood disability. In Australia, the identification and treatment practices and the long-term clinical and neurodevelopmental outcomes of children with cCMV are unknown. The Australasian cCMV Register (ACMVR) is a longitudinal register and resource for research that aims to describe and explore, in Australian children with cCMV: (1) their clinical characteristics over time, (2) antiviral therapy use/prescribing up to 1 year of age and (3) risk factors and potential avenues for prevention of adverse sequelae of the virus.

Participants
Children

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Effect of transcranial magnetic stimulation on perioperative neurocognitive dysfunction: study protocol for a systematic review and meta-analysis of randomised controlled trials

Introduction
Perioperative neurocognitive disorders (PNDs), a common postoperative complication associated with anaesthesia and surgical procedures, are characterised by impairments in memory, attention, language comprehension and social functioning. Accumulating evidence from clinical studies indicates that transcranial magnetic stimulation (TMS)—a non-invasive neuromodulatory modality capable of targeted cortical stimulation—may offer therapeutic promise for PND management. To comprehensively assess the intervention efficacy and safety parameters of TMS in mitigating postoperative cognitive decline, we propose conducting a systematic review and meta-analysis of randomised controlled trials adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Our findings aim to provide evidence-based insights into the neuroprotective potential of TMS for mitigating cognitive decline in surgical populations.

Methods and analysis
The investigation will implement a multifaceted search protocol encompassing international and Chinese scholarly resources. The search will be conducted in major databases, including Web of Science, Embase, PubMed, Cochrane Library, China Biology Medicine, China National Knowledge Infrastructure, Wan Fang Database and Chinese Scientific Journal Database from inception to 31 March 2025. To capture the latest research trends, ongoing trials will be simultaneously searched in the WHO International Clinical Trial Registry Platform, ClinicalTrials.gov and the China Clinical Trial Registry. Grey literature will be supplemented through resources such as GreyNet International, OpenGrey and Google Scholar. The inclusion criteria for this review are restricted to randomised controlled trials investigating the application of TMS as an intervention for PND. Primary endpoints comprise clinically confirmed incidence rates of postoperative delirium and delayed neurocognitive recovery. Two researchers will independently perform literature screening, data extraction and risk of bias assessment. The risk of bias in included studies will be evaluated using the Cochrane Risk of Bias Tool 2.0. Evidence certainty will be appraised through the GRADE framework with explicit justification for downgrading decisions. Meta-analysis will be conducted using STATA V.15.1 statistical software. The data synthesis process will incorporate standardised methodologies, including heterogeneity testing, sensitivity analysis and assessment of publication bias.

Ethics and dissemination
This study will not involve the collection of biometric information or medical privacy data throughout the research process, thus complying with the exemption criteria outlined in the ‘Measures for Ethical Review of Biomedical Research Involving Human Subjects.’ The findings will adhere to academic standards and be submitted for publication in reputable international medical journals following a rigorous double-blind peer-review process.

Systematic review registration
The research protocol has been prospectively registered on the PROSPERO international prospective systematic review registration platform (registration number: CRD42025636978).

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Burden of disease using disability adjusted life years in the Middle East and North Africa (MENA) region: protocol of a systematic review

Introduction
In the Middle East and North Africa (MENA) region, changing demographic and epidemiological profiles have resulted in a diverse and shifting burden of disease (BoD). Disability-adjusted life years (DALYs), which combine years of life lost (YLL) due to premature mortality and years lived with disability (YLD), offer a valuable metric for assessing disease burden at the national level. While global burden of disease (GBD) estimates provide broad insights, national burden of disease (NBD) estimates offer country-specific data that can better inform tailored health policies and resource allocation. This systematic review protocol outlines our methodology for collating and analysing the NBD estimates in the MENA region using DALYs as the primary outcome measure.

Methods and analysis
This review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We will systematically search PubMed, Scopus, Web of Science and EMBASE for studies published from 1993 to 2024 that report national-level DALY estimates for diseases, injuries or risk factors in MENA countries. Eligible studies must report DALY estimates using national methodologies, while studies using exclusively GBD estimates will be excluded. Two independent reviewers will conduct title/abstract and full-text screening, data extraction and quality assessment using Standardised Reporting of Burden of Disease Studies (STROBOD), with disagreements resolved by a third reviewer when necessary.

Ethics and dissemination
Ethical approval is not required for this review as it involves analysis of previously published data. The findings will be disseminated through publication in a peer-reviewed journal and presented at relevant academic and policy forums.

Prospero Registration Number
PROSPERO CRD42024498688.

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Prevalence and severity of coronary artery disease in asymptomatic military air crew in the Netherlands: a prospective, cross-sectional study (SUSPECT)

Objective
Coronary artery disease (CAD) is a main cause of incapacitating adverse cardiac events in aviation. Military aircrew ≥40 years in the Netherlands undergo a 5-year exercise ECG (X-ECG), which lacks precision to identify relevant CAD. The study aim was to identify the screening value of cardiac CT (CCT) in asymptomatic military aircrew.

Design
Prospective, single-centre, cross-sectional study.

Setting
Conducted at the Centre for Man in Aviation, Royal Netherlands Air Force. CT scans were performed at the University Medical Centre, Utrecht.

Participants
Asymptomatic military aircrew ≥40 years were asked to undergo CCT, with coronary artery calcium score (CACS) and coronary CT angiography (CCTA), following their aeromedical exam. CCT was performed in 211 participants (median age 49.3 years (43.6–52.8), 98% men, 65% pilots).

Outcome measures
The main objective was to determine the prevalence of relevant CAD. Clinically relevant CAD (CR-CAD) is defined as CACS ≥100 and/or a stenosis ≥50%. Aeromedically relevant CAD (AR-CAD) includes CR-CAD and/or a left main stenosis >30% or an aggregate stenosis ≥120%. Secondary objectives included assessing the prevalence of mild coronary stenosis (defined as 25%–49% stenosis), the presence of high-risk plaque (HRP) features and CCT safety.

Results
CR-CAD was found in 25 male aircrew (12%), with a CACS of ≥100 in 21 (10%) and a stenosis ≥50% in 10 (5%), including two with CACS 0. Two additional men had ≥120% aggregate stenosis, bringing total AR-CAD to 27 (13%). Twenty-nine men (14%) had mild stenosis. HRP features were present in 44 (21%). There were no CT-related complications. Of 196 participants who underwent X-ECG, seven showed abnormal results; one had relevant CAD.

Conclusions
Contrast-enhanced CCTA provides additional information both on high-risk features and obstructive CAD compared with CACS only. CCT is safe and is of additional value to X-ECG in a low-risk population with a high-hazard occupation.

Trial registration number
NCT05508893.

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Community-based type 2 diabetes screening programmes designed for priority populations: a scoping review protocol

Background
Type 2 diabetes is a growing public health concern, and it continues to disproportionately impact priority populations. Although earlier and more frequent screening of diabetes promotes early detection to prevent adverse outcomes, this is a significant barrier for priority populations due to inequities that hinder access to critical preventive screening in primary care settings. The purpose of this scoping review is to better understand the design and implementation of screening and early detection of type 2 diabetes in community settings for priority populations to reduce missed or delayed diagnoses and future potential adverse outcomes.

Methods
This scoping review will adopt the methodological framework of Arksey and O’Malley and be enhanced using Levac et al recommendations. A search strategy was designed using insights from experienced librarians through the Peer Review for Electronic Search Strategies to conduct a comprehensive search using the following databases: Medline, Embase, PsycINFO, Web of Science, Scopus, CINAHL and Google. The search will capture studies focused on community-based diabetes screening using point-of-care testing and deployed in community settings serving priority populations with undiagnosed diabetes. Studies will be excluded if priority populations were not a focus, individuals living with diabetes, the intervention is not implemented in a community setting and did not use point-of-care screening. Two authors will independently review and screen the articles (title, abstract and full-text), while a team-based approach will be applied to chart the data. A thematic analysis will be used to identify emerging themes and subthemes according to barriers and enablers of implementing an equitable community-based diabetes screening intervention.

Ethics and dissemination
The findings from this review will inform future diabetes screening interventions in community settings to enable an equity-informed approach in the design, planning and implementation of such strategies. Equally important, it will inform a larger project, in which the team plans to implement a community-based diabetes screening programme in Ontario, Canada.

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Development of prediction models for screening depression and anxiety using smartphone and wearable-based digital phenotyping: protocol for the Smartphone and Wearable Assessment for Real-Time Screening of Depression and Anxiety (SWARTS-DA) observational study in Korea

Introduction
Depression and anxiety are highly prevalent mental health conditions that significantly affect quality of life and cause societal burdens. However, their detection and diagnosis rates remain low owing to the limitations of the current screening methods. With rapid technological advancements and the proliferation of consumer-grade wearable devices and smartphones, their integration into digital phenotyping research has enabled the unobtrusive screening for depression and anxiety in natural settings. The Smartphone and Wearable Assessment for Real-Time Screening of Depression and Anxiety study aims to develop prediction algorithms to identify individuals at risk for depressive and anxiety disorders, as well as those with mild-to-severe levels of either condition or both. By collecting comprehensive data using smartphones and smartwatches, this study aims to facilitate the translation of artificial intelligence-based early detection research into clinical impact, thereby potentially enhancing patient care through more accurate and timely interventions.

Methods and analysis
This cross-sectional observational study will enrol up to 2500 participants (at least 1000) aged 19-59 years from South Korea via social media outreach and clinical referrals. The eligible participants must use a compatible smartphone. Each participant will be followed up for 4 weeks. Data will be collected using a custom-developed smartphone application called PixelMood. Active data collection will include daily, weekly and monthly self-report questionnaires incorporating validated scales, such as the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7. Passive data from smartphones include information on physical activity, location, ambient light and smartphone usage patterns. Optionally, participants using the Apple Watch or Galaxy Watch devices can provide additional data on physiological responses and sleep health. The primary outcome will be the development of machine-learning algorithms to predict depression and anxiety based on these digital biomarkers. We will employ various machine-learning techniques, including random forest, support vector machine and deep-learning models. The secondary outcomes will include the association between digital biomarkers and clinical measures, and the feasibility and acceptability of data collection methods. Various features characterising mobile usage behaviours, physical/social activity, sleep patterns, resting physiological states and circadian rhythms will be exploited to serve as potential digital phenotyping markers. Advanced machine-learning and deep-learning techniques will be applied to multimodal data for model generation.

Ethics and dissemination
This study protocol was reviewed and approved by the Institutional Review Board of the Korea University Anam Hospital (approval number: 2023AN0506). The results of this study will be disseminated via multiple channels. The findings will be presented at local, national and international conferences in relevant fields, such as psychiatry, psychology and digital health. Manuscripts detailing the study results will be submitted to peer-reviewed journals for publication.

Trial registration number
The present study was registered with the Clinical Research Information Service (CRIS, https://cris.nih.go.kr; identifier: KCT0009183).

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Effects of microgravity on neuromuscular control of the spine: a protocol for a systematic review and meta-analysis

Introduction
As spaceflight missions become more frequent and prolonged, the effects of microgravity on the musculoskeletal system represent a critical concern for astronauts’ health given their increased risk of spinal pain and injury. A better understanding of the adaptations induced by microgravity on neuromuscular control of the spine is essential to guide the development of effective countermeasures. Thus, this systematic review will aim to investigate the effects of microgravity on the neuromuscular control of the spine.

Methods and analysis
This protocol has been developed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. MEDLINE, EMBASE, CINAHL, Web of Science, PubMed, grey literature and specialised space research resources will be searched from inception up to December 31, 2024. Screening processes, data extraction and risk of bias assessment will be conducted by two independent reviewers. Studies investigating the acute and long-term effects of microgravity on neuromuscular control of the spine will be included. Studies investigating spaceflight conditions or other protocols simulating microgravity, such as parabolic flights, dry immersion and long-term bed rest, will be considered eligible. Non-randomised studies of intervention with before-and-after design will represent the main studies of interest, and their risk of bias will be evaluated with the Risk Of Bias In Non-randomised Studies-of Interventions tool. Random-effect meta-analyses will be conducted for quantitative synthesis when clinical and methodological consistency is ensured. The certainty of evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluation guidelines.

Ethics and dissemination
As this systematic review is based on previously published studies, no ethical approval is required. The findings will be disseminated through publication in an international peer-reviewed journal and presented at conferences. All data relevant to the study will be included in the article or uploaded as supplementary information.

PROSPERO registration number
CRD42024608544.

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Factors influencing career plateau in nurses: a protocol for systematic review and meta-analysis

Introduction
Career plateau is a situation that has many negative effects on individual nurses, nursing management and nursing profession. Despite global research examining career plateaus among nurses, a comprehensive data synthesis on its prevalence and influential factors is still missing. The study aims to systematically analyse the prevalence of career plateau in nurses and explore the related influencing factors.

Methods and analysis
The anticipated start date for the study is December 2025, and the anticipated end date is August 2027. We will search PubMed, Web of Science, Embase, PsycINFO, CINAHL, Scopus, the China National Knowledge Infrastructure, the Wanfang database and the China Biomedical Literature Database (SinoMed) from the establishment of the database to the present for studies on the prevalence and influencing factors of career plateau in nurses. Two researchers will independently conduct literature screening and data extraction. They will evaluate the quality of the included studies using the Joanna Briggs Institute critical appraisal tool and the mixed-methods appraisal tool. If possible, we will conduct a meta-analysis, which is according to the data heterogeneity. If the heterogeneity is too large to be resolved, we will present them narratively and descriptively according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria, summarise status and influencing factors of the career plateau in nurses.

Ethics and dissemination
No formal ethics approval is required for this protocol and no primary data will be collected. The results will be disseminated through peer-reviewed journals and presented at conferences.

PROSPERO registration number
CRD42024545439.

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Evaluating 10 years of premature mortality costs associated with liver cancer: a retrospective economic analysis of productivity loss in Spain

Objectives
To assess the economic burden of premature mortality due to liver cancer in Spain over 10 years (2013–2022) using a retrospective economic analysis.

Design
A population-based retrospective study using the Human Capital approach.

Setting
We analysed national registry data from the Spanish National Institute of Statistics on mortality, employment and wage structure. Sensitivity analyses were conducted using discount rates of 0%, 3% and 6%.

Participants
All individuals who died from liver cancer between 2013 and 2022, with a focus on the working-age population under 65 years of age.

Primary and secondary outcome measures
Primary outcomes included years of potential life lost (YPLL), years of potential labour productive life lost (YPLPLL) and associated productivity losses due to premature liver cancer mortality. Secondary outcomes involved trend analyses of productivity loss and YPLL over time, and assessment of sex-specific and age-specific differences in productivity losses.

Results
Between 2013 and 2022, 36 635 individuals died from liver cancer, including 6622 individuals of working age. This led to 9924–12 068 YPLL annually. The cumulative productivity loss was 12.88 billion (range: 12.52–13.26 billion).

Conclusions
These findings highlight the substantial economic impact of liver cancer mortality in Spain and underscore the importance of targeted prevention and screening programmes for high-risk populations.

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Mediating effect of the normalised difference vegetation index between PM2.5 and its components and cardiovascular disease: evidence from CHARLS

Objectives
To investigate the associations between fine particulate matter (PM2.5) and its components and cardiovascular disease (CVD) and to explore the potential mediating role of the normalised difference vegetation index (NDVI) in mitigating PM2.5 exposure and its related health risks.

Design and setting
Using data from the 4th and 5th waves of the China Health and Retirement Longitudinal Study, we included 11 279 eligible participants after strict screening.

Methods
A logistic regression model was used to assess the effects of PM2.5 and its components on CVD. The logistic regression, combined with restricted cubic splines, was used to explore non-linear associations, and a mediation analysis was performed to assess the role of the NDVI.

Results
Among the 11 279 participants, 775 (14.7%) developed CVD during the follow-up period. The results revealed that every 1 µg/m3 increase in the PM2.5 concentration was associated with a 2.1% (95% CI: 1.013 to 1.029) increased risk of CVD, and the sulphate, ammonium, nitrate, organic matter and black carbon components of PM2.5 also exhibited significant positive correlations. Mediation analysis revealed that the NDVI significantly mediated the effects of PM2.5 and its components on CVD, with mediation proportions ranging from 42.27% to 56.13%. Stratified analyses revealed significant interactions of PM2.5 and its components with CVD risk in different settlement types.

Conclusions
Exposure to PM2.5 and its constituents increases the risk of CVD. Increasing green space may help mitigate the adverse effects of air pollution on cardiovascular health, particularly in different types of settlements.

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Case-finding for depression in primary care (CAIRO): a multicentre, cross-sectional study in England

Objectives
To examine the number of patients screening positive for depression, while self-completing an automated check-in screen prior to a general practice consultation.

Design
A descriptive cross-sectional study.

Setting
10 general practices in the West Midlands, England. Recruitment commenced in March 2023 and concluded in June 2023.

Participants
All patients aged 18 years and over, self-completing an automated check-in screen for any general practice prebooked appointment, were invited to participate during a 3-week recruitment period.

Primary and secondary outcome measures
The number of patients screening positive for depression using the Whooley case finding research questions was the primary outcome measure. Secondary outcome measures included: demographic and (general practice level) deprivation differences in completion responses.

Results
73.5% (n=3666) of patients self-completing an automated check-in screen participated in the CAse-fInding foR depressiOn in primary care (CAIRO) study, (61.1% (n=2239) female, mean age 55.0 years (18–96 years, SD=18.5)).
28.3% (n=1039) of participants provided a positive response to at least one of the two Whooley research questions (31.2% female and 23.8% male). Significantly more positive responses were obtained from females, those aged between 35 years and 49 years and those from more deprived practices.

Conclusions
Over a quarter of CAIRO participants provided a positive response to at least one of the two Whooley questions, suggesting possible unmet need in the population studied. A follow-up study could investigate whether responses provided at the point of check-in are raised and addressed in the subsequent consultation.

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Screening for depression among Spanish-speaking patients in primary care settings within the USA: a scoping review protocol to inform clinical practices

Introduction
In 2016, the United States Preventive Services Task Force (USPSTF) recommended depression screening for all adults in the public sector, with screening frequency determined by clinical judgement and patient circumstances. This practice aims to enable timely diagnosis and treatment, reducing long-term healthcare costs associated with this chronic health condition. However, the USPSTF offered no written recommendations for primary care settings serving non-English-speaking populations, particularly where providers speak English and patients speak Spanish. While some research exists on depression screening in linguistically diverse settings, the use of validated Spanish-language screenings in primary care settings is underexplored when it comes to implementing the USPSTF’s recommendation. This scoping review addresses this knowledge gap by (1) assessing the extent to which Spanish-speaking patients in the USA receive depression screening in Spanish and (2) using the Consolidated Framework for Implementation Research (CFIR) 2.0 to categorise barriers and facilitators to implementing Spanish-language depression screening tools in USA primary care settings. The findings will identify areas needing further research to improve depression screening guidelines for primary care practices serving Spanish-speaking patients.

Methods and analysis
This scoping review follows the Joanna Briggs Institute Manual for Evidence Synthesis and the Arksey and O’Malley scoping review methodology, updated by Levac and colleagues. The reporting protocol adheres to PRISMA-ScR. A systematic search will be conducted in PubMed, Embase, APA PsycINFO, CINAHL and Web of Science Core Collection for studies on Spanish-language depression screening for adults in non-Veterans Affairs Medical Centers in the USA, excluding those focused on youth or adolescents. We will extract data from qualitative, quantitative and mixed-methods studies on screening. We will also examine studies addressing provider-reported comfort and competency in screening Spanish-speaking patients. We hypothesise that primary care clinics have implemented strategies for screening Spanish-speaking patients for depression driven by healthcare provider initiatives, local policies, research funding or community needs. The review will extract data on sample size, study methodology, primary care settings, patient and provider demographics, depression screeners used, and barriers and facilitators to screening. The quality of the studies will be appraised using the Mixed Methods Appraisal Tool (MMAT).

Ethics and dissemination
At Brown University, scoping reviews that analyse and synthesise existing research do not require Institutional Review Board (IRB) approval, provided they do not involve primary data collection or direct interaction with human subjects. Findings will be disseminated through peer-reviewed journals, conference presentations and community workshops to improve practices and policies addressing language barriers in depression screening and care.

Registration details
This scoping review protocol is registered with the Open Science Framework (OSF) at https://osf.io/dyru5.

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Consumer perceptions and preferences of pharmacist-led professional services and attributes in Australia: a qualitative focus group study

Objective
This study investigates consumer views of pharmacist-led professional services in Australia, emphasising factors influencing their uptake and attributes valued by users.

Design
Semi-structured online focus groups explored the awareness, experiences and expectations of pharmacists and pharmacy professional services. Audio recordings were transcribed verbatim and de-identified. Data were analysed using the thematic analysis technique to identify common themes.

Setting
Three online focus groups were conducted, inviting participants from Australia

Participants
15 adults aged 18 years and above, English-speaking and self-identified as a consumer of health services or a health carer.

Results
Participants recognised pharmacists primarily as medication experts but also valued additional services like health screening, vaccination and chronic disease management. Consumer perceptions and experiences of professional pharmacy services focused on three themes: (1) convenience, (2) credibility and trust, and (3) communication and awareness. More specifically, attributes that influence service uptake include pharmacist competency, general practitioner (GP) endorsement, service availability, convenience, awareness and cost. Competency was associated with visible qualifications and specialised training, fostering consumer trust. Limited awareness of available services and privacy concerns posed barriers. Collaborative relationships between pharmacists and GPs, flexible hours and minimal waiting times, provision of services within pharmacists’ scope of practice and recognition from the government were particularly appealing factors.

Conclusions
The findings highlight opportunities to expand pharmacists’ roles in primary care, emphasising the need for tailored attributes, robust competency frameworks, GP endorsement and government support for sustainable service models. This work contributes to the growing evidence base on enhancing consumer-centred pharmacy services, guiding policy and practice improvements to meet evolving healthcare demands. Future research quantifying how much consumers value each attribute can help providers with limited resources prioritise better.

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The MOTILITY Mother-Child Cohort: a Danish prospective longitudinal cohort study of the infant gut microbiome, nutrition and bowel habits – a study protocol

Introduction
Concurrent with infants’ progression in dietary complexity and gut microbiome diversity, infants gradually change their defecation patterns during the first year of life. However, the links between bowel habits, the gut microbiota and early life nutrition remain unclear. The primary outcome is to characterise the gut microbiome development from birth to 1 year of age. Second, to investigate how bowel habits and nutrition in early life relate to the gut microbiome and metabolome during this period of life, and to explore how the development of the gut microbiome associates with host development.

Methods and analysis
The MOTILITY Mother-Child Cohort (MOTILITY) is a Danish prospective longitudinal cohort study enrolling up to 125 mother–infant dyads. Assessments occur at 36 weeks gestation (visit 1), birth (screening of infant) and 3, 6, 9 and 12 months (±2 weeks) post partum (visits 2–5). At visit 1, maternal anthropometrics, self-collected faecal and urine samples, and questionnaires on bowel habits and lifestyle are obtained. Between visits, infant faecal (biweekly), urine (monthly) and maternal breast milk (monthly until 6 months of age) samples are collected at home, and bowel habits and dietary intake are assessed biweekly by self-reported questionnaires. At visits 2–5, infant blood and saliva samples are collected, and anthropometric measurements are obtained. In addition, dietary intake is recorded thrice throughout the study period for mother and infant, respectively, and infant whole-gut transit time is estimated by sweet corn tests at 9 and 12 months of age. Birth, growth, motor development, sleep patterns, tooth development, overall health and well-being are assessed using questionnaires. Univariate and multivariate statistics will be applied to identify associations between the gut microbiome, early life nutrition and host physiology including bowel habits during the first year of life.

Ethics and dissemination
The MOTILITY study has been approved by the Research Ethics Committee for the Capital Region of Denmark (reference number: H-21063016). Selected results will be made available to the participants in the form of a summary document. Results will be published in peer-review journals and by means of national and international conferences.

Trial registration number
NCT05491161.

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Family Screening in Relatives at Risk for Plakophilin-2–Associated Arrhythmogenic Right Ventricular Cardiomyopathy

Circulation, Ahead of Print. BACKGROUND:Penetrance and risk of ventricular arrhythmias (VAs) in arrhythmogenic right ventricular cardiomyopathy (ARVC) are increasingly recognized as being genotype specific. Therefore, genotype-informed family screening protocols may lead to safer and more personalized recommendations than the current one-size-fits-all screening recommendations. We aimed to develop a safe, evidence-based plakophilin-2 (PKP2)–specific longitudinal screening algorithm.METHODS:We included 295 relatives (41% male; age 30.9 years [18.0–47.7 years]) with a pathogenic or likely pathogenicPKP2variant from 145 families. Phenotype was ascertained with ECG, Holter monitoring, and cardiac imaging and classified by the 2010 Task Force Criteria. VA was defined as a composite of sudden cardiac arrest or death, spontaneous sustained ventricular tachycardia, ventricular fibrillation, or appropriate implantable cardioverter defibrillator intervention. We performed Cox regression to determine predictors of ARVC development and multistate modeling to assess the probability of ARVC development and occurrence of VA.RESULTS:At baseline, 110 relatives (37%) had definite ARVC. During 8.5 years (4.2–12.9 years) of follow-up, 62 of 185 relatives (34%) without definite ARVC at baseline progressed to definite ARVC diagnosis, and 35 of 295 of all relatives (12%) had VA. VAs occurred only in relatives who previously fulfilled definite ARVC diagnosis. Relatives with borderline ARVC (fulfillment of one minor criterion plus the major family history criterion) progressed 5 times faster in the multistate model to definite ARVC diagnosis and compared with genotype-positive/phenotype-negative (G+/P−) relatives (ie, major family history criterion alone). Relatives 20 to 40 years of age had increased risk for developing definite ARVC (hazard ratio, 2.23;P=0.012) compared with those ≥40 years of age. New Task Force Criteria fulfillment most commonly occurred first on ECGs, followed by Holter monitoring and cardiac imaging. Consequently, 3 risk profiles were identified, and appropriate screening protocols were derived: relatives with borderline ARVC (annual ECG and Holter monitoring; complete evaluation [ie, ECGs, Holter monitoring, and imaging] every 2 years), younger (

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