TRanscutaneous lImb reCovEry Post-Stroke (TRICEPS): study protocol for a randomised, controlled, multiarm, multistage adaptive design trial

Introduction
Arm weakness after stroke is one of the leading causes of adult-onset disability. Invasive vagus nerve stimulation (VNS) paired with rehabilitation has been shown to improve arm recovery in chronic stroke. Small studies of non-invasive or transcutaneous VNS (tVNS) suggest it is safe and tolerable. However, it is not known whether tVNS paired with rehabilitation is effective in promoting arm recovery in chronic stroke and what the mechanisms of action are.

Methods and analysis
TRICEPS is a UK multicentre, double-blinded, superiority, parallel-group, three-arm two-stage with an option to select promising arm(s) at 50% accrual, individually randomised, sham-controlled trial. Up to 243 participants will be randomised (1:1:1) using minimisation via a restricted, web-based centralised system. tVNS will be delivered by a movement-activated tVNS system (TVNS Technologies), which delivers stimulation during repetitive task practice. Rehabilitation will consist of repetitive task training for 1 hour a day, 5 days per week for 12 weeks. Participants will be adults with anterior circulation ischaemic stroke between 6 months and 10 years prior with moderate-severe arm weakness. The primary outcome measure will be the change in Upper Limb Fugl-Meyer total motor score at 91 days after the start of treatment. Secondary outcome measures include the Wolf Motor Function Test, the Modified Ashworth Scale to assess spasticity in the affected arm and the Stroke-Specific Quality of Life Scale. A mechanistic substudy including 40 participants will explore the mechanisms of active versus sham tVNS using multimodal MRI and serum inflammatory cytokine levels. Participant recruitment started on 30 November 2023.

Ethics and dissemination
The study has received ethical approval from the Cambridge Central Research Ethics Committee (REC reference: 22/NI/0134). Dissemination of results will be via publications in scientific journals, meetings, written reports and articles in stakeholder publications.

Trial registration number
ISRCTN20221867.

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Recurrent Stroke Prediction by Applying a Stroke Polygenic Risk Score in the Japanese Population

Stroke, Ahead of Print. BACKGROUND:Recently, various polygenic risk score (PRS)–based methods were developed to improve stroke prediction. However, current PRSs (including cross-ancestry PRS) poorly predict recurrent stroke. Here, we aimed to determine whether the best PRS for Japanese individuals can also predict stroke recurrence in this population by extensively comparing the methods and maximizing the predictive performance for stroke onset.METHODS:We used data from the disease-oriented BBJ1 (BioBank Japan first cohort; recruited between 2003 and 2007, n=179 938) to derive and optimize the PRSs using a 10-fold cross-validation. We integrated the optimized PRSs for multiple traits, such as vascular risk factors and stroke subtypes to generate a single PRS using the meta-scoring approach (metaGRS). We used an independent BBJ2 (BBJ second cohort; recruited between 2012 and 2017, n=41 929) as a test sample to evaluate the association of the metaGRS with stroke and recurrent stroke. In addition, we analyzed its association stratified by risk factors. We administered 3 distinct tests to consider the potential index event bias.RESULTS:We analyzed recurrent stroke cases (n=174) and nonrecurrent stroke controls (n=1153) among subjects within the BBJ2. After adjusting for known risk factors, metaGRS was associated with stroke recurrence (adjusted odds ratio per SD, 1.18 [95% CI, 1.00–1.39];P=0.044), although no significant correlation was observed with the published PRSs. The outcomes derived from these examinations did not provide any significant indication of the influence of index event bias. The high metaGRS group without a history of hypertension had a higher risk of stroke recurrence than that of the low metaGRS group (adjusted odds ratio, 2.24 [95% CI, 1.07–4.66];P=0.032). There was no association at all in the hypertension group (adjusted odds ratio, 1.21 [95% CI, 0.69–2.13];P=0.50).CONCLUSIONS:The metaGRS developed in a Japanese cohort predicted stroke recurrence in an independent cohort of patients. In particular, it predicted an increased risk of recurrence among stroke patients without hypertension. These findings provide clues for additional genetic risk stratification and help in developing personalized strategies for stroke recurrence prevention.

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Effects of aquatic high-intensity interval training on aerobic capacity in adults with rheumatic and musculoskeletal diseases: the AquaHigh randomised controlled trial

Objectives
To examine the effects of 12 weeks aquatic high-intensity interval training (AHIIT) compared with aquatic moderate-intensity continuous training (AMICT) on aerobic capacity and lower limb functional strength in adults with rheumatic and musculoskeletal diseases (RMDs).

Design
An assessor-blinded randomised controlled trial.

Setting
Community-based setting.

Participants
89 participants (91% female, mean age 62 (SD 13) years) with RMDs were randomly allocated to AHIIT (n=44) or AMICT (n=45).

Interventions
Both groups participated in group-based peer-led exercise programmes two times per week for 12 weeks. The AHIIT group included four intervals of 4 min at high intensity (Borg scale 14–18). The AMICT group maintained moderate continuous intensity level (Borg scale 12–13).

Main outcome measures
Peak aerobic capacity (VO2peak) was estimated by time to exhaustion and lower limb functional strength with the 30-second sit-to-stand test (30sSTS) at baseline, 3 months and 6 months. A linear mixed model for repeated measures estimated the mean difference with 95% CI in VO2peak and 30sSTS.

Results
Mean exercise intensity was Borg scale 15 (SD 2) and 13 (SD 2) in the AHIIT and AMICT, respectively. Mean improvement in VO2peak in AHIIT was 1.9 mL•kg–1•min–1 (95% CI 0.045 to 3.77) compared with AMICT after 12 weeks (p0.05). No adverse events during exercise were reported.

Conclusions
AHIIT demonstrated significant improvements in aerobic capacity after 12 weeks, and the intervention was well tolerated with no adverse events reported. However, there was no maintenance of aerobic capacity at 6 months.

Trial registration number
NCT05209802.

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Development and cross-validation of a short questionnaire to evaluate self-reported positive health: a cross-sectional panel study of structural validity among a general Dutch population

Objectives
This study aimed to further develop and cross-validate a short questionnaire to measure self-reported Positive Health in general (Dutch) populations for evaluative purposes, stemming from the original 42 items of the My Positive Health (MPH) dialogue tool. Positive Health refers to ‘health from the perspective of patients and citizens’ following the concept of Huber et al.

Design and setting
A cross-sectional study was performed among a panel representative for the general adult Dutch population living at home.

Participants
The response rate was 76%, 1327 of a total of 2457 respondents were female, and mean age (years) was 53.3±17.8.

Methods
First, item reduction was carried out through content discussions following statistical output retrieved from factor structures and loadings, inter-item correlations and internal consistency (Cronbach’s alpha). Next, among the other half of the study population, measurement properties for the developed short questionnaire were calculated using goodness of fit indices from confirmatory factor analysis (CFA).

Results
The item reduction process (n=1199) resulted in a questionnaire of 22 items (PH22) with a four-factor structure and explained variance of 62.4%. Cronbach’s alpha values were 0.84, 0.92, 0.81 and 0.78 for the renamed factors ‘Physical fitness’ (5 items), ‘Contentment with self, others and life’ (nine items), ‘Daily life management’ (5 items) and ‘Future perspective’ (3 items), respectively. Cross-validation (n=1258) showed adequate goodness-of-fit indices of the PH22, based on both first-order and second-order CFA. The scores of the PH22 were normally distributed. No floor or ceiling effects were present.

Conclusions
A short 22-item questionnaire to measure self-reported Positive Health in a general (Dutch) population for evaluative purposes such as scientific or policy research at Positive Health or patient-centred interventions was developed and cross-validated, named PH22. This study supports its structural validity. To use this questionnaire in practice, its test-retest reliability and responsiveness should also be known. Future research has to reveal this.

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Cardiovascular risk factors and cognitive performance among people living with HIV: cross-sectional study in the country of Georgia

Objectives
Older people living with HIV (PLWH) globally are experiencing a combination of both communicable and non-communicable disease (NCD) morbidities. Vascular contributions to cognitive impairment and dementia (VCID) can contribute to adverse ageing brain health. This study aimed to measure VCID and HIV-related factors and evaluate their association with cognitive performance.

Design
A cross-sectional study.

Setting
Five cities in the country of Georgia.

Participants
We enrolled PLWH age ≥40 years. Recruitment and data collection were carried out between February and September 2023. We conducted face-to-face interviews and collected data on sociodemographic characteristics, medical history, HIV history, cardiovascular health, mental health, clinical measurements and cognitive performance.

Primary outcome measures
We calculated the estimated 10-year cardiovascular risk using the Framingham risk score (FRS). Descriptive analyses were conducted using the frequency distributions of relevant categorical variables and median and IQR for continuous variables. Multivariable linear regression analyses were conducted separately for each cognitive assessment score.

Results
A total of 125 PLWH aged ≥40 years were enrolled in the study. The median FRS was 9% (IQR: 4, 15), with 37 (30%) participants having intermediate risk and 17 (14%) with high risk of cardiovascular event. In univariate correlation analysis, FRS was associated with worse cognitive performance. The FRS remained associated with worse performance on the Trails Making Test B and Grooved Pegboard Test using multivariable models. On average, every 1 per cent increase in FRS corresponded to an increase of 1.65 s (95% CI: 0.11, 3.19, p=0.04) for completing the Trails Making Test B and an increase of 1.02 s (95% CI: 0.43, 1.60, p=0.001) for completing the Grooved Pegboard Test.

Conclusions
We found a high prevalence of cardiovascular risk and an association between this risk and cognitive performance in our sample. Our findings provide a baseline that can be further investigated in larger-scale studies with longitudinal assessment of cardiovascular risk factors and cognitive performance. Furthermore, it can inform the development of policies and programmes to mitigate adverse effects of VCID on the health of PLWH in Georgia and the Eastern Europe and Central Asia region.

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Time to recovery from severe pneumonia and its predictors among children aged 2-59 months admitted to the Asella Referral and Teaching Hospital, Asella, Ethiopia, 2023: a retrospective cohort study

Objective
To determine the time to recovery from severe pneumonia and its predictors in children aged 2–59 months admitted to the Asella Referral and Teaching Hospital, Ethiopia.

Design, participants, and setting
An institution-based retrospective cohort study was conducted on 424 children aged 2–59 months in Asella Town, Ethiopia. Medical records of eligible children were selected using a simple random sampling technique. The Kaplan-Meier curve and log-rank test were used to describe the survival function. Independent predictors of recovery time were identified using Cox regression analysis. The 95% CI of the HR with a corresponding p value of 0.05 was used to declare statistical significance.

Primary and secondary outcomes
Recovery time from severe pneumonia and its predictors.

Results
The median recovery time was 5 days. The incidence density of recovery was 16 (95% CI: 14.44 to 17.76) per 100-person-day observation. Being a rural resident (adjusted HR (AHR): 0.68; 95% CI: 0.57 to 0.82), aged 36–59 months (AHR: 0.70; 95% CI: 0.50 to 0.98), being underweight (AHR: 0.75; 95% CI: 0.59 to 0.95), the presence of danger signs (AHR: 0.31; 95% CI: 0.24 to 0.39) and having comorbidity (AHR: 0.38; 95% CI: 0.30 to 0.48) were significant predictors of time to recovery in children aged 2–59 months.

Conclusion
In this study, the median recovery time was longer than that reported in similar studies. Age, residence, underweight, danger signs and comorbidities were significant predictors. Therefore, families of children with identified predictors need counselling to prepare for the likelihood of slow recovery.

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Smartphone intervention for pregnancy smoking cessation with peer support: the study protocol of the SmokeFree Together 2.0 (SFT 2.0) randomised controlled trial

Introduction
Smoking in pregnancy negatively impacts the mother’s and offspring’s health. Mobile health, especially mobile phone-based approaches, shows promise in supporting pregnant women to quit smoking. Our previous research indicated that support from laypersons, such as family, friends and coworkers, can increase smoking cessation. Building on these findings, we developed an innovative smartphone application (app) that combines the power of social support with artificial intelligence. The app leverages the unique functionality of smartphones and reinforcement learning (RL) to provide a deeply tailored intervention that continuously adapts while emphasising positive support through reciprocal interactions between the smoker and the support person. Herein, we report the methods used to develop, implement and test the feasibility and effectiveness of a novel adaptive mobile pregnancy tobacco cessation app-based intervention using deep tailoring and a self-nominated supporter.

Methods and analysis
The study is a type II hybrid effectiveness-implementation randomised controlled trial. In total, 300 pregnant smokers and their supporters will be randomised to (1) the SmokeFree Together 2.0 app and an RL-based intervention that continuously decides if a counselling call is needed using a fixed algorithm measuring motivation and craving or (2) a control group. The intervention will be administered throughout pregnancy up to 1 month after giving birth, with a 5-month follow-up period and outcome assessments at 3-month and 6-month post partum. Cessation (primary outcome) is defined as 7-day point biochemically verified prevalence of tobacco use and abstinence since birth, assessed at 6 months post partum. The central hypothesis is that the intervention will show evidence of feasibility and effectiveness in increasing social support, pregnancy cessation and postnatal abstinence.

Ethics and dissemination
The Institutional Review Board of Michigan State University (#IRB00000297) approved this trial. The findings will be disseminated through peer-reviewed publications and participation in scientific conferences.

Trial registration number
NCT05337722. Protocol version: 1.3 from 15.05.2024.

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Cohort profile: the Genetics of Glucose regulation in Gestation and Growth (Gen3G) – a prospective prebirth cohort of mother-child pairs in Sherbrooke, Canada, 3-year and 5-year follow-up visits

Purpose
Initiated in 2010, the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort investigates the pathophysiology of impaired glycaemic regulation in pregnancy and evaluates its impact on both the mothers and her offspring health trajectory. Follow-up visits 3 and 5 years after delivery aimed to investigate pregnancy-related risk factors such as maternal obesity and gestational hyperglycaemia in relation to the mother’s metabolic health after pregnancy, and with offspring health outcomes such as risk of obesity and neurodevelopmental problems in early childhood. We also investigated molecular mechanisms involved in the fetal programming of these later health outcomes.

Participants
Of the 1024 women originally recruited in the first trimester of pregnancy, we have targeted the 854 who had complete glucose tolerance test data and the 724 newborns who provided placenta and/or cord blood samples for follow-up recruitment. Of these, 695 mother–child dyads agreed to be contacted for the prospective follow-up visits. 448 and 521 mother–child dyads completed the research visits at 3 and 5 years after delivery respectively.

Findings to date
At both visits, we collected the mother’s and child’s medical history, lifestyle (using validated questionnaires), sociodemographic status, anthropometric measurements, mother’s blood samples, child’s saliva samples and growth charts. At the 5-year-old visit, we additionally collected the mother’s and child’s urine and stool samples and the child’s blood samples; we performed a 75 g oral glucose tolerance test in the mothers and assessed the body composition in children using dual-energy X-ray absorptiometry. Using the Gen3G rich longitudinal data set, we have enhanced the understanding of the pathophysiology and characterisation of the heterogeneity of gestational diabetes mellitus, and we have shown that gestational hyperglycaemia and insulin resistance are associated with offspring epigenetics (DNA methylation) variations in the placenta, cord blood and blood at 5 years of age, as well as with offspring anthropometric, metabolic and neurodevelopmental outcomes in early childhood.

Future plans
We are currently conducting a prospective follow-up of mothers and their children 12 years after delivery to study how prenatal and early-life metabolic factors may programme childhood adiposity and obesogenic dietary behaviours. This follow-up should be completed by the end of 2026.

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HiSNAP trial–a multicentre, randomised, open-label, blinded end point, safety and efficacy trial of conventional (300 mg/kg) versus higher doses of acetylcysteine (450 mg/kg and 600 mg/kg) in patients with paracetamol overdose in the UK: study protocol

Introduction
In overdose, a larger proportion of paracetamol (acetaminophen) is converted in the liver to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Glutathione (GSH) is the endogenous antioxidant that protects cells from NAPQI-induced injury. In overdose, GSH stores may become depleted, leaving NAPQI free to produce liver damage. N-Acetylcysteine (NAC) helps prevent paracetamol toxicity by replenishing liver GSH. This protective effect of NAC produces specific metabolites in the circulation. Currently, regardless of the paracetamol dose ingested, patients in the UK receive a dose of NAC based only on their weight. Basic pharmacology, mathematical modelling and observational studies suggest that this dose may be insufficient in some patients (particularly those taking a large overdose).

Methods and analysis
A multicentre trial, taking place across several hospitals in Scotland, UK, within Emergency Departments and Acute Medical Units. Recruitment commenced on 19 February 2024 and is anticipated to run for approximately 2 years. This is a three-group dose-finding trial, in which participants are assigned in a 1:1:1 ratio to either Standard NAC (300 mg/kg) or higher doses of 450 mg/kg (Group 1) and 600 mg/kg (Group 2). The primary outcome is the proportion of paracetamol metabolites in the circulation that are directly produced by GSH/NAC detoxification of NAPQI. A higher proportion of these metabolites will indicate that the additional NAC is reducing the amount of toxic paracetamol metabolites in the body. The study will first test the primary outcome on the HiSNAP Group 2 against Standard NAC; only if that is significant will HiSNAP Group 1 be tested against Standard NAC.

Ethics and dissemination
The HiSNAP trial has been approved by the East Midlands (Derby) Research Ethics Committee (reference 23/EM/0129), NHS Lothian Research and Development Department, and the MHRA. Results will be disseminated by peer-reviewed publication, conferences and linked on isrctn.com.

Trial registration number
ISRCTN17516192.

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Probiotics influencing response of antibodies over time in seniors after COVID-19 vaccine (PIRATES-COV): a randomised controlled trial protocol

Introduction
The elderly are particularly vulnerable to morbidity and mortality from COVID-19, the disease caused by the SARS-CoV-2. Approximately 20% of the elderly showed no antibodies 3–5 months post-second dose of the COVID-19 vaccine. As probiotics have been shown to increase influenza-specific antibody levels post-influenza vaccination, we aim to reduce the percentage of participants without antibodies against the SARS-CoV-2 spike protein receptor-binding domain (anti-S1-RBD) at 6 months post-vaccination.

Methods and analysis
Our study design is a double-blind randomised controlled trial, using intention-to-treat analysis. Eligible participants are a purposive sample of 688 adults aged 65–89 years, in Quebec, Canada, not diagnosed with COVID-19 in the 3 months prior to recruitment and who wish to receive a government-recommended mRNA booster (Pfizer-BioNTech, Moderna) vaccine. The intervention consists of one capsule/day of a probiotic dietary supplement of Lacticaseibacillus rhamnosus and Lacticaseibacillus casei 6×109 CFU/capsule or a placebo, for 15 days pre-booster and post-booster vaccine. All participants provide dried blood spot samples at three timepoints (inclusion, 3 and 6 months post-vaccination) and a stool sample for microbiome analysis. A subgroup of 100 participants living near Sherbrooke, Quebec, is expected to volunteer for two onsite blood-test visits (at inclusion and 6 months post-vaccination). The primary outcome is the percentage of participants without anti-S1-RBD antibodies at 6 months post-vaccination. Secondary outcomes include longitudinal analysis of anti-S1-RBD and anti-N antibodies at three timepoints. In the subgroup, serum levels of neutralising antibodies will be determined at inclusion and 6 months post-vaccination. Probiotic and vaccine side effects are monitored. At the end of the study, we expect to identify the adjuvant effect of probiotic on vaccine-induced immune response.

Ethics and dissemination
The study was approved by Research Ethics Board of the Centre Intégré Universitaire de Santé et des Services Sociaux de l’Estrie- Centre Hospitalier Universitaire de Sherbrooke (CIUSSS de l’Estrie-CHUS) and the CHU de Québec-Université Laval # MP-31-2022-4598 as well as Health Canada. All participants will provide informed consent. Results will be disseminated to the scientific community and to all networks related in this research.

Trial registration number
NCT05195151.

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GPT for RCTs? Using AI to determine adherence to clinical trial reporting guidelines

Objectives
Adherence to established reporting guidelines can improve clinical trial reporting standards, but attempts to improve adherence have produced mixed results. This exploratory study aimed to determine how accurate a large language model generative artificial intelligence system (AI-LLM) was for determining reporting guideline compliance in a sample of sports medicine clinical trial reports.

Design
This study was an exploratory retrospective data analysis. OpenAI GPT-4 and Meta Llama 2 AI-LLM were evaluated for their ability to determine reporting guideline adherence in a sample of sports medicine and exercise science clinical trial reports.

Setting
Academic research institution.

Participants
The study sample included 113 published sports medicine and exercise science clinical trial papers. For each paper, the GPT-4 Turbo and Llama 2 70B models were prompted to answer a series of nine reporting guideline questions about the text of the article. The GPT-4 Vision model was prompted to answer two additional reporting guideline questions about the participant flow diagram in a subset of articles. The dataset was randomly split (80/20) into a TRAIN and TEST dataset. Hyperparameter and fine-tuning were performed using the TRAIN dataset. The Llama 2 model was fine-tuned using the data from the GPT-4 Turbo analysis of the TRAIN dataset.

Primary and secondary outcome measures
The primary outcome was the F1-score, a measure of model performance on the TEST dataset. The secondary outcome was the model’s classification accuracy (%).

Results
Across all questions about the article text, the GPT-4 Turbo AI-LLM demonstrated acceptable performance (F1-score=0.89, accuracy (95% CI) = 90% (85% to 94%)). Accuracy for all reporting guidelines was >80%. The Llama 2 model accuracy was initially poor (F1-score=0.63, accuracy (95% CI) = 64% (57% to 71%)) and improved with fine-tuning (F1-score=0.84, accuracy (95% CI) = 83% (77% to 88%)). The GPT-4 Vision model accurately identified all participant flow diagrams (accuracy (95% CI) = 100% (89% to 100%)) but was less accurate at identifying when details were missing from the flow diagram (accuracy (95% CI) = 57% (39% to 73%)).

Conclusions
Both the GPT-4 and fine-tuned Llama 2 AI-LLMs showed promise as tools for assessing reporting guideline compliance. Next steps should include developing an efficient, open-source AI-LLM and exploring methods to improve model accuracy.

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Systematic review and meta-analysis protocol of patient-centred interventions for sustained viral suppression among patients on antiretroviral therapy in South Africa

Background
Sustained viral suppression is critical not only for ensuring long and healthy livelihoods among the people who are living with Human immunodefficiency virus (HIV), but it is also crucial for prevention of new infections of HIV perinatally and to HIV negative sexual partners through unsafe sex. Available data, however, suggest that some of the patients who are on antiretroviral therapy (ART) fail to maintain the suppressed state once they have achieved it, with others reporting subsequent episodes of viral rebound following resuppression. The association of depression, social issues including day-to-day routine and stigma with poor adherence inadvertently calls for the formulation of intervention strategies that are patient centric. The proposed systematic review and meta-analysis study will identify studies of intervention strategies that are in place to address viral suppression and viral rebound among HIV positive patients who are on ART.

Methods and analysis
The proposed study will conduct a systematic search of peer-reviewed articles through PubMed, Scopus and EBSCOhost databases. Data collection will occur in March 2025. The reviewers will include studies if they were published in South Africa, between 2013 and 2024, and if they were observational in design and written in English. Identified articles will be exported onto Rayyan software where processes of de-duplication and screening by two independent reviewers will be performed. A meta-analysis of data will be conducted on Stata 17 software using the random effects model. The results will be generated in a table and displayed graphically in a forest plot which will indicate type of study, type of intervention, point effect size and the corresponding 95% CI, weight per cent contributed by each study to the pooled estimate, pooled estimate and the 95% CI and measures of heterogeneity. Sensitivity analysis will be performed to identify the source of heterogeneity. Publication bias will be assessed by funnel plot and the Egger’s asymmetry test.

Ethics and dissemination
The study protocol has obtained ethical clearance from the ethics committee of Sefako Makgatho Health Sciences University (SMUREC/H/31/2024:PG). As this will be a systematic review study, involving no human participants, informed consent will not be required. However, for integrity, the findings will be prepared and disseminated widely through peer-reviewed publication and in various media, including conferences, congresses or symposia.

PROSPERO registration number
CRD42024532244.

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Intermittent Theta Burst Stimulation Over Cerebellum Facilitates Neurological Recovery in Poststroke Depression via the cAMP/PKA/CREB Pathway

Stroke, Ahead of Print. BACKGROUND:Stroke causes somatic dysfunction and psychological disorders, leading to poststroke depression (PSD). This study investigates mood alterations in PSD models via cerebellar intermittent theta burst stimulation (iTBS).METHODS:PSD animal models were developed using middle cerebral artery occlusion and chronic unpredictable mild stress procedures. PSD models underwent cerebellar iTBS with different pulse numbers. Neurological recovery was evaluated using open-field test, sucrose preference test, forced swimming test, and balance beam test. Golgi and hematoxylin-eosin staining assessed neuronal repair, while quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and Western blotting evaluated effects on BDNF (brain-derived neurotrophic factor), hypothalamic-pituitary-adrenal axis factors, and the cAMP/PKA (protein kinase A)/CREB (cAMP-response element–binding protein) pathway. The study first determined the effects of different intensities of iTBS stimulation on neurological recovery in PSD rats. Second, the effects of iTBS stimulation on the cAMP/PKA/CREB pathway were verified using adenoviral blockade of PKA and CREB at iTBS-1800.RESULTS:PSD models showed decreased vertical movement, locomotor distance, and sucrose preference and increased immobility time and balance beam test score, which were reversed by iTBS. iTBS increased dendritic length and spine density in Purkinje cells, alleviated neuronal damage in multiple brain regions, and enhanced BDNF synthesis. It also regulated adrenocorticotropic hormone, cortisol, and GR (glucocorticoid receptor) expression, and activated the cAMP/PKA/CREB pathway.CONCLUSIONS:Cerebellar iTBS improves PSD by activating the cAMP-PKA/CREB pathway, increasing BDNF, and reducing hypothalamic-pituitary-adrenal axis hyperactivity, suggesting potential for human PSD treatment.

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Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial

Stroke, Ahead of Print. BACKGROUND:Past failures in translating stroke cerebroprotection provoked calls for a more rigorous methodological approach, leading to the stroke preclinical assessment network SPAN (Stroke Preclinical Assessment Network), where uric acid (UA) treatment exceeded a prespecified efficacy boundary for the primary functional outcome. Still, successful translation to humans requires confirmation of the effect of UA across key biological variables relevant to patients with stroke.METHODS:We measured the effects of intravenous UA treatment (16 mg/kg) versus intravenous saline in groups of animals enrolled in the SPAN network with diverse comorbidities, sex, and age. The masked study drug or placebo was administered during reperfusion in rodents undergoing a transient middle cerebral artery filament occlusion. The primary outcome was the modified corner test index at day 30 poststroke, and numerous secondary outcomes were collected. A modified intention-to-treat population was used in the analysis. We tested for any interactions with sex, age, and comorbidities (obesity-induced hyperglycemia and hypertension).RESULTS:In total, 710 animals were randomized to receive either intravenous UA or saline. After accounting for procedural dropouts and exclusions from treatment, a total of 687 animals were qualified and analyzed, including 458 assigned to UA and 229 to intravenous saline control. UA-treated animals exhibited a better primary functional outcome at day 30 (probability, 0.56 [95% CI, 0.52–0.60];P=0.006). UA-treated animals also had a better corner test index at day 7 (probability, 0.55 [95% CI, 0.5–0.59];P=0.035) and a higher survival rate at day 30 (hazard ratio, 1.41 [95% CI, 1.08–1.83];P=0.011). Brain morphometry at day 2 and 30 was comparable between the treatment groups. The improved functional outcome and survival in UA-treated animals were preserved across different species, sexes, ages, and comorbidities.CONCLUSIONS:UA provides ischemic stroke cerebroprotection across key relevant biological variables, making it a promising intervention to be further tested in human clinical trials.

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Impact of digital antenatal care intervention on paper-based antenatal care recordkeeping: a before-and-after study in primary healthcare facilities in Nepal

Objective
To assess the impact of introducing electronic decision support systems (EDSS)—electronic data entry implemented alongside existing paper-based antenatal care (ANC) records—on the completeness and agreement of ANC records.

Design
Two-phase cross-sectional (before and after) substudy of the mobile health integrated model of hypertension, diabetes and ANC (mIRA project) process evaluation.

Setting
Four rural districts in Bagmati Province, Nepal, in 19 primary healthcare facilities.

Participants
ANC records from pregnant women attending facilities before (n=136) and after (n=138) EDSS implementation.

Main outcome measures
For selected indicators in the ANC card and ANC register, we estimated the percentage completeness (any value recorded) and agreement (whether values matched) before and after EDSS implementation. We also reported the completeness of indicators in the EDSS and calculated the agreement between the ANC card and EDSS. 2 or Fisher’s exact test, as appropriate, was used to assess differences in completeness before and after implementation.

Results
Completeness of paper-based ANC records was high before implementation ( >90%) for all indicators, except tetanus vaccination (15% improvement in the completeness of tetanus vaccination date in paper-based ANC records (77.0%–96.4% for ANC cards and 81.9%–98.9% for ANC register). Agreement between the ANC card and ANC register increased slightly for all indicators after implementation, and the tetanus vaccination date showed the largest increase (38.2%–57.2%). Indicator completeness in the EDSS was low, ranging from 38.2% to 88.7%.

Conclusion
We found slight improvements in the completeness and agreement of paper-based ANC records following EDSS implementation. The lower percentage of completeness in the EDSS suggests that any large-scale implementation should consider how to integrate digital and paper-based records to decrease the data entry burden on ANC providers. However, the study’s small sample size limited the ability to examine variation in effects.

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