Impact of antidiabetic medication type on a new episode of depression: a retrospective cohort study in Texas, USA

Objectives
To examine the associations between antidiabetic medication type and a new episode of depression using 100% Texas Medicare database during 2009 and 2018.

Design
A retrospective cohort study.

Setting
A population-based study using the Texas Medicare data.

Interventions
11 common antihyperglycaemic medication types, alone and in combinations: metformin-only, five non-metformin-containing regimens (dipeptidyl peptidase-4 inhibitor (DPP4i) only, sulfonylureas (SU) only, thiazolidinediones (TZD) only, SU/DPP4i and SU/TZD) and five metformin-containing combination treatments (metformin/DPP4i, metformin/SU, metformin/TZD, metformin/SU/DPP4i and metformin/SU/TZD).

Participants
This study included 59 057 type 2 diabetes (T2D) patients from a cohort of Texas Medicare beneficiaries who were aged ≥66 years, had consistent diabetes medication intake, were not diagnosed with depression or prescribed antidepressants during the 2-year look-back period and received regular care from Medicare providers.

Main outcomes and measures
The main outcome was a new episode of depression, identified by a new depression diagnosis during the follow-up period.

Results
A total of 59 057 T2D patients (mean (SD) age, 75.4 (6.4) years; 30 798 (52.1%) female) were followed up to 96 months. Of these, 22.5% patients had a new episode of depression at the 5-year follow-up. Compared with the metformin-only group, patients in the non-metformin-containing regimens had a higher risk of new episode depression (HR: 1.17, 95% CI 1.05 to 1.30 for DPP4i-only; HR: 1.06, 95% CI 1.01 to 1.12 for SU-only), but there was no significant difference among patients receiving metformin-containing combination therapy. Metformin/TZD and metformin/SU/DPP4i combination treatments had a lower risk of new episodes of depression than metformin-only (HR: 0.88, 95% CI 0.78 to 0.99 and HR: 0.83, 95% CI 0.71 to 0.98 separately). The same direction of association was observed in sensitivity analyses.

Conclusions
This retrospective cohort study found that T2D patients treated with metformin/TZD and metformin/SU/DPP4i had the lowest risk of new episodes of depression. These findings suggest that certain combinations of metformin with other antidiabetic medications may be associated with a reduced risk of new-onset depression. Therefore, it could be beneficial to incorporate depression risk evaluation into routine diabetes care and consider it in the decision-making process for diabetes medication types, especially when deprescribing metformin.

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Replicating a COVID-19 study in a national England database to assess the generalisability of research with regional electronic health record data

Objectives
To assess the degree to which we can replicate a study between a regional and a national database of electronic health record data in the UK. The original study examined the risk factors associated with hospitalisation following COVID-19 infection in people with diabetes.

Design
A replication of a retrospective cohort study.

Setting
Observational electronic health record data from primary and secondary care sources in the UK. The original study used data from a large, urbanised region (Greater Manchester Care Record, Greater Manchester, UK—2.8 m patients). This replication study used a national database covering the whole of England, UK (NHS England’s Secure Data Environment service for England, accessed via the BHF Data Science Centre’s CVD-COVID-UK/COVID-IMPACT Consortium—54 m patients).

Participants
Individuals with a diagnosis of type 1 diabetes or type 2 diabetes prior to a positive COVID-19 test result. The matched controls (3:1) were individuals who had a positive COVID-19 test result, but who did not have a diagnosis of diabetes on the date of their positive COVID-19 test result. Matching was done on age at COVID-19 diagnosis, sex and approximate date of COVID-19 test.

Primary and secondary outcome measures
Hospitalisation within 28 days of a positive COVID-19 test.

Results
We found that many of the effect sizes did not show a statistically significant difference, but that some did. Where effect sizes were statistically significant in the regional study, then they remained significant in the national study and the effect size was the same direction and of similar magnitude.

Conclusions
There is some evidence that the findings from studies in smaller regional datasets can be extrapolated to a larger, national setting. However, there were some differences, and therefore replication studies remain an essential part of healthcare research.

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TRANSCENDENT (Transforming Research by Assessing Neuroinformatics across the Spectrum of Concussion by Embedding iNterdisciplinary Data-collection to Enable Novel Treatments): protocol for a prospective observational cohort study of concussion patients with embedded comparative effectiveness research within a network of learning health system concussion clinics in Canada

Introduction
Concussion affects over 400 000 Canadians annually, with a range of causes and impacts on health-related quality of life. Research to date has disproportionately focused on athletes, military personnel and level I trauma centre patients, and may not be applicable to the broader community. The TRANSCENDENT Concussion Research Program aims to address patient- and clinician-identified research priorities, through the integration of clinical data from patients of all ages and injury mechanisms, patient-reported outcomes and objective biomarkers across factors of intersectionality. Seeking guidance from our Community Advisory Committee will ensure meaningful patient partnership and research findings that are relevant to the wider concussion community.

Methods and analysis
This prospective observational cohort study will recruit 5500 participants over 5 years from three 360 Concussion Care clinic locations across Ontario, Canada, with a subset of participants enrolling in specific objective assessments including testing of autonomic function, exercise tolerance, vision, advanced neuroimaging and fluid biomarkers. Analysis will be predicated on pre-specified research questions, and data shared with the Ontario Brain Institute’s Brain-CODE database. This work will represent one of the largest concussion databases to date, and by sharing it, we will advance the field of concussion and prevent siloing within brain health research.

Ethics and dissemination
This study was approved by the Children’s Hospital of Eastern Ontario Research Ethics Board and preregistered on OSF (25 June 2024); https://doi.org/10.17605/OSF.IO/HYDZC. Dissemination of findings will be multifaceted, including conference presentations, peer-reviewed publications and sharing of adapted materials (eg, videos, infographics, plain language summaries) with community groups and key knowledge users.

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Effects of Spirulina platensis supplementation on quality of life, severity of disease and serum total antioxidant capacity, malondialdehyde and zonulin in constipation-predominant irritable bowel syndrome: protocol for a randomised, double-blinded, placebo-controlled clinical trial from Iran

Introduction
Irritable bowel syndrome (IBS) is one of the most common chronic gut–brain interaction disorders. Nevertheless, there is currently no treatment for IBS. Low-grade inflammation and oxidative stress are contributing factors to the increased perception of abdominal pain and heightened sensitivity of the nervous system in these patients. Spirulina platensis is a rich source of essential nutrients, including amino acids, vitamins, minerals, phytochemicals, essential fatty acids and fibre. It has been found that Spirulina possesses a variety of therapeutic properties such as antioxidant, anti-inflammatory and antidepressant effects, which may be advantageous in reducing complications of IBS. The aim of present randomised clinical trial (RCT) is to assess the efficacy of Spirulina supplementation on IBS.

Methods and analysis
This study is a 12-week, 1:1 parallel-group, double-blinded, randomised controlled trial. Sixty adult individuals diagnosed with IBS according to the Rome IV criteria will be randomised to consume either Spirulina capsules (500 mg) or a placebo, two times a day. The primary outcomes of this RCT are the changes in the IBS quality of life, severity of IBS symptoms, and gut permeability from baseline to 12 weeks of the intervention. The secondary outcomes are the changes in the serum total antioxidant capacity and serum malondialdehyde from baseline to the end of intervention. If this RCT demonstrates significant results in gut permeability, antioxidant status and reduction in IBS symptoms, it could support the use of Spirulina in managing IBS and could potentially reduce healthcare costs.

Ethics and dissemination
The study protocol has been approved by the Medical Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (ID: IR.MUI.RESEARCH.REC.1401.370). Findings will be presented in subsequent publications.

Trial registration number
IRCT20140208016529N8; Iranian Registry of Clinical Trials; registered on 25 April 2023.

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C-reactive protein in the first 30 postoperative days and its discriminative value as a marker for postoperative infections, a multicentre cohort study

Objective
To assess the association of C-reactive protein (CRP) with postoperative infections for eight different types of surgery using big data.

Design
A multicentre cohort study with longitudinally collected data from electronic health records, collected from 1 January 2011 to 22 September 2023.

Setting
Data of two tertiary medical centres in the Netherlands were used.

Participants
This study included all procedures (42 125 in total) in adult patients undergoing surgery in two tertiary medical centres in the Netherlands.

Outcome measures
The primary outcome was the association between CRP and a postoperative infection in the first 30 days postoperatively. Postoperative infection was defined by an action-based definition, that is, patients had to be treated for an infection with anti-microbial treatment and/or an intervention (eg, surgical drainage) to be classified as having a postoperative infection. CRP measurements were divided into a reference group (0–5.0 mg/dL) and four groups for comparison (5.1–10.0 mg/dL, 10.1–15.0 mg/dL, 15.1–20.0 mg/dL and >20.0 mg/dL). Subgroup analyses were performed for eight major surgical subspecialties and for the two medical centres separately.

Results
A total of 175,779 CRP measurements were performed, of which the majority was drawn in the first postoperative week. The ORs for developing a postoperative infection varied between 1.0 (0.9–1.1 95% CI) and 12.0 (9.5–15.1 95% CI), with a stronger association for the higher level of CRP categories and when more time had elapsed since surgery. Sensitivity ranged between 11% and 34%, specificity ranged between 64 and 95%, and the positive and negative predicting value ranged between 12% and 51% and 88% and 94%, respectively. For the surgical subspecialties and the two hospitals separately, similar results were found.

Conclusion
In this study, an elevated postoperative CRP was associated with postoperative infections with a stronger association for higher CRP levels. The association was stronger if a longer time had elapsed since surgery, which contrasts with the moment most CRP measurements were done, namely in the first postoperative week. Clinicians should take the evolving value of CRP in mind when using it in the diagnosis of postoperative infections.

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Mapping evidence on educational interventions for adolescents with cancer: a scoping review protocol

Introduction
Adolescents diagnosed with cancer face unique challenges that can significantly impact their physical, emotional and social well-being. Educational interventions are essential in providing these young patients with the knowledge and skills necessary to navigate their cancer journey effectively. This scoping review aims to map the existing evidence on educational interventions tailored for adolescents with cancer, identifying gaps in the literature and informing future research and practice.

Methods and analysis
The review will follow a systematic scoping review as outlined by the Joanna Briggs Institute. A preliminary search was conducted in June 2024 with the PubMed database. This will be followed by a comprehensive search strategy across multiple databases, including PubMed, SCOPUS, WoS, PsycINFO, GIM and CINAHL, to identify relevant literature published in English. All types of educational interventions targeting adolescents with cancer will be included, while studies focusing on non-cancer populations or published in non-English languages will be excluded. Data extraction will be conducted by two independent reviewers using a standardised tool, and qualitative content analysis will be performed to summarise the findings. The results will be presented in tables and figures, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: Extension for Scoping Reviews guidelines. This scoping review has been registered with Open Science Framework (https://osf.io/7p93v).

Ethics and dissemination
As this scoping review will use secondary data from published literature, ethical approval is not required. The findings will be disseminated through peer-reviewed publications, conference presentations and stakeholder engagement.

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Association between herpes simplex virus 1 and dementia: a systematic review protocol

Introduction
Herpes simplex virus 1 (HSV-1) infects approximately two-thirds of the global population under the age of 50 years. Although widely prevalent, the possible implications of HSV-1 in neurodegenerative diseases, especially dementia and Alzheimer’s disease, remain poorly understood. This review seeks to elucidate this association and explore the potential benefits of preventing or treating herpesvirus infections on dementia risk. The goal is to enhance our understanding of HSV-1’s potential role in dementia, which could inform the development of future therapeutic interventions for these conditions.

Methods and analysis
PubMed, Embase (Elsevier/Ovid), Web of Science, Scopus, Global Health, PsycInfo, Cochrane Library and Clinicaltrials.gov will be searched from the inception of each respective database. Studies that have HSV-1 as an exposure and dementia, or its subtypes, as a primary outcome will be included. Two researchers will independently screen titles, abstracts and full texts, with discrepancies resolved by a third researcher. Systematic data extraction from eligible studies will be performed using a standardised template. Risk of bias of individual studies will be assessed with the Cochrane Collaboration approach. We will assess the overall quality of cumulative evidence using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Statistical analysis will employ a random effects model, and heterogeneity will be determined with Cochrane’s Q test and assessed using I2. Studies will be grouped by population subgroups and dementia subtypes when possible to explore nuances in results. We will consider performing meta-regression if heterogeneity remains after subgroup analyses. All statistical analyses will be conducted using Stata V.18 software (College Station, Texas, USA).

Ethics and dissemination
No ethical approval is required since data will be collected from existing studies. The review will be disseminated through peer-reviewed publication and at national and international conferences.

PROSPERO registration number
CRD42024516789.

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Influence of context on engagement with COVID-19 testing: a scoping review of barriers and facilitators to testing for healthcare workers, care homes and schools in the UK

Objective
The UK government’s response to the COVID-19 pandemic included a ‘test, trace and isolate’ strategy. Testing services for healthcare workers, care homes and schools accounted for the greatest spend and volume of tests. We reviewed relevant literature to identify common and unique barriers and facilitators to engaging with each of these testing services.

Design
Scoping review.

Search strategy
PubMed, Scopus and the WHO COVID-19 Research Database were searched for evidence published between 1 January 2020 and 7 November 2022. This was supplemented by evidence identified via free-text searches on Google Scholar and provided by the UK Health Security Agency (UKHSA).

Data extraction and synthesis
Data were extracted by a team of reviewers and synthesised thematically under the broad headings of perceptions, experiences, barriers and facilitators to engaging with the COVID-19 testing programme.

Results
This study included 40 sources, including 17 from projects that informed UKHSA’s decisions during the pandemic. Eight themes emerged and were used to categorise barriers and facilitators to engaging with the testing services for healthcare workers, care homes and schools: (1) perceived value, (2) trust in the tests and public bodies, (3) importance of infrastructure, (4) impact of media and social networks, (5) physical burden of the test, (6) perceived capability to undertake testing, (7) importance of relevant information and 8) consequences of testing.

Conclusions
Universal barriers and facilitators to engagement with the testing programme related to the core elements of each testing service, such as uncomfortable specimen collection and the influence of media and peers; these could be mitigated or leveraged to increase engagement across settings. However, the individuals involved, perceptions of value and available resources differed across services, leading to unique experiences between settings. Thus, consideration of context is crucial when designing and implementing a testing programme in response to a pandemic.

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Iron deficiency in patients with cardiogenic shock: protocol for a scoping review

Introduction
Cardiogenic shock (CS) is a severe condition characterised by low cardiac output and often hypotension, which results in organ hypoperfusion due to cardiac failure. As a form of acute heart failure, this condition seems to share similar underlying pathological mechanisms. It is well established that iron deficiency is correlated with chronic and acute heart failure, causing worsening of the symptoms, reduction of quality of life and survival and simultaneously increasing the rehospitalisation rates for all causes in these patients. It remains unclear whether there is an association between iron deficiency and CS. The objective of this scoping review will be to determine the actual state of the art regarding the significance of iron deficiency in patients affected by CS.

Methods and analysis
We will conduct a systematic review of the literature using MEDLINE and EMBASE via ‘Ovid’ (Elsevier) and Web of Science (2024 Clarivate). The goal is to analyse the incidence and clinical significance of iron deficiency in patients affected by cardiogenic shock. To gain a deeper insight into the underlying pathophysiological mechanisms, the review will include basic research conducted on both human subjects and on animal models as well as observational, randomised controlled studies and systematic reviews and meta-analysis. To maximise the identification of relevant reports and reduce loss of information, a systematic search of the literature will be performed from inception until January 2025 using the terms “iron deficiency” as well as “iron”, “ferritin”, “transferrin”, “transferrin saturation”, “hepcidin” and “soluble transferrin receptor” matching these terms with the keywords “cardiogenic shock”, “acute heart failure”, “advanced heart failure”, “decompensated heart failure”, “lvad”, “left ventricular assist device”, “mechanical circulatory support”, “VA-ECMO” and “Extracorporeal Life Support”. We will also use the corresponding MeSH and Emtree terms. In order to find grey literature, we will use the OADT.org internet-based database.

Ethics and dissemination
No additional ethics approval is required, as this review is based on existing research without new data collection. Only studies with ethics approval will be included. We plan to publish our findings in a peer-reviewed journal and present them at international conferences on cardiology, intensive and acute cardiovascular care, cardiac surgery and cardioanaesthesiology.

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Hypoxic Preconditioning Enhances the Potential of Mesenchymal Stem Cells to Treat Neonatal Hypoxic-Ischemic Brain Injury

Stroke, Ahead of Print. BACKGROUND:Neonatal hypoxic-ischemic (HI) brain injury is one of the leading causes of long-term neurological morbidity in newborns. Current treatment options for HI brain injury are limited, but mesenchymal stem cell (MSC) therapy is a promising strategy to boost neuroregeneration after injury. Optimization strategies to further enhance the potential of MSCs are under development. The current study aimed to test the potency of hypoxic preconditioning of MSCs to enhance the therapeutic efficacy in a mouse model of neonatal HI injury.METHODS:HI was induced on postnatal day 9 in C57Bl/6 mouse pups. MSCs were cultured under hypoxic (hypoxic-preconditioned MSCs [HP-MSCs], 1% O2) or normoxic-control (normoxic-preconditioned MSCs, 21% O2) conditions for 24 hours before use. At 10 days after HI, HP-MSCs, normoxic-preconditioned MSCs, or vehicle were intranasally administered. Gold nanoparticle–labeled MSCs were used to assess MSC migration 24 hours after intranasal administration. At 28 days post-HI, lesion size, sensorimotor outcome, and neuroinflammation were assessed by hematoxylin and eosin staining, cylinder rearing task, and IBA1 staining, respectively. In vitro, the effect of HP-MSCs was studied on transwell migration, neural stem cell differentiation and microglia activation, and the MSC intracellular proteomic content was profiled using quantitative LC-MS/ms.RESULTS:Intranasally administered HP-MSCs were superior to normoxic-preconditioned MSCs in reducing lesion size and sensorimotor impairments post-HI. Moreover, hypoxic preconditioning enhanced MSC migration in an in vitro set-up, and in vivo to the lesioned hemisphere after intranasal application. In addition, HP-MSCs enhanced neural stem cell differentiation into more complex neurons in vitro but had similar anti-inflammatory effects compared with normoxic-preconditioned MSCs. Lastly, hypoxic preconditioning led to elevated abundances of proteins in MSCs related to extracellular matrix remodeling.CONCLUSIONS:This study shows for the first time that hypoxic preconditioning enhanced the therapeutic efficacy of MSC therapy in a mouse model of neonatal HI brain injury by increasing the migratory and neuroregenerative capacity of MSCs.

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