Insurance type and risk of dementia diagnosis after traumatic brain injury: a study of 267 473 US civilians from 2000 to 2022

Objectives
To evaluate how insurance influences the risk of a dementia diagnosis among a large, diverse cohort of US civilian adults with traumatic brain injury (TBI) over a 22-year period.

Design
This is a retrospective cohort study involving individuals diagnosed with TBI.

Setting
The study used the Merative MarketScan Research Database, specifically drawing from the Commercial Claims and Encounters, Medicare Supplemental and Medicaid databases, from 2000 to 2022 in the USA. These databases provide comprehensive insights into healthcare services received by enrollees, including inpatient and outpatient services, outpatient prescription claims, clinical utilisation records and healthcare expenditures.

Participants
267 473 adults aged 55 and older who were diagnosed with a TBI between 1 January 2000 and 31 December 2022. Individuals with unknown TBI severity and dementia claims 2 years preceding TBI were excluded. TBI and dementia diagnoses were identified using International Classification of Disease 9th and 10th editions codes from inpatient and outpatient admission records.

Interventions
None.

Primary and secondary outcome measures
We compared the incidence of all-cause dementia across different insurance types to assess potential disparities in diagnosis following TBI. Cox proportional hazards models, with age as the time scale, were used to study the association between insurance type and dementia diagnosis following a TBI. Models were adjusted for key demographic variables, medical comorbidities and psychiatric conditions to account for potential confounding.

Results
Of the 267 473 individuals with TBI, 12.7% were diagnosed with dementia over a mean follow-up period of 40 months (SD of 42 months). Dementia incidence differed significantly by insurance type, with 18.2% for Medicaid recipients, 17.3% for Medicare beneficiaries and only 2.3% among individuals with commercial insurance. The adjusted HR for dementia was notably higher among individuals enrolled on Medicaid (HR 2.9, 95% CI: 2.8 to 3.1) and Medicare (HR 2.1, 95% CI: 2.0 to 2.2), when compared with those with commercial insurance.

Conclusions
Individuals with TBI covered by Medicaid and Medicare are significantly more likely to be diagnosed with dementia, with a 2.9-fold and 2.1-fold increase risk, respectively, compared with those with commercial insurance. Addressing insurance-related disparities in dementia diagnosis is crucial for building a more equitable healthcare system. It is essential that individuals with TBI cases, regardless of their insurance type, have access to comprehensive care and preventive interventions to achieve the best possible long-term outcomes.

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Blood-Based Colorectal Cancer Screening

Despite a significant decline in colorectal cancer (CRC) incidence and mortality over the past several decades in the US, CRC remains the second leading cause of cancer deaths. Most of these deaths could be prevented if the 42% of Americans aged 45 to 75 years who are not up to date with screening would participate. There is strong evidence supporting screening with lower intestinal endoscopy (ie, colonoscopy or flexible sigmoidoscopy) or repeated rounds of occult blood–based stool screening tests. These screening tests are effective in detecting cancer at early, curable stages as well as preventing cancer through detection and removal of advanced precancerous lesions, including adenomas and serrated colorectal lesions. Despite public awareness campaigns, organized screening (eg, programmatic mailed stool-based tests), and patient decision aids and navigation, participation is suboptimal, and closing the screening gap remains elusive. This gap may result from reluctance to complete screening due to inconvenience, discomfort, embarrassment, aversion to handling stool, or fear of complications. The ideal CRC screening test would be noninvasive and acceptable to those being screened, be highly sensitive for both early cancer and advanced precancerous lesions, have excellent specificity, and be widely accessible. All of the currently available CRC screening test options fall short of this ideal in at least 1 way, limiting their effectiveness. Thus, there is an ongoing search for more agreeable screening test options.

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Efficacy of mailed surveillance invitations and telephone patient navigation to improve hepatocellular carcinoma surveillance uptake: study protocol of VIGILANT–a single-centre, two-arm randomised controlled trial

Introduction
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and mortality rates have continued to rise despite advancements in treatment. Six-monthly ultrasound surveillance is recommended by professional bodies for early detection of HCC in high-risk cohorts. However, surveillance rates remain poor; only 20% of patients attend for regular surveillance. Population health outreach strategies may be able to enhance surveillance rates by addressing patient-related barriers to engagement with healthcare. Using a co-design approach, we have developed outreach material in tandem with patients, with the aim of boosting HCC surveillance. VIGILANT aims to compare the effectiveness of bespoke mailed surveillance invitations with or without patient navigators (PNs) in improving attendance rates at surveillance appointments.

Methods and analysis
This is a two-arm randomised controlled trial that will recruit 652 participants. Participants will be patients with chronic liver disease or cirrhosis, who are eligible for HCC surveillance as defined by criteria from the National Institute for Health and Care Excellence and European Association for the Study of the Liver. Participants will be randomised (in a 1:1 ratio) to receive either (a) a mailed surveillance invitation or (b) a mailed invitation plus telephone call reminder from a PN 1 week prior to the appointment. The primary objective is to evaluate the impact of PNs and mailed invitations on attendance rates. Secondary objectives include rates of diagnosis of early-stage HCC among patients undergoing surveillance and cost-effectiveness of each arm.

Ethics and dissemination
Approval has been sought to conduct the research from Aberdeen Research Ethics Committee (REC Reference: 335338). The study is sponsored by Imperial College London and funded by RM Partners (West London Cancer Alliance). Study findings will be presented at medical conferences and published in peer-reviewed journals.

Trial registration number
NCT06635694.

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Comparative efficacy and acceptability of nonpharmacological interventions for sleep disturbance among pregnant women: protocol for a systematic review and network meta-analysis

Introduction
Sleep disturbance is prevalent in pregnancy and can result in significant adverse outcomes for women and their infants. Numerous clinical trials of various nonpharmacotherapies for preventing or treating sleep disturbances have been conducted previously; however, previous systematic reviews with direct comparisons have failed to demonstrate the best options for different kinds of treatments. This systematic review and network meta-analysis (NMA) aims to explore the comparative efficacy and acceptability of nonpharmacological interventions for sleep disturbances in pregnancy and to assist clinical decision-making through ranking interventions concerning critical clinical outcomes.

Methods and analysis
We will follow the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. Two reviewers will systematically search five major bibliographic databases (PubMed, Embase, Cochrane Library, Web of Science and Cumulative Index to Nursing and Allied Health Literature) and registries for published and unpublished randomised controlled trials (RCTs) of any nonpharmacological interventions for sleep disturbances from inception to 24 June 2025. To ensure the search is up to date, we will also perform an updated search up to the time of final analysis submission. Primary outcomes will consider efficacy (the overall mean change of any predefined sleep disturbances, including sleep quality, sleep duration and sleep-specific symptoms) and acceptability (all-cause discontinuation). The risk of bias of each included RCT will be assessed using the Cochrane Risk of Bias 2.0 Tool (RoB2). Traditional pairwise meta-analyses and NMAs will be performed to compare the efficacy and acceptability of different nonpharmacological interventions. Surface under the cumulative ranking curve for the outcomes of interest will be used to rank the competing interventions. The Grading of Recommendations, Assessment, Development and Evaluation system will be used to assess the quality of evidence associated with the main results.

Ethics and dissemination
This review is a secondary analysis of published data and, therefore, does not require ethical approval. The results will be disseminated in a peer-reviewed journal.

PROSPERO registration number
CRD42024546340.

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Mitochondrial Tumor Suppressor 1A Attenuates Myocardial Infarction Injury by Maintaining the Coupling Between Mitochondria and Endoplasmic Reticulum

Circulation, Ahead of Print. BACKGROUND:Pathological cardiac remodeling after myocardial infarction (MI) is a leading cause of heart failure and sudden death. The detailed mechanisms underlying the transition to heart failure after MI are not fully understood. Disruptions in the endoplasmic reticulum (ER)–mitochondria connectivity, along with mitochondrial dysfunction, are substantial contributors to this remodeling process. In this study, we aimed to explore the impact of mitochondrial tumor suppressor 1A (Mtus1A) on cardiac remodeling subsequent to MI and elucidate its regulatory role in ER-mitochondria interactions.METHODS:Single-nucleus RNA sequencing analysis was performed to delineate the expression patterns of Mtus1 in human cardiomyocytes under ischemic stress. MI models were induced in mice by left coronary artery ligation and replicated in vitro using primary neonatal rat ventricular myocytes exposed to oxygen glucose deprivation. Cardiac-specific deletion of Mtus1 was achieved by crossing floxed Mtus1 mice with the Myh6-MerCreMer mice. The impact of Mtus1A, a mitochondrial isoform of Mtus1, on cardiac function and the molecular mechanisms were investigated in both in vivo and in vitro settings. Mitochondria-associated ER membranes coupling levels were evaluated by transmission electron microscopy and live-cell imaging. Protein interactions involving Mtus1A were explored through immunoprecipitation–mass spectrometry, coimmunoprecipitation, and proximity ligation assay. The roles of Mtus1A and Fbxo7 (F-box protein 7) were validated in a murine MI model using adeno-associated virus serotype 9 (AAV9).RESULTS:Bioinformatics analysis revealed a significant downregulation of Mtus1 expression in human cardiomyocytes under ischemic conditions, indicating its potential role in stress response. The predominant isoform in murine cardiomyocytes, Mtus1A, showed reduced expression in the left ventricle of mice after MI, which is consistent with the decreased levels of its orthologs in heart tissues from patients with MI. Cardiac-specific knockout of Mtus1 in mice exacerbated cardiac dysfunction after MI. Both in vitro and in vivo studies demonstrated the vital role of Mtus1A in modulating mitochondria-associated ER membranes coupling and preserving mitochondrial function. Mechanistically, Mtus1A functions as a scaffold protein that maintains the formation of inositol 1,4,5-trisphosphate receptor 1 (IP3R1)–glucose-regulated protein 75 (Grp75)–voltage-dependent anion channel 1 (VDAC1) complex through its amino acid sequence 189-219. In addition, Mtus1A protein is stabilized by K6-linked ubiquitination through the E3 ubiquitin ligase Fbxo7. Mtus1A overexpression in mice mitigated MI-induced cardiac dysfunction and remodeling by maintaining ER-mitochondria connectivity.CONCLUSIONS:Our study demonstrates that Mtus1A is crucial for modulating MI-induced cardiac remodeling by preserving ER-mitochondria communication and ameliorating mitochondrial function in cardiomyocytes. Mtus1A may serve as a potential therapeutic target for treating heart failure after MI.

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Real-world effectiveness and safety of oral azvudine versus Paxlovid in patients with COVID-19 and pre-existing hypertension: a multicentre, retrospective, cohort study in Henan Province, China

Objectives
Azvudine and Paxlovid are the primary antiviral agents for the management of COVID-19. However, there is currently insufficient evidence regarding the effectiveness and safety of these drugs in treating COVID-19 patients with pre-existing hypertension. The objective of this study was to assess their effectiveness and safety among those patients in a real-world context.

Design
Retrospective cohort study.

Setting
Electronic medical record data of COVID-19 patients with pre-existing hypertension were extracted from nine hospitals in Henan Province from 5 December 2022 to 31 January 2023.

Participants
Following 2:1 propensity score matching (PSM), 996 individuals who received treatment with azvudine and 498 individuals who received treatment with Paxlovid were included in the analysis.

Primary and secondary outcome measures
The primary outcome was all-cause death and the secondary outcome was the composite disease progression.

Results
Following adherence to the inclusion and exclusion criteria and 2:1 PSM, 996 individuals were included in the azvudine group and 498 in the Paxlovid group. The Cox regression analysis revealed that the azvudine group had a significantly lower risk of all-cause death compared with the Paxlovid group (HR 0.64, 95% CI 0.455 to 0.911, p=0.013). However, there was no statistically significant difference in composite disease progression between the two groups (HR 0.93, 95% CI 0.711 to 1.229, p=0.629). Subgroup analysis indicated that, compared with Paxlovid, patients with moderate disease receiving azvudine treatment exhibited a significantly reduced risk of composite disease progression (HR 0.46, 95% CI 0.24 to 0.89). The safety analysis showed that the azvudine group had fewer adverse events.

Conclusions
Among COVID-19 patients with pre-existing hypertension, the effectiveness of azvudine is not inferior to Paxlovid in reducing all-cause death and composite disease progression, with fewer adverse events.

Trial registration number
NCT06349655.

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New Algorithm for Estimating Left Ventricular Filling Pressure by Echocardiography

Circulation, Ahead of Print. BACKGROUND:Evaluation of whether dyspnea has a cardiac cause is essential. Guidelines from 2016 were reported to result in a high incidence of indeterminate left ventricular (LV) filling pressure. We sought to validate a new algorithm for the estimation of LV filling pressure (LVFP) in a multicenter study, with the objective of decreasing the yield of indeterminate filling pressure and increasing accuracy.METHODS:In an observational study, echocardiography was performed in 951 patients referred for cardiac catheterization. Echocardiographic measurements included mitral inflow, pulmonary vein and tissue Doppler mitral annulus velocities, tricuspid regurgitation velocity, assessment of mean right atrial pressure, biplane LV and left atrial volumes, and LV and left atrial strain. A stepwise approach was applied in a new algorithm for estimation of LVFP, whereby pressure >15 mm Hg was considered abnormally elevated. The first step included mitral annulus early diastolic velocity (e′), the ratio of mitral early flow velocity to e′, and pulmonary artery systolic pressure. With concordant findings in all 3 variables, conclusions about LVFP could be reached. In case of discordant or incomplete variables, left atrial reservoir strain, left atrial maximum volume index, isovolumic relaxation time, and pulmonary vein flow were analyzed in a second step. In the presence of ≥1 abnormal measurement in the second step, the conclusion of elevated LVFP could be reached.RESULTS:Only 2 patients had indeterminate LVFP as per the new algorithm versus 38 applying 2016 guidelines (P

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EARLYBIRD: catching the earliest changes of the bone and intervertebral discs in children at increased risk for scoliosis development with MRI – study protocol of a prospective observational cohort study

Introduction
Adolescent idiopathic scoliosis (AIS) is an acquired deformity that develops in 2–4% of otherwise healthy children during adolescent growth, substantially reducing their quality of life and creating a life-long burden of disease. Despite many years of dedicated research, the cause and mechanism of AIS are still unknown and no effective curative treatments are available for children suffering from this spinal and chest deformity. To date, all etiological studies focused on children with an already established scoliosis. EARLYBIRD aims to uncover the earliest pathoanatomical changes in AIS, by studying longitudinal spinal growth in children at increased risk for scoliosis development with MRI, starting before adolescence.

Methods and analysis
This prospective observational cohort study will follow two groups: 60 adolescent girls (8–10 years old) who have an older sibling or parent diagnosed with AIS (cohort 1) and 60 adolescents with 22q11.2 deletion syndrome, a genetic microdeletion associated with 50% scoliosis prevalence (cohort 2). Data collection will be completely radiation-free and occur at baseline and yearly during adolescence up to 15 years of age in girls and up to 16 in boys. A comprehensive physical examination, a dedicated spine and chest MRI as well as a standing three-dimensional (3-D) spinal ultrasound will be obtained at each time point. The main parameter will be the longitudinal changes in segmental axial rotation during growth in subjects that do and do not develop AIS. Secondary endpoints are longitudinal changes in 3-D morphology of the bone and intervertebral discs (IVDs) during normal spinal development and during scoliosis development, determining biomarkers for bone growth, implementing radiation-free imaging methods for spinal monitoring in adolescent patients at risk for scoliosis development and use these for spinal skeletal maturity and patient-specific spinal biomechanical analyses.

Ethics and dissemination
This protocol has been approved by the Medical Ethics Committee NedMed and is registered on clinicaltrials.gov (NCT05924347). Written informed consent will be obtained from all parents/legal representatives. Key findings will be disseminated via peer-reviewed journals and presentation at conferences. This study is funded by the European Research Council.

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Regional Differences in Presentation, Cause, and Outcome of Reversible Cerebral Vasoconstriction Syndrome

Stroke, Ahead of Print. BACKGROUND:National studies on reversible cerebral vasoconstriction syndrome (RCVS) point to differences between Asian and European patients. We investigated geographic variations in neurological complications, outcomes, and causes.METHODS:We conducted an exploratory analysis of pooled individual patient data from the Reversible Cerebral Vasoconstriction Syndrome International Collaborative network, a multicenter observational cohort study including patients with definite RCVS from 2 French, 32 Italian, 1 South Korean, and 1 Taiwanese centers. Data on demographics, precipitants, symptoms, imaging, treatment, and outcomes were collected. The primary end point was RCVS-associated brain lesions, including ischemic stroke, cortical subarachnoid hemorrhage, intracerebral hemorrhage, posterior reversible encephalopathy syndrome, and subdural hematoma. Secondary end points included unfavorable 3-month outcomes (modified Rankin Scale score ≥1) and causes (idiopathic versus secondary). Odds ratios and 95% CIs were calculated using multivariable logistic regression, adjusting for potential confounders.RESULTS:From 2009 to 2021, we included 1127 patients (528 European and 599 Asian). Recruitment occurred either through emergency settings or outpatient clinics, with most Asian patients recruited from outpatient clinics (65.8%) and most European patients from emergency settings (99.8%). Brain lesions were more frequent in European patients (29.2% versus 6.3%; odds ratio, 4.09 [95% CI, 2.66–6.30]). In a sensitivity analysis restricted to hospitalized patients (n=651), the association persisted. Unfavorable 3-month outcomes (5.5% versus 1.7%; odds ratio, 3.01 [95% CI, 1.35–6.68]) and secondary RCVS (50.4% versus 10.9%; odds ratio, 7.09 [95% CI, 5.14–9.76]) were also associated with European residency.CONCLUSIONS:RCVS presentations vary across regions, with higher lesion rates, more secondary forms, and worse outcomes in European patients. While these exploratory results may reflect selection bias from differing health care structures, further research is needed to determine the contribution of genetic, environmental, and societal factors.

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