Citations

Abstract INTRODUCTION The infectious hypothesis suggests that microbes like herpesviruses may play a role in the pathogenesis of Alzheimer's disease (AD) and other related dementias through methods that may include viral genome integration. The occurrence of herpesvirus genome integration in dementia patients has not been thoroughly characterized. METHODS Over 7500 total whole‐genome sequences from control, frontotemporal dementia/amyotrophic lateral sclerosis spectrum, Lewy body dementia (LBD), multiple system atrophy (MSA), and AD cohorts were screened for the integration of pathogen genomes using the PathSeq computational tool. RESULTS Low PathSeq scores for human herpesvirus 6 (HHV‐6) were consistent with the suspected integration of viral genome segments. The LBD and MSA cohorts had a significantly higher prevalence of this partial HHV‐6 genome integration. DISCUSSION This higher prevalence in both synucleinopathies was not noted in other herpesviruses, suggesting that the integration of HHV‐6 may play a role in a subset of these patients. Highlights Over 7500 whole‐genome sequences from controls and dementia patients were analyzed. Sequences consistent with integrated herpesviruses were identified using PathSeq. Prevalence of partial HHV‐6 integration was higher in synucleinopathies. Herpesviruses genome integration may play a role in subsets of dementia patients.

Abstract Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia‐related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex‐specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non‐disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex‐specific AD susceptibility and potential footholds for sex‐based interventions targeting these systems. We conclude by outlining immediate and long‐term actions to address the intersection of NSSs, sex, and AD.

ABSTRACT Introduction Cardiac myosin inhibitors (CMIs) improve hemodynamics and symptoms in hypertrophic cardiomyopathy (HCM), but recent real‐world data have raised concerns regarding an increased risk of atrial fibrillation (AF). We sought to reassess AF risk using randomized controlled trial (RCT) evidence and to contextualize discrepancies with observational reports. Methods and Results We performed a systematic review and random‐effects meta‐analysis of RCTs evaluating the effect of CMIs on incident AF in HCM. MEDLINE, Scopus, and CENTRAL were searched through November 25, 2025. Eight RCTs ( n = 1581) comparing mavacamten or aficamten with placebo or active control were included. Event counts were pooled as risk ratios (RRs) with 95% confidence intervals (CIs). CMIs were not associated with increased AF risk (RR 1.11, 95% CI 0.62–1.98; heterogeneity I 2 = 0%). No differences were observed between mavacamten and aficamten, with consistent findings across HCM subtypes (obstructive and non‐obstructive). Importantly, most trials (7/8) excluded patients with uncontrolled, persistent, or permanent AF, five excluded paroxysmal AF at screening, and one excluded any AF history. Baseline left atrial enlargement was generally in the mild to moderate range across trials, suggesting limited representation of high‐risk AF phenotypes. Conclusion Randomized evidence to date does not demonstrate an increased AF risk with CMIs. Differences between RCT populations and real‐world cohorts, including restrictive AF eligibility criteria, lower baseline atrial remodeling, and limited rhythm surveillance may explain discordant observational findings and highlight the need for longitudinal monitoring in clinical practice.

BACKGROUND: For reasons not fully understood, Black adults experience more socioeconomic disadvantages (SED) than their White counterparts, as well as earlier onset and greater mortality from heart failure (HF). The John Henryism hypothesis predicts that repeated high-effort coping, that is, John Henryism (JH), with socioeconomic adversity can accelerate cardiovascular aging, thus increasing the risk for HF. METHODS: The analysis sample consisted of participants from the JHS (Jackson Heart Study), a cohort of Black adults from the Jackson, Mississippi Metropolitan area. The analysis sample included participants with no cardiovascular disease at baseline (2000–2004) with complete SED and JH scores. Indicators of SED included low household income, low educational attainment, and low maternal educational attainment scores. JH scores (0–36) were categorized as low (<28), moderate (29–32), and high (>32). Effect moderation of JH in the SED and incident HF association was assessed using interaction terms and stratification. Proportional hazards regression determined the hazard ratio and 95% CI, and models adjusted for age, sex, and established lifestyle risk factors. RESULTS: Among 1704 participants (mean age: 52.15 years, 64.3% female), 100 HF events occurred by 2016 (mean follow-up, 10 years). A statistically significant interaction between income and JH was observed for incident HF ( P =0.04). For every 1-unit increase in income disadvantage score, the risk of HF increased 2-fold among those with high JH (hazard ratio, 2.00 [95% CI, 1.39–2.86]) after full adjustment. Among participants with low JH, the corresponding unadjusted association was hazard ratio, 1.40 [95% CI, 1.04–1.90], but this association attenuated after adjusting for age and sex (hazard ratio, 1.19 [95% CI, 0.87–1.63]). CONCLUSIONS: The association between income disadvantage and HF differed by JH level. Because SED and high JH tend to co-occur, both should be considered in future research aiming to decrease the burden of HF in Black Americans.

Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy affecting 1 in 5000 individuals, is the second most common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the US Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median age of 53 (range, 0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13 years, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of postmenarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring IV iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). These data from CHORUS, the first national US registry of its kind, provide reliable, real-world estimates of the incidence, prevalence, and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of &gt;2 decades, during which substantial, serious, and preventable HHT morbidity, including early intracranial hemorrhage, may occur. This trial was registered at clinicaltrials.gov as NCT06259292.

Triple-negative breast cancer (TNBC) remains highly aggressive and refractory to conventional treatments, underscoring the need for novel combination strategies. Here, we employed 2D and 3D in vitro models, transcriptomic profiling, and in vivo xenograft studies to evaluate the anticancer efficacy of cannabinoids combined with the terpene β-caryophyllene (BC) in resistant TNBC models. Among the tested cannabinoids, cannabichromene (CBC) exhibited the greatest potency, and its combination with BC at sub-toxic concentrations significantly reduced IC50 values, enhanced cytotoxicity in spheroids, and suppressed colony formation and migration. The combination treatment induced pronounced G1 cell cycle arrest and increased apoptotic cell death. Western blot analyses revealed downregulation of PARP, Survivin, mTOR, Vimentin, Glypican-5, and PD-L1, while RNA sequencing demonstrated suppression of proliferative and migratory signaling pathways alongside activation of apoptosis, autophagy, and ferroptosis-related pathways. In vivo, CBC + BC significantly inhibited tumor growth in MDA-MB-231 xenografts, outperforming single-agent treatments. Collectively, these findings demonstrate that BC synergistically enhances cannabinoid activity, yielding superior antiproliferative and anti-migratory effects, and highlight this combination as a promising therapeutic strategy for resistant TNBC.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of 13.3%. First-line treatment relies on two chemotherapy regimens, FOLFIRINOX (FOLFNX) or gemcitabine plus nab-paclitaxel (GEMPAC). However, direct clinical comparisons between these regimens have yielded inconsistent results across survival and toxicity endpoints, and the molecular basis of heterogeneous treatment responses remains poorly defined. To investigate regimen-specific tumor-cell-intrinsic mechanisms, we performed quantitative proteomic profiling of a primary PDAC-derived MIA PaCa-2 cell line following treatment with FOLFNX or GEMPAC. Differentially expressed proteins were analyzed using Gene Ontology, KEGG, and Ingenuity Pathway Analysis to define pathway-level alterations, and findings were contextualized using TCGA transcriptomic data. Proteomic analyses revealed that FOLFNX and GEMPAC engage in distinct cytotoxic programs. FOLFNX predominantly suppressed ribosome biogenesis and mitochondrial translation, consistent with sustained metabolic and biosynthetic stress, whereas GEMPAC preferentially disrupted mitotic cytokinesis and phosphatidylinositol phosphate biosynthesis, consistent with mitotic failure. Integration with TCGA data showed that FOLFNX-altered proteins aligned with favorable prognostic expression signatures, whereas GEMPAC-associated proteins were enriched among adverse profiles, reflecting engagement of distinct tumor-intrinsic programs. Together, these findings provide mechanistic insight into differential chemotherapy responses and establish a foundation for proteomics-based biomarkers to guide personalized chemotherapy selection in PDAC.

Background: Femoroacetabular impingement (FAI) is a common injury experienced by basketball players. Surgical management with arthroscopic labral repair and femoral osteochondroplasty can lead to successful outcomes for athletes whose nonoperative management fails. Recent studies have demonstrated that athletes undergoing hip arthroscopy in the setting of FAI had favorable return-to-sport (RTS) and sport continuation outcomes. Purpose: To evaluate patient-reported outcome measures (PROMs) and RTS rates at minimum 5-year follow-up in basketball players after hip arthroscopy for FAI. Study Design: Case series; Level of evidence, 4. Methods: All active basketball players at the recreational, high school, and collegiate levels who underwent primary hip arthroscopy with labral repair for FAI between August 2009 and December 2019 were identified. Postoperative RTS, revision rates, and surgery satisfaction at final follow-up were evaluated. PROMs were also analyzed as follows: visual analog scale, Tegner Activity Scale, modified Harris Hip Score, Hip Outcome Score–Activities of Daily Living, and Hip Outcome Score–Sport. Results: Fifty-three patients (64 hips) were included with a mean ± SD age of 21.2 ± 6.0 years. Most athletes played recreational or high school basketball (85%), while 15% played college basketball. Forty-three patients attempted to return to basketball. Of these patients, 35 (81%) returned to basketball after surgery, with 32 (91%) returning to the same level of play. Patients who returned to basketball had significantly improved outcomes on the modified Harris Hip Score ( P = .006), Hip Outcome Score–Activities of Daily Living ( P = .007), Hip Outcome Score–Sport ( P = .004), Tegner Activity Scale ( P = .010), and visual analog scale with use ( P = .041) as compared with those who did not return. High school athletes had decreased odds of RTS when compared with recreational athletes ( P = .01). There was significant improvement in all PROMs from baseline to minimum 5-year follow-up ( P < .05). Conclusion: At minimum 5-year follow-up, basketball players demonstrated durable improvements in PROMs and an RTS rate of 81% after hip arthroscopy for FAI. The majority of athletes returned to the same level of competition. There were significantly improved PROMs in patients who returned to sport versus those who did not. High school athletes had decreased odds of RTS when compared with recreational athletes. However, body mass index, sex, age, alpha angle, and basketball position did not significantly correlate with RTS outcomes.

Background Difficulty tolerating the uncertainty of ambiguous or unpredictable situations may influence how patients with functional motor disorder (FMD) respond to treatment. However, only one study has examined the role of intolerance of uncertainty (IU) in FMD treatment. Objectives This study sought to expand on prior findings in a larger sample of patients with FMD who completed an intensive motor-retraining programme. Methods A consecutive cohort of 109 patients with FMD completed a 1-week intensive outpatient motor-retraining programme. Patients rated their IU using the Intolerance of Uncertainty Scale-12 and functional motor outcomes using three empirical measures before and after treatment. Univariate and multivariable analyses were conducted to (1) characterise the rate of elevated IU, (2) evaluate potential changes in IU across the programme, (3) examine whether changes in IU predict improvements in motor functioning and (4) determine if IU incrementally predicts functional improvements in patients with clinically elevated IU. Results Findings revealed that clinically elevated IU was common (yielding a base rate of 44%) and that the ‘prospective’ subtype of IU significantly decreased with 1 week of FMD treatment. Change in IU was not significantly associated with improved functional outcomes across the sample. However, change in prospective IU did predict patient-specific functional outcomes among those with clinically elevated IU ( R 2 =11%). Conclusions Findings support prior work suggesting that certain subtypes of IU are common, modifiable and related to treatment outcomes in FMD. The ‘prospective’ subtype of IU may represent an operative factor that can enhance the efficacy of existing FMD rehabilitation programmes.