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Importance In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ–positron emission tomography (PET; 18 F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET ( 18 F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET–positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217–negative and Aβ-PET–positive; 7 participants were p-tau217–positive and Aβ-PET–negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Abstract Frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick’s disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

Aims: The primary aim of this study was to determine whether CYP2D6 phenotypes are associated with atomoxetine treatment outcomes in children and adolescents with attention-deficit hyperactivity disorder. Patients and Methods: Patients 21 years and younger with a known CYP2D6 genotype and a prescription for atomoxetine were included in this electronic health record review. The primary outcome was defined as discontinuation of atomoxetine due to a lack of efficacy or due to toxicity. CYP2D6 activity scores were adjusted to account for phenoconversion if patients were concomitantly taking a CYP2D6 inhibitor medication. Results: Of 108 patients that met inclusion criteria, including 13 poor, 30 intermediate, 61 normal, and 4 ultra-rapid CYP2D6 metabolizers after adjusting for phenoconversion. Normal/ultrarapid metabolizers were significantly more likely to discontinue atomoxetine due to lack of efficacy (subdistribution hazard ratio [sHR] = 1.9, p = 0.04), while poor/intermediate metabolizers were significantly more likely to stop due to toxicity (sHR 0.4, p = 0.03). A significant nonlinear effect of adjusted activity score on likelihood of discontinuation due to lack of efficacy ( p < 0.001) or toxicity ( p < 0.001) was identified, where higher CYP2D6 activity scores were associated with more discontinuation due to lack of efficacy and lower activity scores were associated with more discontinuation due to toxicity. When CYP2D6 genotype was available prior to prescribing atomoxetine in intermediate/poor metabolizers, lower median initial doses were observed (0.5 mg/kg/day) compared to those who underwent CYP2D6 genotyping after the initial atomoxetine prescription (0.8 mg/kg/day). Conclusion: Patients with normal or increased CYP2D6 phenotypes may be more likely to discontinue atomoxetine due to a lack of efficacy, while those with reduced function CYP2D6 phenotypes may be more likely to discontinue atomoxetine due to toxicity.

BACKGROUND: Intraventricular hemorrhage and subarachnoid hemorrhage are associated with neuroinflammation and increased morbidity and mortality. Rapid clearance of blood from the cerebrospinal fluid space may mitigate neuroinflammatory cascades and improve clinical outcomes. This systematic review and meta-analysis aimed to compare the clinical effectiveness of active cerebrospinal fluid exchange, including neuroendoscopic lavage and IRRAflow systems, versus external ventricular drainage in patients with intraventricular hemorrhage or subarachnoid hemorrhage. METHODS: The study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and thoroughly assessed databases, including PubMed, Embase, Scopus, Cochrane, and Web of Science, up to September 18, 2025. Statistical analysis, both fixed-effect and random-effect model analyses, was performed by the Comprehensive Meta-Analysis software. In addition, the Cochran Q test was conducted to determine the statistical heterogeneity. In terms of low heterogeneity, the fixed-effect model is reported. RESULTS: This review included 7 studies with a total sample size of 834. Our analysis showed that active cerebrospinal fluid exchange was associated with significantly higher hematoma clearance (odds ratio, 2.72 [95% CI, 1.22–6.08]; P =0.015), better functional outcomes (odds ratio, 1.66 [95% CI, 1.12–2.48]; P =0.012), lower shunt dependency (odds ratio, 0.22 [95% CI, 0.10–0.50]; P <0.001), and reduced infection rates (odds ratio, 0.22 [95% CI, 0.12–0.42]; P <0.001). Subgroup analysis showed that neuroendoscopic lavage was most effective for hematoma clearance, while IRRAflow reduced infection rates. Also, younger patients had better neurological recovery. CONCLUSIONS: Active cerebrospinal fluid exchange techniques demonstrated superior outcomes over external ventricular drainage in managing intraventricular hemorrhage and subarachnoid hemorrhage, particularly in clot resolution and neurological recovery. Large-scale trials are warranted.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

Exercise and physical activity are recognized as essential tools to optimize fitness and longevity, improve overall health, and reduce the risk of cardiovascular disease and other major comorbidities. However, there are inherent risks associated with participation in sports and exercise, regardless of the level of competition or skill required. As such, there is a need for cardiologists to understand the unique aspects of competitive and recreational athletics, as well as sport and exercise science, as it relates to overall heart health and cardiovascular risk. In this article, we provide an overview of the essential aspects of sports and exercise cardiology. We describe the roles and responsibilities of a sports and exercise cardiologist as a member of a comprehensive team of experts who provide care of athletes at all levels of sport, emphasize the importance of risk stratification and prevention of sudden cardiac arrest, the role of exercise for maintaining and optimizing overall health in the general population, describe the growing field of sports electrophysiology and also discuss unique aspects of sports cardiology applied to environmental health and care of the tactical athlete. Knowledge gaps and directions for future clinical and research investigation are reviewed.

Primary enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the “hand-in-glove” development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.