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Pericardial disease represents a diverse clinical spectrum, including acute pericarditis, pericardial effusion, cardiac tamponade, effusive-constrictive pericarditis, and constrictive pericarditis, which vary significantly in presentation, urgency, and management. Recent consensus guidelines from the European Society of Cardiology and the American College of Cardiology have enhanced clinical phenotyping, multimodal imaging techniques, and targeted immunomodulatory therapies; however, their implementation in clinical practice remains variable. We introduce our updated pathway-based framework that structures diagnosis and treatment around five key clinical scenarios: chest pain, hemodynamic collapse, dyspnea, incidental pericardial effusion, and right-sided heart failure. Each scenario guides a systematic process of risk stratification, tiered diagnostic evaluation, and phenotype-specific therapy. In cases of acute pericarditis, management employs a three-tier escalation approach, with interleukin-1 inhibitors (rilonacept, anakinra) as the preferred escalation for inflammatory phenotypes unresponsive to NSAIDs and colchicine. Cardiac magnetic resonance imaging is integral to phenotyping, utilizing late gadolinium enhancement and T2-STIR sequences to inform treatment escalation. Management of pericardial effusion is standardized through a validated drainage scoring system that considers etiology, size, and echocardiographic hemodynamics. Constrictive pericarditis is classified into three subtypes: transient/inflammatory, effusive-constrictive, and chronic/fixed, each with a distinct management pathway, reserving surgical pericardiectomy at specialized centers for fibrotic or medically refractory cases. This pathway consolidates current evidence into a reproducible clinical framework designed to standardize care, enhance diagnostic precision, and facilitate shared decision-making among multidisciplinary pericardial disease teams.

To evaluate the diagnostic performance of four-dimensional flow MRI alone and in combination with spleen volume and splenic extracellular volume fraction (ECV) for identifying high-risk esophageal variceal (HRV) in patients with liver cirrhosis. A total of 58 cirrhosis patients who underwent four-dimensional flow MRI and endoscopy were prospectively recruited and were divided into HRV group (n = 25) and non-HRV (NHRV) group (n = 33). The hemodynamic parameters of the portal vein (PV), superior mesenteric vein (SMV), and splenic vein (SV) derived from four-dimensional flow MRI for identifying HRV were analyzed and compared with spleen volume and splenic ECV. Then a combined model for identifying HRV was constructed by using the least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis with stepwise forward. The peak velocity and maximum pressure gradient of the PV, SMV, and SV, as well as the total volume of the SMV, were significantly greater in the HRV group than in the NHRV group. The SV peak velocity had the highest AUROC for identifying HRV and was comparable to the spleen volume and splenic ECV. The combined model incorporating these three indicators showed superior performance with an AUC of 0.945, outperforming individual imaging indicators and other laboratory-based models. Four-dimensional flow MRI is a valuable noninvasive technique for detecting HRV in cirrhosis patients. The combined model incorporating SV peak velocity, spleen volume, and splenic ECV provided an accurate prediction of HRV, which may help avoid unnecessary screening endoscopy. The combined model incorporating spleen vein peak velocity derived by 4D flow MRI, spleen volume, and spleen ECV performed better than individual imaging indicators and laboratory-based models, which may help to avoid unnecessary screening endoscopy and aid in clinical decision-making. Noninvasive assessment of the risk of HRV in cirrhosis remains crucial but inadequate. Four-dimensional flow MRI can effectively identify HRV in patients with cirrhosis. Combining SV peak velocity, splenic volume, and ECV effectively identifies HRV.

To investigate the mechanical correlations between intraocular pressure (IOP) variations and glaucoma, this study presents a linear transversely isotropic poroelastic model of the lamina cribrosa (LC) based on Reissner-Mindlin plate theory. A key feature of the proposed framework is its analytical tractability, which allows the governing poroelastic equations to be solved in closed form under appropriate mechanical and hydraulic boundary conditions. Within this setting, linearity is used to capture the reversible component of the tissue response, providing a baseline description of the coupled solid-fluid feedback on which more complex time-dependent phenomena, such as viscoelastic effects and remodelling, may build. The results indicate that both strain and stress measures (in the form of shear strain and deviatoric stress measures) peak in the peripheral region of the LC, which is currently suspected to be the initial site of glaucomatous damage. These quantities increase with IOP, suggesting a pressure-dependent mechanical insult to the retinal ganglion cell (RGC) axons. In parallel, the model predicts a monotonic reduction in fluid content as IOP rises, which may contribute to ischemic phenomena and disc haemorrhages. The influence of material anisotropy was also examined, revealing that isotropic assumptions tend to overestimate the fluid content while underestimating shear strain. Given the current experimental challenges in measuring blood flow within the LC, the proposed model provides a valuable framework for exploring the coupled mechanical-hemodynamic behavior of the tissue and for inverse estimation of its mechanical parameters, such as the stiffness of the opening for the central retinal vessels.

The coordination polymers (CPs)/metal-organic frameworks (MOFs) incorporating hetero-bridging ligands have remarkable efficiency and versatility towards fulfilling the objectives of the Sustainable Development Goals (SDGs). In this aspect, two CPs, [Cu2(3-bph)2(adc)4]n (CP1) and [Zn2(3-bph)2(adc)4]n (CP2) (3-bph = (1E,2E)-1,2-bis(pyridin-3-ylmethylene)hydrazine and adc- = 1-adamantanecarboxylate), are characterised, and their significant semiconducting property and selective dye sorption activity are explored. The CPs comprise a secondary building unit (SBU) of a carboxylate-bridging adc- paddle-wheel, [M2(adc)4] (M = Cu(II), Zn(II)), which undergoes pyridyl-N linking by 3-bph to form a 1D chain, where the pyridyl rings undergo π-π interaction to construct a 2D honeycomb-supramolecular network. Interestingly, CP1 demonstrates the selective sorption of methyl red (MR) dye out of four dyes (methylene blue, rhodamine B, methyl red, and methyl orange) with a removal efficiency of 95.37% from aqueous solution within 1 h, whereas CP2 does not show measurable sorption activity. The sorption of CP1 fits the Langmuir isotherm (R2 = 0.9875) and follows pseudo-second-order kinetics, indicating chemisorption on a heterogeneous surface. The DFT calculations using crystallographic parameters determined the band gaps in the semiconducting region (2.39 eV (cal.) and 3.68 eV (exp.) for CP1 and 2.32 eV (cal.) and 3.65 eV (exp.) for CP2). This inspired the measurement of the electrical conductivity from a fabricated Schottky device with thin film electrodes, ITO/CPs/Al. The experiments show that CP2 (5.27 × 10-3 S m-1) has higher electrical conductivity than CP1 (2.72 × 10-3 S m-1) under identical conditions, which explains the superior charge-transport features of CP2 in comparison with CP1. These findings highlight that CP1 serves as a promising material for application as a sustainable MR dye removal agent from wastewater, while both CP1 and CP2 are potential candidates for semiconducting applications.

The prognostic nutritional index (PNI), a marker reflecting nutritional and immunological status, has been proposed as a predictor of adverse postoperative outcomes. However, whether its association with postoperative delirium (POD) differs between femoral neck fractures and intertrochanteric fractures remains unclear. This retrospective cohort study included patients aged &#x2265;60 years who underwent hip fracture surgery between 2023 and 2024 PNI was calculated preoperatively, and POD was diagnosed during hospitalization using&#xa0;standardized clinical criteria. Analyses were conducted separately for femoral neck and intertrochanteric fracture groups for comparison. Restricted cubic spline (RCS), cox regression, subgroup analyses, receiver operating characteristic (ROC), propensity score matching (PSM), and Kaplan-Meier analyses were performed. A total of 339 patients with femoral neck fractures and 260 patients with intertrochanteric fractures were included in this study. A significant association between preoperative PNI and POD was observed in&#xa0;patients with femoral neck fractures. In patients with femoral neck fractures, RCS analysis demonstrated an approximately linear inverse relationship between PNI and POD risk (p for trend < 0.001). In Cox proportional hazards models, each one-unit increase in PNI was associated with a 24% reduction in the risk of POD (HR = 0.76, 95% CI: 0.66-0.88, p&#x2009;<&#x2009;0.001). ROC curve analysis indicated moderate predictive performance(AUC = 0.699).Sensitivity analyses confirmed the robustness of the association. A lower preoperative PNI was associated with an increased risk of POD among older adults with femoral neck fractures, but not among those with intertrochanteric fractures. PNI may serve as a simple tool for preoperative risk stratification in patients with femoral neck fractures.

Risk assessment is essential for planning esophagectomy in patients with esophageal or gastro-esophageal junction (GEJ) cancers. However, previous reports using only preoperative variables (preoperative risk models) have poorly predicted postoperative anastomotic leakage. This study aimed to develop a novel risk model for anastomotic leakage using a combination of preoperative, intraoperative, and postoperative variables (perioperative risk model). Clinical data of 20,113 patients with esophageal or GEJ cancer who underwent esophagectomy followed by reconstruction between 2016 and 2019 were retrieved from the National Clinical Database (NCD), a Japanese web-based nationwide registry. Preoperative and perioperative risk models for anastomotic leakage were developed using only preoperative variable and a combination of preoperative, intraoperative, and postoperative variables within 72&#xa0;h, respectively. The performance of the perioperative risk model was validated using NCD data of 5,147 esophagectomies registered in 2020. In the overall population, 11,360 (45.0%) patients were aged&#x2009;&#x2265;&#x2009;75&#xa0;years, and 81.3% were male. Preoperative variables were comparable between the development and external validation cohorts. Anastomotic leakage was observed in 13.7% and 14.4% of the development and validation cohorts, respectively, and in 13.9% of all patients. The optimism-corrected C-statistics was higher in the perioperative risk model (0.610; 95% CI, 0.599-0.621) than in the preoperative risk model (0.565; 95% CI, 0.554-0.577). In the validation analysis, the C-statistics was 0.602 (95% CI, 0.580-0.623) for predicting anastomotic leakage. Postoperative risk assessment using perioperative variables, including operative factors and early postoperative events, may help surgeons predict anastomotic leakage and improve patient management after esophagectomy.

The arterial anatomy of the lips is highly variable, influencing both reconstructive and aesthetic procedures. Despite extensive anatomical studies, potential perfusion relationships within the perioral region remain underexplored. This review introduces a new anatomical hypothesis, the "steal phenomenon", which describes a possible redistribution of perfusion (or filler material) from the upper lip toward the nasal and ophthalmic territories through pre-existing anastomoses. Electronic databases, including Medline (PubMed), Embase, Scopus, and Web of Science, were systematically searched to gather studies examining the blood supply to the lips. Twenty-three studies were included. The superior labial artery (SLA) was absent in 3.55% of cases; when present, it most commonly originated above the oral commissure (OC) (80.71%) at a mean distance of 11.95 mm. The inferior labial artery (ILA) was absent in 13.45% of cases and most frequently located below the OC (72.44%) at an average distance of 21.99 mm. Both arteries most commonly coursed through the submucosal plane, with the SLA and ILA, reported in this layer in up to 84.8 and 81.25% of cases, respectively. Mean arterial depths were approximately 5.2 mm for both vessels. This review highlights the considerable variability of the labial vasculature and its implications for procedural safety. No lip plane can be regarded as entirely free of vascular structures, emphasizing the need for individualized, anatomically guided injection technique. The proposed steal phenomenon offers a theoretical explanation for the upper lip's greater susceptibility and underscores the importance of cautious, patient-specific practice supported by ultrasound when available. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Human metapneumovirus (hMPV) is an important cause of acute respiratory infections in children, but genomic surveillance data from Ningbo, a coastal port city of China, remain limited. We investigated the epidemiology, genetic diversity and phylogeographic patterns of hMPV among children in Ningbo from 2020 to 2024 using 6,632 respiratory specimens from paediatric outpatients and 26 hMPV-positive samples. The overall hMPV-positive rate was 3.62% (240/6,632), with a peak in 2022 (6.86%). An atypical summer peak in 2022 and a prolonged 2023-2024 season suggested altered seasonality in the post-COVID-19 period. Preschool-aged children (1-6&#x2009;years) were the most affected age group and the proportion of viral co-infections among hMPV-positive cases increased significantly over time. Phylogenetic analysis of the 26 genomes showed co-circulation of four lineages, with B2 and A2.2.2 predominating across multiple years. We identified one A2.2.2 strain (20240959) carrying a 111-nt (37-aa) insertion in the G gene, whereas other A2.2.2 strains retained the classical non-duplicated G sequence. Several lineage-associated substitutions in F protein were observed between lineages A, B1 and B2, and mapping suggested that a substantial proportion of these sites fell within predicted linear B-cell epitope-prone regions. Phylogeographic reconstruction indicated multiple introductions of hMPV into Ningbo from other parts of China and from overseas. These findings demonstrate the genetic and epidemiological complexity of hMPV circulation in a major port city and underscore the need for continued, genome-informed surveillance to monitor hMPV evolution.

Adjuvant therapy after neoadjuvant treatment and R0 esophagectomy for esophageal squamous cell carcinoma (ESCC) remains controversial, and benefit may vary by post-neoadjuvant pathology. We evaluated heterogeneity of adjuvant benefit across prespecified pathologic strata and quantified absolute survival gains. In this two-center retrospective cohort (January 2018-May 2023), patients with ESCC who underwent neoadjuvant therapy followed by R0 resection were classified as pCR (ypT0N0), ypT+N0, or ypT0-4N+. The exposure was early postoperative adjuvant therapy initiated within 8 weeks after surgery. To reduce immortal-time bias, we used an 8-week landmark design with follow-up from the landmark. Confounding was addressed using stabilized inverse probability of treatment weighting (sIPTW) based on preoperative covariates, center, and surgical approach. Outcomes were overall survival (OS) and disease-free survival (DFS) using weighted Cox models with robust standard errors; absolute differences in survival probability (&#x394;S) were derived from weighted Kaplan-Meier curves. Among 781 patients (pCR 142, ypT+N0 317, ypT0-4N+&#x2009;322), survival for pCR and ypT+N0 largely overlapped, whereas ypT0-4N+&#x2009;had consistently worse outcomes. In the overall cohort, adjuvant therapy was not associated with improved OS (HR 0.99, 95% CI 0.75-1.31; P&#x2009;=&#x2009;0.946) or DFS (HR 1.15, 95% CI 0.89-1.48; P&#x2009;=&#x2009;0.283). Benefit was concentrated in ypT0-4N+ (OS HR 0.48, 95% CI 0.33-0.72; P&#x2009;<&#x2009;0.001; DFS HR 0.64, 95% CI 0.46-0.90; P&#x2009;=&#x2009;0.011), with &#x394;S +13.2 percentage points for DFS at 1 year and +21.0 percentage points for OS at 3 years. No clear benefit was observed in pCR or ypT+N0. After neoadjuvant therapy and R0 resection for ESCC, post-neoadjuvant nodal status strongly stratified prognosis, with similar survival for pCR and ypT+N0. Adjuvant benefit is heterogeneous and concentrated in ypN-positive disease, supporting a pathology-informed, risk-adapted postoperative strategy targeting ypT0-4N+.

Infectious bursal disease (IBD), caused by infectious bursal disease virus (IBDV), poses a major threat to the global poultry industry. In this study, we identified and characterized a novel field IBDV strain NN040124, which exhibits both reassortment and recombination features. Genotyping identified this field strain as A3B1a, with segment A derived from a very virulent IBDV (vvIBDV) strain (A3) and segment B from a classical-like attenuated vaccine (attIBDV) strains (vv-A/att-B IBDV)). Crucially, recombination analysis revealed that segment B is a backbone originated from vaccine strain B87, with the N-terminal part replaced by the homologous region from a vvIBDV strain (Harbin-1). This replacement is implicated in the restored virulence of the strain, as demonstrated by a challenge experiment in 4-week-old commercial Three-Yellow chickens, which resulted in 40% mortality, typical clinical signs, and severe bursal lesions. These findings confirm the emergence of a novel dually reassortant and recombinant IBDV in Southern China, identify the N-terminal region of segment B as a potential virulence determinant in a naturally occurring field strain, and highlight the potential risks of live vaccine use. Our findings underscore the importance of continuous genetic and pathogenic surveillance of IBDV to inform effective prevention and control strategies.

Accurate segmentation of brain metastases (BM) is essential for diagnosis, stereotactic radiosurgery planning, and longitudinal assessment. However, manual contouring is time-intensive, limiting clinical scalability, and exhibits substantial inter-observer variability. This variability complicates objective assessment of automated segmentation methods and challenges interpretation of model performance. To address these limitations, we developed TUM-SAM, a hybrid foundation-model framework for fully automated BM segmentation, and introduced a bias-controlled, blinded multi-rater evaluation paradigm to determine whether AI-based BM segmentation has reached expert-level performance and whether AI-generated contours are preferred by human experts under unbiased assessment. TUM-SAM integrates nnU-Net-based lesion detection with a tumor-adapted Med-SAM segmentation model to enable prompt-free, fully automated segmentation. Training used 301 patients (2548 lesions), and external evaluation used an independent cohort of 105 patients (397 lesions). Segmentation accuracy was benchmarked against DeepMedic and nnU-Net using Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (HD95). Two physicians contoured all external cases, and a third physician contoured a 20-patient subset for a blinded, tumor-level, multi-rater preference study. Pairwise contour preferences were analyzed using a Bradley-Terry probabilistic model to obtain bias-adjusted estimates of relative contour quality while accounting for rater-specific tendencies and case difficulty. In the external cohort, TUM-SAM achieved a lesion-wise detection sensitivity of 0.94 and outperformed DeepMedic and nnU-Net across all tumor sizes, with a mean DSC of 0.84 and HD95 of 1.9&#xa0;mm (nnU-Net/DeepMedic: DSC&#xa0;<&#xa0;0.70, HD95&#xa0;>&#xa0;3.3&#xa0;mm). Across voxel-wise evaluation, TUM-SAM's geometric performance fell within the range of inter-observer variability among physicians and was sensitive to reference construction. In contrast, in the blinded rater study, experts preferred TUM-SAM-generated contours over individual physician contours in 81-87% of raw comparisons; Bradley-Terry analysis yielded conservative, bias-corrected win probabilities of 55-56%, indicating consistent preference after adjustment for rater and case difficulty. Using a bias-controlled, blinded multi-rater evaluation framework, TUM-SAM demonstrates brain metastasis segmentation quality that is consistently preferred by expert physicians, highlighting the limitations of agreement-based voxel-wise metrics under inter-observer variability. These findings underscore the dependence of conventional evaluation on reference definition and support preference-based assessment as a complementary approach for evaluating AI segmentation quality in BM MRI.

Epilepsy is one of the most common chronic neurological disorders, and temporal lobe epilepsy (TLE) is its most prevalent form in adults. Although TLE is classified as a focal epilepsy, it has traditionally been defined by hippocampal and extra-hippocampal atrophy. However, several studies also report regions of increased cortical thickness, or cortical hypertrophy, in TLE, challenging the notion that structural change in epilepsy is unidirectional. In this narrative review, we synthesize evidence for cortical hypertrophy in TLE and place these findings in a broader neurobiological context. We provide an overview of cortical thickness and MRI approaches used to measure it, highlighting differences between surface-based, volume-based, and voxel-based methods. We then review MRI studies reporting cortical hypertrophy in TLE, noting variability in affected regions, patient populations, and analytical techniques. We discuss potential mechanisms that may underlie cortical hypertrophy, including seizure-related structural remodeling, glial or inflammatory processes, compensatory neuroplasticity, network effects, and methodological limitations. Finally, we outline key gaps and controversies regarding the biological validity, temporal dynamics, and clinical relevance of cortical hypertrophy in TLE. We conclude that consideration of both cortical atrophy and hypertrophy may improve broader understanding of TLE as a disorder involving brain remodeling rather than isolated regional atrophy.

This review aims to address the therapeutic potential of new generation of oncolytic viruses (OVs) for liver cancer with the focus on hepatocellular carcinoma (HCC). We evaluate the therapeutic status of oncolytic virus therapy (OVT) for liver cancer, addresses the research question of how different OVs perform in treating the malignancy, and and analyze the challenges remain in their clinical treatment based on the synthesis of both preclinical and clinical studies investigating various OVs, including Herpes simplex virus (HSV), Adenovirus (AdV), Vaccinia virus (VV), Coxsackievirus (COX), and Newcastle disease virus (NDV). OVs selectively infect and lyse tumor cells, stimulating anti-tumor immunity. HSV and VV have demonstrated high efficacy and safety in studies. Genetically engineered AdV and NDV platforms, especially those expressing immune checkpoint inhibitors or cytokines, show promising anti-tumor activity. Advances in viral engineering and delivery systems have improved tumor selectivity and immune activation. Key challenges identified include host antiviral immunity, delivery efficiency, and optimal patient selection. OVT represents a promising immunotherapeutic strategy for liver cancer. While significant progress has been made in both efficacy and safety through genetic modification, ongoing innovation in viral engineering, combination therapies.

Animals integrate knowledge about how the state of the environment evolves to choose actions that maximise reward. Such goal-directed behaviour - or model-based (MB) reinforcement learning (RL) - can flexibly adapt choice to changes, being thus distinct from simpler habitual - or model-free (MF) RL - strategies. Previous inactivation and neuroimaging work implicates prefrontal cortex (PFC) and the caudate striatal region in MB-RL; however, details are scarce about its implementation at the single-neuron level. Here, we recorded from two PFC regions - the dorsal anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC), and two striatal regions, caudate and putamen - while two rhesus macaques performed a sequential decision-making (two-step) task in which MB-RL involves knowledge about the statistics of reward and state transitions. All four regions, but particularly the ACC, encoded the rewards received and tracked the probabilistic state transitions that occurred. However, ACC (and to a lesser extent caudate) encoded the key variables of the task - namely the interaction between reward, transition, and choice - which underlies MB decision-making. ACC and caudate neurons also encoded MB-derived estimates of choice values. Moreover, caudate value estimates of the choice options flipped when a rare transition occurred, demonstrating value update based on structural knowledge of the task. The striatal regions were unique (relative to PFC) in encoding the current and previous rewards with opposing polarities, reminiscent of dopaminergic neurons, and indicative of an MF prediction error. Our findings provide a deeper understanding of selective and temporally dissociable neural mechanisms underlying goal-directed behaviour.

Mitochondrial dysfunction and dysregulated microglial phenotypes are central contributors to the pathogenesis of Alzheimer's disease (AD), driving persistent neuroinflammation, synaptic loss, and impaired clearance of amyloid and tau aggregates. Disruptions in microglial mitochondrial metabolism lead to bioenergetic deficits, elevated oxidative stress, and shifts into maladaptive reactive states that exacerbate neuronal vulnerability. Recent insights into immune checkpoint pathways, including programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), highlight their roles in maintaining neuroimmune balance within the central nervous system (CNS). Although sustained engagement of these pathways in the peripheral compartment may contribute to immune exhaustion and reduced debris clearance, their CNS-resident roles in microglial homeostasis are protective, and this compartment-specific duality must be carefully considered in the design of targeted therapeutic strategies. Immune checkpoint inhibitors (ICIs), initially developed for oncology, are now being explored for their potential to modulate microglial responses, enhance amyloid removal, and mitigate neuroinflammation in AD. Emerging evidence suggests that combining ICIs with mitochondrial modulators may cooperatively support microglial homeostasis and potentially reprogram dysfunctional neuroimmune circuits, though direct combinatorial evidence in AD remains limited. Together, these findings provide a conceptual basis for considering a dual-targeted therapeutic framework for modulating neuroinflammation in AD. This review integrates current mechanistic insights into mitochondrial dysfunction and immune checkpoint signaling in AD and evaluates their translational potential as combined therapeutic strategies.

This cross-sectional study compares trends in insurance coverage and out-of-pocket medical spending from 2014 to 2024 among US adults aged 19 to 65 years with and without visual impairment.

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Among US teenagers, 79% of HIV infections are attributable to male-to-male sexual contact; yet, few interventions have been shown to effectively reduce sexual risk among gay and bisexual adolescents (GBA). Parent communication about sex is associated with adolescent sexual risk, and interventions to improve parent communication have been shown to successfully reduce sexual risk among heterosexual samples. However, no interventions designed specifically for parents of GBA have been tested in clinical trials. Parents and Adolescent Talking About Healthy Sexuality (PATHS) is a web-based intervention we created for parents of GBA that aims to improve parent communication about sexuality and HIV and increase parent behaviors supportive of GBA sexual health. This trial aims to test whether delivering PATHS to parents of GBA ages 14-19 years will improve GBA sexual health outcomes in the 6 months following intervention delivery. Secondary aims are to test whether the intervention's effects are sustained at 12 months after the intervention and to examine whether effects are mediated through specific parent behaviors. In total, 350 parents of GBA will be recruited online via social media advertising and randomized to receive either PATHS or an active control. PATHS is fully automated, self-paced, and can be completed in a single session lasting under an hour. The active control is an education entertainment film created to provide general support and guidance to parents of GBA. Both parents and their GBA sons will complete online assessments every 3 months over a 1-year period. Primary outcomes will be evaluated at 6 months after the intervention, and then, the control arm will crossover and receive PATHS, and dyads will be followed for another 6 months. Primary outcomes include both adolescent sexual preparedness (eg, condom skills) as well as HIV-related sexual risk behavior (ie, condomless anal or vaginal sex that is not protected by pre-exposure prophylaxis). The study was funded in March 2022, and we completed enrollment of 393 parent-GBA dyads in September 2025. We project that all participants will have completed study activities by November 2026, with data analysis and results of the trial forthcoming in the first quarter of 2027. If proven efficacious, PATHS will be among the first HIV prevention interventions shown to reduce sexual risk for GBA. Moreover, as other adolescent-focused interventions emerge, PATHS' unique focus on parents will offer a complementary, additional means for reaching GBA who do not engage with other intervention options. ClinicalTrials.gov NCT05852600; https://clinicaltrials.gov/study/NCT05852600. PRR1-10.2196/81316.

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent and heritable of neurodevelopmental disorders. To characterize the genetic variants contributing to this heritability, we studied families with members affected by ADHD. Genome-wide array data were obtained on two cohorts: NHGRI Family Cohort (359 nuclear families,1538 individuals) and NCR Family Cohort (25 multigenerational and 132 nuclear families, 631 members). A meta-analysis of family-based association tests (FBAT) of the two cohorts identified three genome-wide significant associations, one upstream from TFRC, and two that were intronic to GSDME and to TRIM31, with the last gene previously implicated in ADHD. Genes associated with ADHD (MAGMA, gene-based association P&#x2009;<&#x2009;0.05) overlapped with genes implicated in ADHD by prior case/control genome-wide association studies. Meta-analyses of the linkage signals identified one significant linkage region (LOD&#x2009;>&#x2009;3) on 19p13.2-13.11 that encompassed a genome-wide significant variant in the FBAT of the NHGRI Family Cohort (rs55741253, P&#x2009;=&#x2009;2.68&#x2009;&#xd7;&#x2009;10-&#x2009;8). Additionally, two of the five linkage regions that reached a LOD&#x2009;>&#x2009;2 in our meta-analysis replicated significant linkages from prior studies (prior studies reporting 13 linkages with LOD&#x2009;>&#x2009;3.0; hypergeometric test of overlapping linkage signals, P&#x2009;<&#x2009;0.01). Using neuroimaging data from the NCR cohort, we found genes associated with ADHD overlapped with genes associated with the brain's total surface area and a feature of functional connectivity, reflecting the interaction between the brain's default mode and task positive networks. Such work begins to delineate the neural substrates of the discovered genetic associations with familial ADHD.