Citations

Abstract Purpose Elective genomic sequencing (EGS) returns monogenic disease findings in multiple genes, including potentially novel variants, and may also provide participants with carrier status, pharmacogenomic and other health-related information. The PeopleSeq Study assessed participants’ motivations for and concerns about EGS and the associated clinical and psychosocial outcomes across diverse EGS providers. Methods We administered a shared questionnaire to participants who chose to undergo EGS via 18 academic, clinical, or commercial EGS platforms. Results We enrolled 1575 participants, of whom 1147 (72.8%) completed a questionnaire after receiving their EGS results. A majority (60.3%) of the participants who completed a post-result questionnaire self-reported receiving results they assessed as important, including negative findings, and 75.9% reported a form of health-related utility. Among a subset (19.4%) who shared their EGS reports, 16.6% (37 of n =223) received a monogenic finding and self-reported results deemed “important” were consistent with EGS reports. Most participants (74.1%) discussed their results with their family, but fewer discussed their results with a healthcare provider other than the site team (41.7%) or had one or more medical visits as a direct result of their EGS testing (23.1%). Participants expressed diverse motivations for EGS, with 91.4% expressing interest in their personal disease risk and 54% who expressed quasi-indication-based motivations related to family medical history. Individuals motivated by family history reported important results at a significantly higher rate. Conclusions Early adopters of EGS are motivated by general interest in their health as well as quasi-indication-based considerations such as family history. A majority of participants learned results they considered medically important, but a much smaller segment engaged healthcare providers with their results.

Abstract The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal assessments. This review synthesizes 122 high‐impact studies using ADNI data or biospecimens from 2023 to mid‐2025 to clarify mechanisms of Alzheimer's disease (AD) progression. Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms. Multifactorial contributions from genetic and epigenetic influences, co‐pathologies and comorbidities, and mechanisms of resilience modulate disease progression. Finally, heterogeneity of clinical presentation and disease course is described in the context of multiple contributing factors, highlighting the complexity of AD. By integrating imaging, fluid biomarkers, genetics, and clinical measures, ADNI provides a comprehensive research dataset for unraveling mechanisms underlying AD progression.

Purpose To assess if hospitals with high physician employment differ in risk-standardized mortality and readmission rates. Design/methodology/approach A cross-sectional evaluation of data from the 2021 Hospital Readmission Reduction program, Hospital Value-Based Purchasing Program, American Hospital Association and Area Health Resource Files was utilized. A binary variable was created to identify hospitals with ≤ 50% or >50% employed physicians. Dependent variables included 30-day mortality and readmission rates for acute myocardial infarction (AMI), congestive heart failure (CHF), pneumonia (PN), and chronic obstructive pulmonary disease (COPD) hospitalizations. Propensity score matching was utilized to compare hospitals. The final matched cohort compared 200 hospitals in each group ( ≤ 50% physicians and > 50% physicians). Findings After matching, hospitals with > 50% physician employment were associated with improved mortality scores for AMI (−0.36, 95% CI: −0.58, −0.14), COPD (−0.38, 95% CI: −0.63, −0.14), and PN (−0.71, 95% CI: −1.15, −0.27). No significant differences were noted for CHF mortality or readmission rates. Originality/value There has been a growth in hospitals employing physician in the United States. This work demonstrates that hospitals with higher physician employment levels are associated with lower mortality scores. This likely reflects a broader organizational phenotype characterized by alignment, scale and clinical integration rather than physician employment as an isolated strategy. Further research should examine organizational features to better disentangle the structure and combination of organizational characteristics underlying these associations.

Importance Currently, there are no standardized outcome domains or measures in clinical trials for facial aging. Heterogeneity in outcome domains and measurement instruments across clinical trials creates difficulty in directly comparing interventions, determining superior therapies, and developing high-quality meta-analyses. Objective To develop a core outcome set (COS) of essential domains to be reported in clinical trials evaluating the efficacy of interventions for facial aging. Evidence Review PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, and CINAHL were searched from September 2005 to September 2015. An updated search of the same databases was performed from September 2015 to February 2026. Studies were included if (1) they were randomized clinical trial or controlled clinical trial in design, (2) they assessed the efficacy or safety of an intervention for facial aging, (3) they were published in English, and (4) they involved human participants. Complementary sources, including patient interviews, were used to capture further relevant outcomes. Two rounds of Delphi surveys, followed by consensus meetings, were used to identify outcome domains considered most important by both patient and physician stakeholders. Findings The final COS consists of 6 outcome domains: (1) overall convenience of treatment; (2) time to return to normal work and social activity; (3) overall assessment of focused area of treatment (at the point in time when treatment is expected to provide peak benefit); (4) duration of treatment effect; (5) severity of persistent local or systemic adverse events, including pigmentary change, skin texture change, delayed healing, scarring, and serious adverse events; and (6) patient satisfaction with treatment. Conclusions and Relevance The 6 outcome domains identified through a Delphi consensus are recommended for reporting in future facial aging trials to ensure that outcomes that matter most to patients and clinicians are measured and that results are comparable across interventions.

TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43–dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN , RAP1GAP , SYT7 , and KCNQ2 . Using human stem cell–derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

Background: Real-time intraoperative discrimination of malignant tissue during pediatric solid tumor resection is limited, constraining margin optimization; the utility of indocyanine green (ICG) fluorescence in this population remains incompletely defined. Study Design: Prospective, observational, multi-institutional study (2019–2023) of pediatric, adolescent, and young adult patients undergoing resection of intra-abdominal solid malignancies following preoperative ICG administration. The primary endpoint was diagnostic accuracy of ICG fluorescence for tumor-containing specimens; secondary endpoints included association with margin status and surgeon-perceived intraoperative benefit. Results: Forty-three operations in 42 patients yielded 55 specimens, of which 47 (85%) were malignant. Diagnostic performance was highest in hepatic tumors (sensitivity 83%, positive predictive value 83%) and lower in adrenal and heterogeneous tumor types. ICG avidity was not associated with improved negative margin rates (86% vs 75%, p=0.47). Surgeons reported intraoperative benefit in 67% of cases, most commonly improved visualization. No ICG-related adverse events occurred. Conclusions: ICG fluorescence provides reliable tumor identification in hepatic malignancies but does not correlate with margin-negative resection, indicating limited utility for margin guidance. These data support tumor-specific application and further investigation of optimized fluorescence strategies, including dosing, timing, and alternative fluorophores, in pediatric oncologic surgery.

Abstract Background Indocyanine green (ICG) fluorescence imaging is increasingly incorporated into robotic liver resections (RLR), yet clinical practice regarding timing, dosage, and staining techniques is divergent. Aims This international expert survey aimed to characterize current practices for ICG in RLR. Methods Experts in RLR were invited to participate based on surgical volume (experience of 50 RLR and 30 annual RLR). A 74-item questionnaire was developed following a literature search and reviewed by a steering committee. The survey addressed indications, timing, dosage, imaging technology, benefits, limitations, training, and future directions of ICG use. Responses collected between September and October 2025 were analyzed. Results Seventy experts from 19 countries completed the survey, corresponding to an 88% response rate. Centers performed a median of 180 annual liver resections, including 55 RLR. Most experts used ICG (96%) during RLR. Anatomical demarcation (91%), tumor localization (60%), and biliary anatomy assessment (60%) were the most frequent indications. 60% of experts use preoperative ICG, while intraoperative ICG is mainly administered for demarcation (67%) and biliary tract visualization (40%). Considerable heterogeneity exists in dosage, timing, and staining techniques, particularly in cirrhotic livers and for tumor localization. Only half of the experts had standard operating procedures, whereas 64% expressed the need for a higher degree of standardization. Reported benefits of ICG use included improved anatomical orientation, margin assessment, lesion detection, and support during complex resections. Perceived limitations included background fluorescence, tissue penetration and variable staining in diseased parenchyma. 80% anticipated improved outcomes with combined ICG and three-dimensional image-guidance. Conclusion ICG fluorescence is widely used in RLR and is an important cornerstone for precision-guided robotic liver surgery. Standardized clinical practice guidelines, structured training, and technological improvements in imaging and navigation systems are claimed to optimize its clinical use.

BACKGROUND: Cardiac computed tomography (CT) acquired during the acute stroke imaging protocol is an emerging modality to detect cardiac thrombi. We determined its yield in patients with acute ischemic stroke. METHODS: We performed a 1-stage individual patient data meta-analysis of 4 prospective observational cohorts (AIS of HEARTS [Acute Ischemic Stroke of Heart-Related Embolic Sources Detected on Acute Cardiac CT Scans]), including patients with acute ischemic stroke who underwent ECG-gated or non–ECG-gated cardiac CT between May 2018 and June 2024. We excluded patients with transient ischemic attack or stroke mimics. The primary outcome was the proportion of patients with a thrombus on cardiac CT. Secondary outcomes were additional scan time, radiation dose, comparison with echocardiography, and 90-day outcomes. We performed logistic regression analyses to compare 90-day outcomes between patients with and without thrombus, adjusting for age, sex, history of atrial fibrillation, ischemic heart disease, chronic heart failure, stroke or transient ischemic attack, anticoagulant use, prestroke modified Rankin Scale score, National Institutes of Health Stroke Scale score, large vessel occlusions, and intravenous thrombolysis, as appropriate for each outcome. RESULTS: We included 3919 patients (median age, 74 [interquartile range (IQR), 63–82], 58% male, median National Institutes of Health Stroke Scale score 6 [IQR, 3–12]). Cardiac CT detected a thrombus in 243 (6.2%) patients. Among 1323 patients that underwent both cardiac CT and transthoracic echocardiography, cardiac CT had a higher yield than transthoracic echocardiography (odds ratio, 7.4 [95% CI, 4.0–15.1]; P <0.001). Median additional scan time was 6 minutes (IQR, 5–7) for ECG-gated and 13 seconds (IQR, 12–61) for non–ECG-gated cardiac CT. Median additional radiation dose was 2.9 mSv (IQR, 1.6–4.1). Patients with thrombi had higher 90-day mortality (33% versus 15%, adjusted odds ratio, 1.6 [95% CI, 1.1–2.3]) and worse modified Rankin Scale scores (median modified Rankin Scale score 3 versus 2, adjusted odds ratio, 1.6 [95% CI, 1.2–2.0]), but similar recurrent stroke rates (5% versus 4%, adjusted odds ratio, 1.4 [95% CI, 0.7–2.5]). CONCLUSIONS: Implementing cardiac CT into the acute stroke imaging protocol is feasible, detects thrombi in ≈6% of patients, and has a higher yield than transthoracic echocardiography. Cardiac thrombi were associated with higher mortality, but not higher stroke recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT07165093.

Objectives: Identify the frequency of abnormal neurological examinations among patients presenting in person for headache consultation. Determine what proportion of patients with abnormal examinations have accompanying red flags in their histories and/or undergo diagnostic workup. Methods: We conducted a retrospective review of patients presenting in person for headache consultation at a tertiary/quaternary headache clinic between June 2022 and May 2023. We excluded examination abnormalities consistent with known comorbidity, functional neurological disorder, and/or non-headache disease. We then calculated the proportion of patients with an abnormal neurological examination. For patients with abnormal examinations, the electronic medical record was further reviewed for red-flag components in the history, diagnostic workup ordered, and the resulting diagnosis. Results: Of 1281 patients presenting for in-person headache consultation, 218 (17%) had abnormal neurological examinations that were not consistent with known comorbidity, functional neurological disorder, or non-headache disease. Of these, 203 (93%) had a red flag in their history. The remaining 15 patients with abnormal examinations and no historical red flags comprised 1.2% of all 1281 patients. Regarding workup, 160 (73%) had neuro-imaging and 61 (28%) had laboratory studies ordered and/or requested for review, of which 13% and 8% were concerning for pathology, respectively. Conclusions: A small but notable proportion of patients presenting for in-person headache consultation had abnormalities on neurological examination. The majority of these patients received imaging, with a diagnostic yield higher than previously reported. However, the vast majority of patients with abnormal examinations also had red flags in their history to prompt diagnostic workup.

BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have expanded from metabolic therapeutics to agents with broad effects on inflammation, tissue repair, cutaneous and adipose biology, and aging-related pathways. Clinicians increasingly encounter cutaneous manifestations and aesthetic sequelae with important implications for dermatologic counseling and multidisciplinary care. OBJECTIVE To review current evidence regarding GLP-1RA effects on skin biology, inflammatory dermatoses, wound healing, cutaneous adverse events, and aesthetic aging. MATERIALS AND METHODS A narrative review of clinical, translational, and mechanistic literature was performed, emphasizing psoriasis, hidradenitis suppurativa, wound repair, skin hypersensitivity reactions, autoimmune blistering disease, and facial volume loss associated with pharmacologic weight reduction. RESULTS GLP-1RAs are hypothesized to improve inflammatory skin conditions and wound repair through anti-inflammatory, immunometabolic, and proreparative pathways. Yet, their use may also be associated with injection-site reactions, hypersensitivity eruptions, rare autoimmune blistering disorders, and clinically significant facial deflation and skin laxity. Current evidence is strongest for mechanistic plausibility and observational clinical signals, whereas dermatology-specific randomized trials remain limited. CONCLUSION GLP-1RAs exert bidirectional effects on cutaneous biology. Recognition of both therapeutic opportunities and potential aesthetic or adverse sequelae is important, with patient counseling ideally occurring within a multidisciplinary framework that integrates metabolic benefits with skin health and appearance.