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ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

PURPOSE Recent studies reveal that 5%-18% of children with cancer harbor pathogenic variants in known cancer-predisposing genes. However, DNA damage repair (DDR) genes, which are frequently somatically altered in pediatric tumors, have not been systematically examined as a source of novel cancer-predisposing signals. METHODS To address this gap, we interrogated 189 DDR genes for presence of germline predisposing variants (PV) among 5,993 childhood cancer cases and 14,477 adult noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts. RESULTS Analysis across all cases with cancer revealed enrichment of TP53 PV. Cancer-specific analyses confirmed known associations including germline TP53 PV in adrenocortical carcinoma, high-grade glioma (HGG), and medulloblastoma (MB), PMS2 in HGG and non-Hodgkin lymphoma (NHL), MLH1 in HGG, BRCA2 in NHL, and BARD1 in neuroblastoma. In addition, four novel associations were uncovered, including BRCA1 in ependymoma, SPIDR in HGG, SMC5 in MB, and SMARCAL1 in osteosarcoma (OS). Importantly, the SMARCAL1 :OS association was significant in the discovery (6/230, 2.6%, false discovery rate [FDR] logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; P Fisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, P Fisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, P Fisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data. CONCLUSION Our study confirms the relevance DDR genetic variation in pediatric cancer risk and establishes SMARCAL1 as a novel OS predisposing gene, providing insights into tumor biology and creating opportunities to optimize care for patients with this challenging tumor.

ABSTRACT The purpose of this 1‐year study was to assess the effect of osteogenic loading combined with melatonin on musculoskeletal health and well‐being in a population with osteopenia. Participants were randomized into one of four groups and received mock loading plus plant fiber as placebo (ML/Placebo), mock loading plus 5 mg melatonin (ML/Melatonin), osteogenic loading plus placebo (OL/Placebo), and osteogenic loading plus 5 mg melatonin (OL/Melatonin). The loading protocol was designed to deliver multiples of body weight (MOB; 1‐2 MOB for mock loading and 1.5–4.2 MOB for osteogenic loading) to the upper body (targeting the arm, chest, and shoulders), core (targeting the spine and core stability), lower body (targeting the legs and hip) and postural (targeting the spine and posture). Following these interventions, musculoskeletal health was measured by DXA and functional testing using timed‐up‐and‐go (TUG) and sit‐to‐stand (STS) assessments. Markers of bone health (e.g., P1NP, CTX, CRP, cortisol, and melatonin) were assessed in urine collected during the night (10 pm–6 am). Mental health assessments were conducted using PSS, CES‐D, STAI and QualiOst. Time‐dependent increases in the amount of force exerted (in lbs) were observed in the OL groups for all musculoskeletal systems targeted, compared to those participants receiving ML. Over 12mos, compared to baseline, participants in the OL/Melatonin group had statistically significant increases in lumbar spine T‐scores (mean difference [MD] = 0.13, standard deviation [SD] = 0.05, p = 0.015) and BMD (MD = 0.013, SD = 0.006, p = 0.021). No other statistically significant effects were noted for T‐scores, BMD, or FRAX scores. Additionally, no significant differences were observed when T‐scores were compared between groups. Functional assessments at 12mos revealed increases in TUG times (MD = −1.7, SD = 0.3, p = 0.002) from baseline and deterioration for STS (MD = 2.8, SD = 0.59, p = 0.004) from month 03 for ML/placebo group, which did not occur for the other interventions. Correlation analysis revealed negative associations between TUG performance and CTX levels starting at 3mos in the OL/Melatonin group ( r = −0.960, p = 0.04). The change in STS repetitions over a 12‐month period (12mo–0mo) was negatively associated with the P1NP:CTX ratio ( r = −0.978, p = 0.02) and positively associated with melatonin levels in the OL/Melatonin group ( r = 0.958, p = 0.04). No changes in nocturnal output of CRP or cortisol and subject‐reported outcomes were observed for any of the interventions within and between groups. The results from this study reveal that osteogenic loading combined with melatonin may be an alternative therapeutic intervention for those with osteopenia.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Background: Deciding to use oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF) is complex. For many, the decision between treatment and non-treatment requires a primary tradeoff between the risks of potential stroke and increased bleeding. Hypothesis: We hypothesized that patient values and empiric stroke risk measured by CHA 2 DS 2 -VASc score would influence OAC decisions. Methods: We conducted a secondary analysis of a randomized clinical trial where eligible clinicians and patients were independently randomized to one of two decision aids (DAs) – a patient decision aid and/or an encounter decision aid. Eligible patients were adults with AF with CHA 2 DS 2 -VASc≥1 for men or ≥2 for women. Patients newly prescribed (OAC-naive subgroup) or already taking OAC (OAC-experienced subgroup) were included. We assessed patient values using a 5-point Likert scale between stroke prevention and bleeding risk after SDM during a clinical encounter. We report preliminary results using descriptive statistics and adjusted analysis to investigate the effects of CHA 2 DS 2 -VASc and expressed values on OAC use. Results: 1005 patients were included in the analysis. 828 (82%) patients valued stroke prevention over bleeding risk. Among the OAC-naive group, 175 (63%) valued stroke prevention more than bleed avoidance, 58 (20%) valued bleed avoidance more than stroke prevention, and 47 (17%) were neutral. In the unadjusted analysis, patients were more likely to value stroke prevention if they were OAC-experienced (p<0.001), older (p<0.001), female (p< 0.001), had patient-reported bleeding (p=0.003), or if CHA 2 DS 2 -VASc ≥ 2 if male, ≥3 if female (p<0.001) Table 1 . After adjustments, there were significant associations for OAC use among patients who valued stroke prevention (OR 5.35, 95%CI 3.13-9.13, p<0.001) or had higher CHA 2 DS 2 -VASc (OR 2.03, 95%CI 1.26-3.27, p=0.004). Patients who valued bleed avoidance had an opposing association not to use OAC (OR 0.23, 95%CI 0.11-0.48, p<0.001). Conclusions: Patients with elevated risk (CHA 2 DS 2 -VASc score, age, and female), and those who reported a prior bleeding event valued stroke prevention more than bleeding avoidance. Both empiric stroke risk and patient values were associated with the decision to use OAC. While the tradeoff between stroke prevention and bleeding risk is only one aspect of the decision-making process, these results indicate variability in patient values may influence OAC use.

Abstract Objective To evaluate the effectiveness of multiple decision aid strategies in promoting high quality shared decision making for prevention of stroke in patients with non-valvular atrial fibrillation. Design Cluster randomized controlled trial. Setting Six academic medical centers in the United States. Participants Patient participants were aged ≥18 with a diagnosis of non-valvular atrial fibrillation, at risk for stroke (CHA 2 DS 2 -VASc ≥1 for men, ≥2 for women), and scheduled for a clinical appointment to discuss stroke prevention strategies. Participating clinicians were those who manage stroke prevention strategies for participating patients. Intervention Patients were randomized to use a patient decision aid or usual care; clinicians were randomized to use an encounter decision aid or usual care with all participating patients. Main outcome measures Primary outcome measures were quality of shared decision making measured by OPTION12, knowledge of atrial fibrillation and its management, and decisional conflict. Results 1117 participants across six sites were included in the analysis. Compared with usual care, the combined use of both the patient decision aid and the encounter decision aid improved the quality of shared decision making (adjusted mean difference 12.1 (95% confidence interval (CI) 8.0 to 16.2; P<0.001), improved patients’ knowledge (odds ratio 1.68 (95% CI 1.35 to 2.09; P<0.001), and reduced patients’ decisional conflict (adjusted mean difference −6.3 (95% CI −9.6 to −3.1; P<0.001). Statistically significant improvements were also observed with the encounter decision aid alone versus usual care for all three outcomes and with the patient decision aid alone versus usual care for quality of shared decision making and knowledge. No important differences were observed in treatment choices for stroke prevention or in participants’ satisfaction. No statistically significant difference in the length of visit across study groups was detected. Conclusion Patients who received any decision aid (encounter decision aid, patient decision aid, or both) had lower decisional conflict, better shared decision making, and greater knowledge than those receiving no decision aid, except for the effect of the patient decision aid on decisional conflict, which did not reach statistical significance. The study establishes that use of either pre-visit or in-visit decision aids individually or in combination is advantageous compared with usual care. Trial registration ClinicalTrials.gov NCT04357288 .

Background: Guidelines recommend shared decision-making (SDM) for patients with atrial fibrillation (AF) making decisions regarding anticoagulation for stroke prevention. Decision support tools (e.g., Decision Aids [DAs]) facilitate SDM. However, little research has compared the effectiveness of the two most common types of DAs: (1) encounter decision aid (EDA) and (2) pre-encounter patient decision aid (PDA). Our study assessed the comparative effectiveness of PDAs and EDAs on SDM during AF clinical encounters where stroke prevention strategies were discussed. Research Question: Do decision aids (PDA or EDA), alone or in combination, improve patients’ AF decision-making experience compared to usual care? Methods: A cluster randomized multi-center trial in patients with AF comparing usual care (no DA) vs. one DA (EDA or PDA) or both DAs. Clinicians and patients were randomized independently into 4 study arms. Clinicians were randomized to use or not use the EDA for all study visits, and patients were randomized to use or not use the PDA. Co-primary outcome domains were: (1) quality of SDM (2) patient knowledge, and (3) decisional conflict. Secondary outcomes included: (1) treatment choice, (2) treatment initiation, and (3) treatment persistence. Patient characteristics were assessed. We will present comparisons of the randomized DAs on the co-primary and secondary outcomes and subgroup analyses. Results: Between December 2020-July 2023, investigators in 6 U.S. healthcare systems enrolled 1117 patients (mean (M) age 69, 63% male, 89% White) and 107 clinicians. Compared to usual care (no DA, M=31.6), SDM was better in patients receiving PDA (M=35.4) and EDA (44.5) alone or together (M=43.7; p’s<0.001). Knowledge about AF was greatest for those receiving both DAs or the PDA alone (84% accurate responses for PDA and both vs 76% with no DA, p<0.001), followed closely by the EDA alone (82%, p=0.003). Finally, both DAs (M=19.5) and EDA alone (M=20.0) had better decisional conflict scores compared to usual care (M=25.8; p’s<0.001). We will present analyses that assess the impact of DAs on secondary outcomes and interactions with DA, patient, and clinical characteristics across each outcome. Conclusions: In one of the first randomized trials examining the comparative effectiveness of EDAs and PDAs on SDM in clinical medicine, both PDAs and EDAs improved shared decision-making, decisional conflict, and knowledge compared to patients receiving usual care.

ABSTRACTApheresis is performed worldwide for an increasing number of indications. The development of common data elements (CDE) for apheresis related areas may facilitate conduct of new research, enhance quality initiatives including benchmarking, and improve patient care. This report describes the systematic development of the Uniform Apheresis Case Report Form (UACRF) as part of the Apheresis in the United States (ApheresUS) program. A consensus panel of 17 diverse experts in apheresis, related specialties, and electronic case report form (eCRF), and database development was assembled. The panel met via online conferencing from November 17, 2020 to December 1, 2021. A draft document was posted online for public comment from October 11, 2021 to November 10, 2021. Feedback was collected using an online survey tool. The consensus panel revised the UACRF. This version was converted to an eCRF with additional changes made to improve usability in this format. The final version of the UACRF was created on August 24, 2023. The UACRF contains 16 modules: procedure and subject eligibility, patient demographics, general procedure information, laboratory parameters, vascular access, common procedure elements, eight procedure specific modules (mononuclear cell collection and seven therapeutic modalities), outcomes, and site information. A total of 137 data elements were created, including 57 with one or more subelements. The UACRF is the first systematic attempt to develop CDE for therapeutic apheresis and white blood cell collections. Further validation of the UACRF is necessary to confirm the tool's ability to collect the relevant data elements and determine the usability of the form.

Background The purpose of this study was to investigate a therapeutic approach targeting the inflammatory response and consequent remodeling from ischemic myocardial injury. Methods and Results Coronary thrombus aspirates were collected from patients at the time of ST‐segment–elevation myocardial infarction and subjected to array‐based proteome analysis. Clinically indistinguishable at myocardial infarction (MI), patients were stratified into vulnerable and resilient on the basis of 1‐year left ventricular ejection fraction and death. Network analysis from coronary aspirates revealed prioritization of tumor necrosis factor‐α signaling in patients with worse clinical outcomes. Infliximab, a tumor necrosis factor‐α inhibitor, was infused intravenously at reperfusion in a porcine MI model to assess whether infliximab‐mediated immune modulation impacts post‐MI injury. At 3 days after MI (n=7), infliximab infusion increased proregenerative M2 macrophages in the myocardial border zone as quantified by immunofluorescence (24.1%±23.3% in infliximab versus 9.29%±8.7% in sham; P <0.01). Concomitantly, immunoassays of coronary sinus samples quantified lower troponin I levels (41.72±7.34 pg/mL versus 58.11±10.75 pg/mL; P <0.05) and secreted protein analysis revealed upregulation of injury‐modifying interleukin‐2, ‐4, ‐10, ‐12, and ‐18 cytokines in the infliximab‐treated cohort. At 4 weeks (n=12), infliximab treatment resulted in significant protective influence, improving left ventricular ejection fraction (53.9%±5.4% versus 36.2%±5.3%; P <0.001) and reducing scar size (8.31%±10.9% versus 17.41%±12.5%; P <0.05). Conclusions Profiling of coronary thrombus aspirates in patients with ST‐segment–elevation MI revealed highest association for tumor necrosis factor‐α in injury risk. Infliximab‐mediated immune modulation offers an actionable pathway to alter MI‐induced inflammatory response, preserving contractility and limiting adverse structural remodeling.