Citations

Abstract INTRODUCTION Risk factors associated with sporadic non‐amnestic and early‐onset Alzheimer's disease (AD) remain underexamined. METHODS We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non–right‐handedness, learning disability, seizures, autoimmune disease). RESULTS Early‐onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non–right‐handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non–right‐handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION Identifying novel factors enriched in early‐onset and non‐amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. Highlights We identified a suite of novel factors overrepresented in early‐onset and non‐amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non–right‐handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.

Background/Objectives: This study aims to evaluate the quality of life (QoL) and oncological outcomes in premenopausal women diagnosed with hormone receptor-positive breast cancer who are receiving either bilateral oophorectomy (BO) or gonadotropin-releasing hormone agonist (GnRH) therapy. Both methods serve to inhibit ovarian function, which is essential for the management of estrogen-dependent tumors; however, their effects on QoL have yet to be fully clarified. Methods: Data were analyzed from the Mayo Clinic Breast Disease Registry, focusing on women under 55 diagnosed with estrogen receptor-positive breast cancer who received either BO or GnRH within one year of diagnosis. QoL was assessed using the Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10) at baseline and annually for five years. Results: A total of 181 patients were enrolled in the study; 40 into the BO group and 141 to the GnRH group. Both groups exhibited similar levels of sexual dysfunction after a one-year period; however, the BO group stated a higher frequency of hot flashes. PROMIS-10 scores improved in both mental and physical health over time, with no significant differences between the groups. Within the BO group, one recurrence was observed, in contrast to the GnRH group, which had six events. Nonetheless, the difference in recurrence rates did not reach statistical significance. Conclusions: The long-term QoL and oncologic outcomes for premenopausal women with hormone receptor-positive breast cancer were similar for BO and GnRH therapy. These findings emphasize the need for individualized treatment decisions, considering patient preferences and side effects.

Abstract Background and Aims In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. Methods VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. Results Over a median of 19.7 months (inter-quartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. Conclusions In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Importance Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with increased risk of diabetic retinopathy (DR) and nonarteritic anterior ischemic optic neuropathy (NAION). The risk of sight-threatening complications associated with GLP-1 RAs is underexamined. Objective To investigate whether the use of GLP-1 RAs in patients with T2D is associated with the development of DR, NAION, or DR complications. Design, Setting, and Participants This retrospective cohort study of adults (aged ≥18 years) with T2D and a recent hemoglobin A 1c level of 6.5% or higher was conducted between January 1, 2015, and September 30, 2022, using the TriNetX database. The cohort was divided into 2 groups, adjusted for baseline characteristics through propensity score matching (PSM), based on whether the individuals received prescriptions for a GLP-1 RA. The statistical analysis was conducted on October 10, 2024. Exposures At least 2 prescriptions of a GLP-1 RA given 6 months apart. Main Outcomes and Measures Cox proportional hazard regression models were used to evaluate the primary outcome: association between GLP-1 RAs and the risk of incident DR, NAION, or sight-threatening complications over a 2-year follow-up period. Results After PSM, 185 066 individuals (mean [SD] age, 59.0 [12.5] years; 93 389 females [50.5%]) were prescribed GLP-1 receptor agonists. Use of GLP-1 RAs was associated with an increased incidence of DR (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11), while no statistically significant difference was observed in the risk of NAION (HR, 1.26; 95% CI, 0.94-1.70). In a subgroup analysis of 32 695 patients with preexisting DR, GLP-1 RAs were not associated with progression to proliferative DR (HR, 1.06; 95% CI, 0.97-1.15) or diabetic macular edema (HR, 0.98; 95% CI, 0.95-1.01) but were associated with a lower occurrence of vitreous hemorrhages (HR, 0.74; 95% CI, 0.68-0.80), neovascular glaucoma (HR, 0.78; 95% CI, 0.68-0.88), or blindness (HR, 0.77; 95% CI, 0.73-0.82). Conclusions and Relevance In this cohort study of individuals with T2D, GLP-1 RA use was associated with a modestly increased risk of incident DR; however, fewer patients experienced sight-threatening DR complications, including blindness, even among those with preexisting DR. These findings suggest that all patients with T2D treated with GLP-1 RAs, regardless of preexisting DR, should be regularly screened and monitored for potential complications of T2D.

Abstract Objectives Large language models (LLMs) offer potential in natural language processing tasks in healthcare. Due to the need for high accuracy, understanding their limitations is essential. The purpose of this study was to evaluate the performance of LLMs in classifying radiology reports for the presence of pulmonary embolism (PE) under various conditions, including different prompt designs and data perturbations. Materials and Methods In this retrospective, institutional review board approved study, we evaluated 3 Google’s LLMs including Gemini-1.5-Pro, Gemini-1.5-Flash-001, and Gemini-1.5-Flash-002, in classifying 11 999 pulmonary CT angiography radiology reports for PE. Ground truth labels were determined by concordance between a computer vision-based PE detection (CVPED) algorithm and multiple LLM runs under various configurations. Discrepancies between algorithms’ classifications were aggregated and manually reviewed. We evaluated the effects of prompt design, data perturbations, and repeated analyses across geographic cloud regions. Performance metrics were calculated. Results Of 11 999 reports, 1296 (10.8%) were PE-positive. Accuracy across LLMs ranged between 0.953 and 0.996. The highest recall rate for a prompt modified after a review of the misclassified cases (up to 0.997). Few-shot prompting improved recall (up to 0.99), while chain-of-thought generally degraded performance. Gemini-1.5-Flash-002 demonstrated the highest robustness against data perturbations. Geographic cloud region variability was minimal for Gemini-1.5+-Pro, while the Flash models showed stable performance. Discussion and Conclusion LLMs demonstrated high performance in classifying radiology reports, though results varied with prompt design and data quality. These findings underscore the need for systematic evaluation and validation of LLMs for clinical applications, particularly in high-stakes scenarios.

Abstract Migraine and functional neurological disorder (FND) are two of the most common conditions in neurological practice. It is assumed that the two conditions have distinct underlying mechanisms. However, it can be clinically challenging to disentangle their relative contributions to a patient's symptoms. In addition, apart from the relationship between persistent postural perceptual dizziness (PPPD) and migraine, the frequency of co-occurrence has not been characterized in detail. Contemporary conceptualizations of FND have driven a re-evaluation of its relationship to other neurological disorders, including migraine. We carried out a narrative review of the literature examining the co-occurrence of migraine and FND. We also explored their comorbidities, aetiological risk factors and mechanisms, focusing especially on areas of potential overlap. Our review suggests increased frequency of migraine in people with functional seizures compared to epilepsy, but data from people with functional motor symptoms is mixed. Robust epidemiological studies evaluating the frequency of FND in migraine are lacking. Similar to other neurological disorders, migraine is an established trigger of FND. Female gender, adverse childhood experiences and comorbid psychiatric and functional disorders, such as irritable bowel syndrome and fibromyalgia, are more common in both conditions than in controls, but perhaps more so in FND. Mechanistic research in both conditions highlights converging frameworks of dysregulated allostatic/stress responses in the context of predictive processing models of the brain. This has implications for pharmaceutical and rehabilitation treatments. The relationship between migraine and FND is poorly studied. An overview of their overlap offers a model of non-dualistic thinking within a clinical neuroscience framework for future studies.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain provide recommendations for the comprehensive management of pain in patients with cancer. This article will focus on methods for screening for pain, safe and appropriate prescription of opioid and miscellaneous analgesics, and the optimization of nonpharmacologic interventions including integrative and interventional strategies for treatment of cancer-related pain. Additionally, the NCCN Guidelines discuss methods for the safe reduction of opioids when appropriate, as well as techniques for encouraging the judicious use of opioids. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional issues that are not covered here, including management of pain during a pain crisis, management of procedure-related pain and anxiety, pain management for cancer survivors, and the use of nonopioid and adjuvant analgesics for cancer-related pain.

Background The optimal timing and type of venous thromboembolism chemoprophylaxis (VTEp) for adults with acute traumatic brain injury (TBI) remains unknown. This systematic review synthesized evidence on the timing and type of VTEp in adults with TBI and highlights evidence gaps. Methods We searched Ovid MEDLINE, Embase, and the Cochrane Library through November 4, 2024 for English language, randomized or non-randomized studies with a comparator that reported VTEp timing or agent in adults with acute TBI, and reported intracranial hemorrhage progression (ICHP), VTE, pulmonary embolism (PE), deep vein thrombosis (DVT), neurosurgical intervention (NSI), adverse events (AEs), length of stay (LOS), function, or mortality. Risk of bias (ROB) was assessed with ROBINS-I as low, moderate, serious, or critical risk in studies that used advanced analytic methods (AAMs) to control selection bias; all other studies were deemed critical risk. We qualitatively synthesized evidence and focused text reporting on studies with AAM. Results From 738 citations, 21 non-randomized studies met criteria (1 moderate, 20 critical ROB): 16 on VTEp timing, 7 on agents. Seven studies used AAM. For VTEp timing (five AAM studies), one study of adults with mostly mild TBI found no significant difference between Early and Late VTEp on ICHP (moderate ROB); no timing studies with AAM reported ICHP for adults with moderate or severe TBI. Findings were mixed for VTE timing on NSI and PE. Early VTEp was associated with fewer DVTs. There was no difference in mortality or serious AEs by VTEp timing. For VTEp agents, three studies with AAM found no significant difference between low molecular weight heparin (LMWH) and unfractionated heparin (UH) on ICHP, PE, DVT, and serious or overall AEs. Results were mixed for LMWH versus UH effects on NSI after VTEp, VTE, LOS and mortality. TBI severity labeling varied across studies and within measures, reducing comparability. Conclusions Clinical evidence on the timing and type of VTEp for adults with acute TBI is of insufficient quality for clinical decision-making. Prospective research designs, standardization of TBI severity labeling, and improved reporting of interventions and outcomes would advance the field. PROSPERO registration number CRD42023421534 Level of evidence Systematic Review, Level IV