Citations

Background TAR DNA-binding protein 43 (TDP-43) proteinopathy contributes to Alzheimer's disease progression, but diagnosis remains autopsy-dependent. Objective This study aimed to develop a predictive model using FDG-PET imaging to identify brain regions associated with TDP-43 pathology in vivo. Methods Penalized logistic regression analyzed data from 294 participants and a subset of 159 with Braak and Thal ≥4. Features included FDG standard uptake value ratios (SUVRs) from 123 brain regions and age. Participants were split into training (90%) and testing (10%) datasets, with significant predictors identified by non-zero coefficients at optimal lambda. Results The model achieved 68% accuracy (AUC = 0.70) in 294 participants, highlighting the middle temporal gyrus, parahippocampal gyrus, and hippocampus. In the subset (n = 159), accuracy was 65% (AUC = 0.71), with the medial amygdala and precentral gyrus as key predictors of TDP-43 pathology. Conclusions This study suggests a moderate predictive accuracy of FDG-PET to identify brain regions associated with Alzheimer's disease-related TDP-43 proteinopathy.

Background Resuming anticoagulation in patients with mechanical heart valves after intracranial hemorrhage presents a clinical dilemma. The optimal timing must balance the risk of thromboembolism against hemorrhagic expansion. Prior studies have addressed this issue, but most were limited by small sample sizes. This systematic review and meta‐analysis aimed to determine the optimal timing for anticoagulation resumption in this population. Methods We conducted a systematic review and meta‐analysis using PubMed, Embase, Web of Science, and Scopus from database inception to August 23, 2024. The target population included adults with intracranial hemorrhage who required anticoagulation for mechanical heart valves. Results Thirteen studies involving 788 patients were included: 12 retrospective and 1 prospective observational study. While off anticoagulation, 32 patients developed ischemic stroke, with a pooled event rate of 5.23% (95% CI, 3.80–7.20%) and negligible heterogeneity ( I 2 = 0%). The pooled average time to stroke was 8.08 days (95% CI, 1.99–14.18). After anticoagulation resumption, 73 patients experienced hemorrhagic recurrence, corresponding to a pooled event rate of 10.95%, with nonsignificant heterogeneity ( I 2 = 40.4%). Conclusions Withholding anticoagulation for up to 7 days after intracranial hemorrhage in patients with mechanical heart valves appears relatively safe. Hemorrhagic recurrence after resumption was more common than ischemic stroke during interruption. However, the included studies were observational and carried serious or critical risk of bias. Prospective multicenter studies, and ideally randomized trials, are needed to provide more definitive evidence.

Background An increasing number of patients with congenital heart disease (CHD) are pursuing pregnancy with the potential for cardiovascular complications. This study aimed to establish patient‐centered national research and care priorities to improve pregnancy‐related outcomes for individuals with CHD. Methods This mixed‐methods study used a modified Stakeholder Engagement in Question Development methodology to systematically identify patient‐centered priorities. Key activities included consortium engagement (phase 1), patient and provider questionnaires (phase 2), and an in‐person facilitated meeting to explore survey results and follow‐up virtual focus groups (phase 3). Reflexive thematic analysis was used to synthesize short‐ and long‐term research priorities (phase 4). Results Three overarching goals emerged: (1) improving access to specialized CHD, cardio‐obstetrics, and mental health care; (2) improving quality and consistency in clinical care; and (3) increasing patient and community engagement. These goals were then expanded into 5 central themes: (1) communication within the health care setting; (2) community engagement; (3) ancillary clinical support; (4) integration of patient‐reported outcomes; and (5) implementation, education, and knowledge mobilization. Short‐term (1–5‐year) goals included expanded telemedicine use, best practice recommendations for multidisciplinary care coordination, and targeted educational resources. Long‐term (5–10‐year) goals included expansion of adult CHD and cardio‐obstetrics programs, integration of mental health services, and advocacy to improve insurance coverage. Conclusions The consortium provided a national, community‐driven prioritization that highlights actionable pathways to improve pregnancy outcomes for people with CHD. Sustained engagement with patients and community partners is essential to achieving durable improvements across cardio‐obstetric care, education, research, and mental health.

Abstract The purpose of the current study was to identify the influence of individual characteristics on differences in body fat percentage between air displacement plethysmography and dual-energy X-ray absorptiometry (change in body fat percentage) in 360 collegiate student-athletes. Body fat percentage was obtained from air displacement plethysmography and dual-energy X-ray absorptiometry. A 2 (sex)×3 (Brozek body fat percentage, Siri body fat percentage, and dual-energy x-ray absorptiometry body fat percentage) analysis of variance was used to evaluate the difference between the body fat percentages obtained from air displacement plethysmography and dual-energy x-ray absorptiometry in men and women. The agreement between air displacement plethysmography and dual-energy X-ray absorptiometry was evaluated via Bland–Altman plot and linear regression. Multiple linear regression was used to identify the influence of sex, race, height, and body mass on the change in body fat percentages. Dual-energy X-ray absorptiometry yielded greater body fat percentages in both men (4.8±2.8; p < 0.001) and women (2.2±2.9; p < 0.001) compared to air displacement plethysmography measurements. Proportional and systematic biases were observed between air displacement plethysmography and dual-energy X-ray absorptiometry. Race, height, and mass were significant predictors of the body fat percentage difference between air displacement plethysmography and dual-energy X-ray absorptiometry (R 2=0.445, p<0.001, and standard error of the estimate=2.527). The present study suggests that air displacement plethysmography underestimates body fat percentages when compared to dual-energy X-ray absorptiometry and this underestimation may not be the same for every athlete due to their individual characteristics.

ABSTRACT Recent advances in the diagnosis and management of reflux disease were the central focus of the inaugural Gatherings in Esophagology (GiE), which convened experts across gastroenterology, surgery, otolaryngology, pulmonology, and basic research. The sessions highlighted innovations in reflux monitoring—including high‐resolution manometry, wireless pH monitoring, and novel salivary biomarkers—while critically evaluating their diagnostic accuracy and clinical utility. Presentations explored the limitations of traditional proton‐pump inhibitor therapy, the emergence of potassium‐competitive acid blockers as a new class of acid suppressants, and the evolving role of adjunctive treatments such as mucosal protectants, reflux reducers, and neuromodulators for refractory symptoms. The discourse extended to advanced interventional procedures, including transoral incisionless fundoplication, magnetic sphincter augmentation, and the RefluxStop device, with discussion of patient selection, efficacy, and complication management. Discussants emphasized the pathophysiology and management of extraesophageal manifestations of reflux, the interplay between reflux and pulmonary disease, and the diagnostic challenges in pediatric populations. The meeting also addressed the integration of behavioral therapies, the role of the microbiome, and the application of artificial intelligence in reflux diagnostics. Collectively, these insights underscore a shift toward precision medicine in reflux disease, emphasizing individualized diagnostic strategies and tailored therapeutic approaches to improve patient outcomes.

Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitor (BCL2i)–containing regimens significantly improve survival outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from randomized clinical trials have demonstrated that time-limited treatment with BCL2i-containing regimens resulted in higher rates of undetectable measurable residual disease (uMRD) than BTKi monotherapy or chemoimmunotherapy (CIT). Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) are newer options for relapsed or refractory disease after prior therapy with BTKi and BCL2i-contining regimens. Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (Richter transformation) is associated with a poor prognosis. Molecular analysis to determine whether there is clonal relationship between CLL/SLL and transformed diffuse large B-cell lymphoma is useful to select an appropriate treatment option. These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL and Richter transformation.

ABSTRACT Background A randomized phase II screening trial of gemcitabine, nab‐paclitaxel, and cisplatin with a medically supervised ketogenic diet (MSKD) versus usual diet (non‐MSKD) was conducted in patients with treatment‐naive metastatic pancreatic ductal adenocarcinoma (PDAC). Methods Patients with untreated metastatic PDAC were randomized 1:1 to MSKD or non‐MSKD while receiving gemcitabine, nab‐paclitaxel, and cisplatin on days 1 and 8 of a 21‐day cycle. The MSKD was guided by a remote health care team and daily ketone (beta‐hydroxybutyrate) levels, with goal beta‐hydroxybutyrate of 0.5 to 3.0 mM. The primary endpoint was progression‐free survival (PFS) using a one‐sided alpha level of 0.20. Secondary endpoints included overall survival (OS), safety, and quality of life (QOL). Changes in microbiome were an exploratory endpoint. Findings Overall, there were 32 evaluable patients. In the MSKD arm, 15 of 16 patients achieved nutritional ketosis; the median proportion of days in ketosis was 39.4%. The median PFS was 8.5 months in MSKD patients and 6.2 months in non‐MSKD patients: hazard ratio, 0.53 (95% CI, 0.21–1.37); one‐sided p = .096. The median OS was 13.7 months with MSKD and 10.2 months in the non‐MSKD arm: hazard ratio, 0.58 (95% CI, 0.25–1.37); one‐sided p = .107). All MSKD‐related adverse events were grade 1‐2. There were no significant differences in grade ≥3 chemotherapy‐related adverse events between the arms. MSKD patients had no decline in QOL and had significant enrichment of beneficial taxa in the microbiome ( p < .05, log‐fold change ≥2). Conclusions The MSKD is feasible in patients with PDAC and, although not powered for definitive outcomes, shows trends in improved PFS and OS when combined with gemcitabine, nab‐paclitaxel, and cisplatin, without added toxicity or detriment to QOL. Larger studies are required to confirm these findings and establish the value of the MSKD in pancreatic cancer treatment.

Abstract Advances in biomarker technology, digital cognitive assessments, and amyloid‐targeting therapies have redefined the opportunities for accurate and early diagnosis and care of Alzheimer's disease (AD). These advances also create new possibilities for intervention before the onset of cognitive impairment. This paradigm shift has increased the focus on Stages 1 and 2 of AD, in which individuals are cognitively unimpaired but exhibit biological evidence of disease. While early identification of AD offers an opportunity to intervene early to delay progression and preserve quality of life, it also presents complex challenges related to communicating diagnostic results to patients and their families, contextualizing the cost effectiveness of early diagnosis and treatment, and implementation of and equitable access to treatments. Recent, successfully enrolled, preclinical AD trials highlight the complex strategies required to identify asymptomatic, biomarker‐positive individuals on a large scale, and demonstrate critical knowledge gaps in inclusion, follow‐up, and long‐term outcome measurement. The Spring 2025 Alzheimer's Association Research Roundtable (AARR) meeting brought together academics, clinicians, industry, and regulatory leaders to exchange perspectives on current challenges, key learnings, and potential strategies for identifying and treating individuals in very early stages of AD, effectively and safely. This paper presents key takeaways from the Spring 2025 AARR meeting. Highlights New criteria for Alzheimer's disease (AD) enable early identification of AD pathology. Blood tests and digital cognitive assessment tools may facilitate early and personalized care. Plasma biomarkers may be scalable in clinical settings but need confirmation or follow‐up assessments in those individuals with equivocal results. Early therapy shows best results in people with lower initial amyloid and tau burden.

Abstract Background The association of germline pathogenic and likely pathogenic variants (GPVs) in hereditary breast cancer genes with underlying tumor biology and clinical outcomes remains incompletely understood. This study characterized differences in somatic alterations and intrinsic subtypes between sporadic and hereditary breast cancers associated with GPVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2. Methods This retrospective cohort study included women with breast cancer and an ATM, BRCA1, BRCA2, CHEK2, or PALB2 GPV who had undergone tumor sequencing and whole transcriptome RNA expression analysis. Clinicopathological features, intrinsic subtypes, somatic alterations, and survival were compared by GPV status and immunohistochemistry-defined subtype and to sporadic cases. All statistical significance tests were 2-sided. Results The 4988 women with breast cancer in this study included 98 BRCA1, 126 BRCA2, 74 PALB2, 54 ATM, and 83 CHEK2 GPVs. Compared with sporadic cases, hormone receptor–positive/(ERBB2) formerly HER2–negative tumors in BRCA1 GPVs were statistically significantly enriched for basal subtype (45.5% vs 11.4%; P &lt; .001), while CHEK2 carriers had a higher prevalence of luminal A subtype (80.4% vs 60.3%; P = .006). In hormone receptor–positive/(ERBB2)-negative breast cancers, BRCA1 GPVs were enriched for TP53 alterations (84.6% vs 29.8%; q &lt; 0.001), ATM GPVs with FGFR1 alterations (35.4% vs 12.7%; q = 0.04), and BRCA2 GPVs with APC alterations (10.1% vs 1.5%; q = 0.004). Conversely, BRCA2 GPVs were inversely associated with PIK3CA alterations (13.0% vs 34.1%; q = 0.005) and CHEK2 GPVs with TP53 alterations (8.0% vs 29.8%; q = 0.02). Conclusions The GPVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2 are associated with distinct intrinsic breast cancer subtypes and somatic genomic alterations. These findings may enhance precision in risk stratification and guide personalized treatment strategies.

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.