Citations

PURPOSE Patients with breast cancer requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a noninferiority trial of hypofractionated versus conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, readmission, capsular contracture, unplanned reoperation, and reconstruction failure. METHODS Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomly assigned (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a noninferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate versus delayed and autologous versus implant-only reconstruction. RESULTS Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary end point. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, corresponding to an estimated difference of -2.1% (95% CI, -6.5 to 2.2). The complication rate was higher (regardless of arm) with implant-only versus autologous reconstruction (odds ratio = 1.65). There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI, 0.7 to 3.2) with hypofractionated and 2.2% (95% CI, 1.1 to 4.3) with conventional PMRT. Acute and late toxicity rates were not statistically different. CONCLUSION A 16-fraction course of hypofractionated PMRT is safe and noninferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.

ABSTRACT BACKGROUND War refugees are prone to psychiatric ailments due to multiple psychosocial stressors. Afghan refugees remain underrepresented in psychiatric studies. Therefore, a study exploring factors contributing to their mental health disorders is essential to guide rehabilitation efforts worldwide. METHODS This descriptive cross-sectional study evaluates the demographics, psychosocial stressors, psychiatric illnesses, and psychotropic drug use among Afghan refugees visiting the Psychiatry Outpatient Department (OPD) in Islamabad, Pakistan. Convenience sampling was employed on a sample population (n) of 75 participants. Data was collected via a structured questionnaire and analyzed using SPSS v21.0. Qualitative and quantitative variables were analyzed statistically. RESULTS Nearly 64%(n=48) of the participants were female. About 46.7%(n=35) of participants were uneducated, and 53.3%(n=40) were unemployed. 86.7%(n=65) of participants were married, while 2.7%(n=2) were divorced. 91%(n=61) of the married and divorced participants had an arranged marriage, 46.3%(n=31) had 5-8 children, and 67.2%(n=45) had experienced physical and/or emotional abuse. 74.7%(n=56) of the total participants reported a loss in the family, while 77.3%(n=58) had experienced trauma. 62.7%(n=47) had depression and associated psychotropic use, e.g., SSRIs (42.7%), TCAs (16%), and Benzodiazepines (13.3%). Alarmingly, 37.3%(n=28) reported a previous suicide attempt. CONCLUSION This study explores the psychosocial stressors faced by Afghan refugees in Pakistan, including displacement, abuse, trauma, and family/income loss. It emphasizes the importance of evidence-based psychiatric care, rehabilitative interventions, and culturally sensitive care to counter psychiatric morbidities and underscores the need for future research to improve the mental health of refugees globally.

Importance Recent case reports suggest that B antigen–containing blood products may be associated with anaphylactic transfusion reactions in recipients with preformed immunoglobulin E to galactose- α -1,3-galactose (alpha-gal). Objective To test the association of local alpha-gal syndrome (AGS) prevalence and allergic transfusion reaction (ATR) in patients with blood type O. Design, Setting, and Participants In this international, multicenter, retrospective cohort study at academic medical centers, sites were assigned to AGS high- or low-prevalence clusters based on the known geographic distribution of AGS. Data were collected on platelet or plasma transfusions and ATRs during 2020 to 2024. Consecutive patients receiving platelet or plasma transfusions were included. Exposures Patients with blood type O who received B or AB units and patients with blood type O who received O units (reference group) in AGS high- and low-prevalence clusters were compared. Main Outcomes and Measures Before data collection, the hypothesis was that if transfusion-related alpha-gal syndrome (TRAGS) is a true clinical entity, excess ATRs to group B or AB units would be detected in AGS high-prevalence regions exclusively. The main measure was the overall risk ratio (RR) for ATRs to B or AB plasma or platelets in AGS high- vs low-prevalence clusters. Results In total, 558 823 platelet and plasma transfusions at 40 sites in 5 countries were analyzed, of which ATRs occurred in 1744 transfusions (0.3%). In the US AGS high-prevalence cluster (9 sites), significantly more ATRs of any severity occurred among patients with blood type O who received B or AB units vs patients with blood type O who received O units (overall RR, 3.93; 95% CI, 2.96-5.21; P < .001). In contrast, in the primary analysis of the AGS low-prevalence cluster (15 sites), excess ATRs to B or AB units were not detected. In subgroup analyses among patients with blood type O receiving B units, the RR for moderate to severe ATRs was 9.14 (95% CI, 5.39-15.52; P < .001) in the AGS high-prevalence cluster vs 2.15 (95% CI, 1.34-3.47; P = .002) in the AGS low-prevalence cluster. Outside the US, a signal consistent with TRAGS was not detected. Conclusions and Relevance This cohort study provides provocative epidemiologic evidence that TRAGS may be a unique manifestation of AGS and a previously unrecognized risk associated with transfusion. In AGS high-prevalence regions, blood collectors and hospital transfusion services should consider approaches to preventing severe ATRs from B or AB plasma or platelet units.

Age-associated mitochondrial decline reduces NAD+ availability, impairs oxidative phosphorylation (OXPHOS), and leads to accumulation of reactive oxygen species (ROS) thereby reshaping cellular metabolism. However, the regulatory logic coupling mitochondrial aging to metabolic dysregulation resulting in tumorigenic cell-fate transitions has not been modeled systematically. In this work, we propose a Boolean biomolecular network model of mitochondrial aging and integrate it with metabolic, cell-cycle, and apoptotic biomolecular networks comprising 94 nodes and 370 edges. We then examined how NAD+ decline, hypoxia and extracellular ROS shifts the balance between OXPHOS and glycolysis. To this end, the consolidated network model underwent dynamical analysis to elucidate the system-level outcomes as well as its molecular triggers. In particular, we investigated whether the metabolic phenotypes are reversible and how cancer-driver perturbations act in the absence of extracellular pyruvate. The model recapitulates a quiescent, OXPHOS-leaning baseline and predicts that progressive NAD+ decline lowers OXPHOS propensity (0.686 to 0.186) while raising glycolysis (0.256 to 0.426). Hypoxia and extracellular ROS synergize glycolytic and hybrid oxidative–glycolytic (W/O) states. Furthermore, these two triggers, together with elevated mitogenic signaling, give rise to a hyperproliferative, glycolytic, and apoptosis-resistant cellular state. Interesting, this state is conditionally reversible wherein receptor tyrosine kinase (RTK) inhibition redirects this cell fate toward apoptosis and collapses the W/O state. Cancer-driver analysis further indicates that, without extracellular pyruvate, VHL loss and RAS, PI3K, or AKT activation preferentially stabilizes glycolytic and hybrid states. Age-resolved TCGA-BRCA analysis provided expression-level support for the predicted remodeling, with declining OXPHOS-associated expression and concurrent OXPHOS/glycolysis activity in older Basal-like tumors. Together, our results show that mitochondrial aging is a priming condition whose tumor-permissive metabolic output is gated by microenvironmental and nutrient inputs. The model provides a novel framework for evaluating age-associated metabolic reprogramming and predicting early tumorigenic cell fates.

Background Advanced chronic kidney disease (CKD) complicates anticoagulant treatment because thromboembolic and bleeding risks compete. We compared treatment outcomes for apixaban and rivaroxaban in adults with atrial fibrillation (AF) and stage 4/5 CKD. Methods Deidentified TriNetX records for patients treated with apixaban (n=49,698) and rivaroxaban (n=2660) underwent 1:1 propensity score matching (demographics, medications, procedures, laboratory values); 2533 matched pairs were identified (absolute standardized mean difference <0.10, indicating adequate balance). The smaller rivaroxaban cohort constrained matching; findings apply only to the matched population. Outcomes were assessed at 1, 3, and 5 years. Myocardial infarction (MI) findings were exploratory. P values were not adjusted for multiplicity. Results Gastrointestinal bleeding was lower for apixaban vs rivaroxaban (5-year: 9.3% vs 10.9%; relative risk [RR], 0.86; 95% CI, 0.71-1.02; P=.09). Cerebrovascular events were significantly higher for apixaban vs rivaroxaban at 3 years only (9.8% vs 7.9%; RR, 1.24; 95% CI, 1.01-1.53; P=.04); this association may reflect chance. Cerebral infarction was significantly higher for apixaban vs rivaroxaban at 1 year (3.0% vs 1.8%; RR, 1.61; 95% CI, 1.09-2.37; P=.02) and attenuated at 3 and 5 years. Rates of MI were nominally higher in the apixaban group. Five-year mortality risk was significantly lower for apixaban vs rivaroxaban (33.3% vs 36.1%; RR, 0.92; 95% CI, 0.86-0.10; P=.04) but differences in time-to-event survival were not significant. Conclusion Apixaban did not have greater bleeding risk than rivaroxaban and may be associated with lower gastrointestinal bleeding, a finding that requires further study. Isolated cerebrovascular, MI, and mortality findings require cautious interpretation. A mortality advantage for either drug was not established.

Background We examined the relationship between infection‐related hospitalization (IRH) and heart failure (HF) in a large clinical health system and assessed whether IRH improved prediction beyond HF risk equations. Methods We studied 80 880 adults (14 150 with IRH and 66 730 age‐ and sex‐matched comparators) aged ≥18 years without HF in the Rochester Epidemiology Project from 1/1/2005–12/31/2019. IRH was identified using International Classification of Diseases ( ICD ) codes. HF incidence was defined as ≥1 HF‐related ICD code. Multivariable Cox models assessed the association between IRH and incident HF. Among 29 219 adults aged 30 to 79 years without baseline cardiovascular disease in the Rochester Epidemiology Project, Harrell's concordance statistic assessed whether IRH improved discrimination of the Predicting Risk of Cardiovascular Disease EVENTs–Heart Failure (PREVENT‐HF) equations. Results Participants were 53.3% women, 85.6% White individuals, and 95.1% non‐Hispanic individuals, with a mean age of 56.0±20.0 years. Median follow‐up time was 6.2 years. Among the IRH group, 2729 developed incident HF (2.75/100 person‐years) versus 4854 (1.00/100 person‐years) in the comparator. The multivariable adjusted hazard ratio for incident HF among participants with versus without an IRH was 1.85 (95% CI, 1.76, 1.94). In a separate cohort, incorporating IRH into PREVENT‐HF increased the concordance statistic from 0.776 to 0.779 (change, 0.003 [95% CI, 0.001–0.004]). The PREVENT‐HF risk score underestimated the 10‐year risk of HF by up to 9% among participants with an IRH. Conclusions IRH was associated with incident HF but provided negligible change to 10‐year HF risk discrimination. However, among individuals with an IRH, incorporating this information meaningfully improved 10‐year HF risk prediction. Severe infections may serve as a risk‐enhancing factor warranting enhanced preventive measures, particularly in populations where IRH is more common.

Atezolizumab-bevacizumab and durvalumab-tremelimumab have established immunotherapy as a first-line standard of care in advanced hepatocellular carcinoma (HCC). Yet, objective response rates (ORRs) remain confined to approximately 15-20%, and no validated predictive biomarker exists for patient selection. Unlike melanoma and lung cancer, conventional markers, including programmed death-ligand 1, microsatellite instability-high status, and tumor mutational burden, have not demonstrated reliable predictive value in HCC. Prior narrative reviews comprehensively catalogued the biomarker landscape through 2022 but predate a wave of clinically significant publications. This narrative review synthesizes evidence published between 2020 and 2026, with particular emphasis on 2023–2026 data, within a unified clinical framework not provided by prior reviews. We critically evaluate tissue-based biomarkers, including the AI-derived Atezolizumab-Bevacizumab Response Signature-Pathology model, spatial multiplex immunohistochemistry, and β-catenin mutational profiling; blood-based biomarkers encompassing circulating tumor DNA for minimal residual disease detection and peripheral immune phenotyping; and serum indices including the CRAFITY score and neutrophil-to-lymphocyte ratio. Hepatitis B virus etiology and non-alcoholic steatohepatitis are discussed as biological modifiers of biomarker performance. We propose an original biomarker-guided clinical algorithm, a comparative clinical readiness table, and a disease-continuum biomarker timeline as practical tools for clinicians and trialists. Prospective biomarker-enrichment trials represent the most critical next step toward clinical translation.

Abstract Background and Objective Management of von Hippel–Lindau (VHL) disease is challenging due to multisystem involvement and limited systemic treatment options. Belzutifan has shown promising efficacy in clinical trials; however, real-world data remain limited. We aimed to evaluate its effectiveness and safety in a real-world cohort. Methods We conducted a retrospective study of 59 patients with VHL disease treated with belzutifan between August 2021 and January 2026. Objective response rates (ORR) for renal cell carcinoma (RCC), central nervous system hemangioblastomas (CNS HB), and pancreatic neuroendocrine tumors (pNET) were assessed by an independent radiologist. Retinal hemangioblastoma outcomes were evaluated through ophthalmology records by chart review. Results Median follow-up was 29 months. ORR was 27.6%, 39.6%, and 85.7% for RCC, CNS HB, and pNET, respectively. Among 13 patients with retinal hemangioblastomas (20 eyes), 17 eyes (85%) showed improvement. At data cutoff, 47 patients (79.6%) remained on treatment, while 12 (20.3%) discontinued (7 due to adverse events, 3 to disease progression, and 2 to other reasons). The most common adverse event was anemia (86.4%). Grade ≥3 events occurred in 10 patients (16.9%). The procedure rate per patient-year decreased from 0.35 in the 3 years prior to treatment to 0.08 during follow-up (Incidence Rate Ratio, 0.23; 95% CI, 0.12–0.47; P &lt; 0.001) Conclusions Belzutifan demonstrated efficacy across VHL-associated lesions, with favorable safety profile. Most adverse events were grade 1–2. A reduction in procedure rate was observed after treatment initiation.