Citations

ABSTRACT Genomic instability is a defining hallmark of breast cancer, yet the mechanisms by which tumors tolerate persistent DNA damage remain poorly understood. We performed a comprehensive, multi-cohort analysis of breast cancer datasets to define how DNA damage response (DDR) and replication stress tolerance (RST) networks are rewired in genomically unstable tumors. Using fraction of genome altered (FGA) as a chromosomal instability metric, we show that BRCA-mutant tumors exhibit elevated genomic instability coupled with increased expression of homologous recombination, Fanconi anemia, mismatch repair, base excision repair, and alternative end-joining pathways. Strikingly, heightened pathway activity correlates with increased genome alteration, supporting a model of damage tolerance rather than repair restoration. RST programs, including fork remodeling, protection, and single strand DNA gap suppression, further contribute to tumor fitness under replication stress. These adaptive states are enriched in aggressive subtypes, intensified with progression, and associate with pathway-specific mutational burden. Co-occurrence and mutual exclusivity mapping uncovered non-random subtype-relevant genetic interactions states among major drivers and DDR genes, nominating context-specific synthetic lethal opportunities. Our findings identify compensatory genome-maintenance programs as central drivers of tumor resilience and highlight pathway-specific vulnerabilities for targeted therapeutic intervention.

Introduction The WHO/UNICEF Nurturing Care Framework (NCF) features five domains necessary for child development—physical/mental health, responsive caregiving, adequate nutrition, security and safety and opportunities for early learning. We explored caregiver perspectives on the NCF in two African settings. Methods Between November 2023 and July 2024, 14 focus group discussions (FGDs) were conducted with caregivers living with and without HIV; eight with mothers in Gaborone, Botswana, and six with mothers and fathers in Nairobi, Kenya. FGDs were stratified by country, sex, HIV status and partnership status. Semi-structured interviews with interactive activities elicited caregiver perspectives on the NCF to identify the most ‘important’, ‘easiest’ and ‘challenging’ domains to fulfil. Thematic analyses identified key themes and compared perspectives. Results Our qualitative study included 101 caregivers, 55 from Kenya (30 mothers, 25 fathers) and 46 mothers from Botswana. Overall, caregivers identified physical/mental health as the ‘most important’ domain to fulfil for children and caregivers, noting how closely tied they were (“ If you have pain, that pain affects your child” ). The ‘most challenging’ domain was adequate nutrition in Botswana and security and safety in Kenya. The ‘easiest’ domains were responsive caregiving in Botswana and opportunities for early learning in Kenya. Kenyan caregivers noted that spiritual nourishment was also critical for well-being but missing from the NCF. Caregivers emphasised the importance of receiving social support with childcare. Caregivers living with HIV expressed similar views compared with caregivers without HIV, but mentioned that social isolation, stigma and treatment disruption impact their ability to provide adequate nurturing care. Conclusions Caregivers face unique parenting challenges depending on cultural environment. HIV disrupts caregivers’ health, which has important implications for raising children within families affected by HIV. Interventions that support caregivers’ abilities to fulfil all NCF domains and address challenges are essential to ensure children reach their developmental potential.

Introduction The unproven stem cell intervention (SCI) industry markets stem cell products to patients navigating chronic and serious conditions who seek alternative options when conventional treatments no longer offer relief or improvement. This market is often characterized by providers using deceptive advertising to misinform potential consumers to seek stem cells that have not been shown to be safe and/or effective through clinical studies. Objective This study examines how patients describe interpersonal and institutional trust in relation to their interest in and decisions about unproven SCIs among two distinct and divergent chronic disease patient groups: patients with little or no interest in unproven SCIs (low seekers) and those with high interest or have undertaken an unproven SCI (high seekers). Methods A semi-structured interview guide was developed deductively and modified inductively based on the Unified Theory of Health Behavior. Qualitative interviews among 36 patients and carers were conduct and transcripts were analyzed using constant comparison based on the principles of grounded theory. Results Trust varies across social contexts as low seekers expressed strong reservations about the commercialization elements of the SCI industry placing greater confidence in conventional medicine. In contrast, high seekers questioned the advice of conventional providers and motives of medical regulators. Across both, personal relationships were commonly described as influential in how participants evaluated unproven SCIs. Conclusion These findings suggest that communication efforts in clinical settings should account for the relational and emotional dimensions of trust. Interventions aimed at countering misleading information and promoting informed choices should engage trusted messengers and address the broader social and psychological contexts in which patients may seek unproven SCIs.

Abstract Background and Aims Burnout affects millions of healthcare workers worldwide, from food service and nurses to physicians and leaders, impairing worklives and threatening health system stability. Methods An international collaborative, PREVAIL, was created to reduce burnout globally. Leaders from six continents shared structured insights into the local state of wellness and burnout contributors and mitigators, which were then subjected to a formal thematic (qualitative) analysis to identify common and region-specific themes. Results Across continents, findings showed the global state of well-being was in danger, though threats varied by region: long shifts in Africa, heavy workloads in Asia, austerity-prone environments in Europe and financially driven care in North America. Vulnerable worker groups included women, nurses, and primary care. Mitigators included workload and schedule adjustments (Africa), shift policies with fair pay (Asia), leader support and regular well-being assessments (Australia), improved psychosocial services (Europe), organizational wellness support and career development (North America), and trainee support (South America). Conclusions A proposed “common pathway” framework explains shared drivers of poor workforce well-being and provides actionable steps for promoting compassionate, supportive environments worldwide. Implications/Learning Points Adopting a coordinated international approach may prevent devastating workforce shortages over the comingdecades. Burnout assessment and reduction in the global workforce is a high priority.

Abstract Context The clinical relevance of etiologic concordance and temporal presentation in bilateral adrenal masses remains poorly defined, creating uncertainty in diagnostic evaluation and management. Objective To characterize the etiologic spectrum of bilateral adrenal masses, evaluate patterns by concordance and synchronicity, and identify predictors of discordance and malignant or pheochromocytoma contralateral lesions. Design Retrospective cohort study (2010-2025). Setting Tertiary referral center. Participants Adults with bilateral adrenal masses. Main Outcome Measures Etiology, concordance, synchronicity, interval to contralateral lesion, and factors associated with discordance and malignant or pheochromocytoma contralateral lesions. Results Among 1035 patients (median age 59.6 years; 51% women), 85% had concordant and 15% discordant etiologies. Concordant cases were predominantly bilateral benign cortical lesions (76%), whereas discordant cases were heterogeneous (benign 35%, malignant 31%, and indeterminate 34%). Presentation was synchronous in 84% and asynchronous in 16%, with a median interval of 45 months (interquartile range 15-87). Asynchronous disease was associated with higher discordance (23% vs 13%, P = .001) and greater prevalence of malignant lesions (bilateral malignant: 17% vs 7%; discordant malignant: 8% vs 4%; overall P < .001). Among asynchronous cases, shorter interval to contralateral lesion (<2 vs ≥5 years) was independently associated with malignant or pheochromocytoma etiology (adjusted odds ratio [OR] 2.63, 95% CI 1.01-6.85), as was larger tumor size (adjusted OR 1.06 per mm, 95% CI 1.02-1.09). Conclusion Most bilateral adrenal masses are benign and concordant; however, discordant or asynchronous disease identifies a higher-risk subgroup enriched for malignancy. Early contralateral lesion development and larger tumor size are key risk factors.

Background Female sex hormones used in feminizing hormone therapy (FHT) may influence activation and persistence of HIV pre‐exposure prophylaxis (PrEP) medications. The clinical relevance of this interaction remains unclear, particularly for transgender and cisgender women (TGW and CGW). To address this gap, we examined drug metabolites in HIV susceptible cells isolated from blood and rectal tissues of TGW and CGW. Materials and Methods We enrolled 23 TGW, 13 on FHT and 10 CGW. Participants received five directly observed daily PrEP doses: emtricitabine 200 mg with either tenofovir disoproxil fumarate 300 mg (FTC/TDF) or tenofovir alafenamide 25 mg (FTC/TAF). Blood and rectal tissue samples were obtained. Mononuclear and CD4 + cells were isolated and analysed for intracellular triphosphorylated nucleotides (TFVdp and FTCtp) and total nucleotide pools (pTFV and pFTC) using HPLC‐MS/MS. Serum hormone concentrations were quantified via enzyme immunoassay. Results and Conclusion Total nucleotide pools (pTFV and pFTC) correlated with active metabolites (TFVdp and FTCtp) in blood and rectal CD4 + cells ( r 2 > 0.75, p < .001). No significant differences in pTFV or pFTC concentrations were observed between high and low oestradiol groups in either CGW or TGW ( p > .1). No correlation was observed between serum oestradiol concentrations and nucleotide concentrations. TAF resulted in 6.8‐fold higher median pTFV concentrations in blood CD4 + cells ( p < .001) but eightfold lower median pTFV concentrations in rectal CD4 + cells compared to TDF ( p = .008). These findings suggest that neither endogenous hormonal fluctuations in CGW nor exogenous FHT in TGW adversely impact intracellular PrEP pharmacology in key HIV target cells.

Objective Positive α‐synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free‐water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA– status. Methods We studied patients with PD with baseline diffusion imaging and α‐synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T ), and clinical characteristics between SAA+ and SAA– groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. Results Among 462 participants (41 SAA– and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA– (pFDR < 0.05). No significant differences in FA T were found between groups. Interpretation Positive α‐synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295–304

Abstract Objectives Per National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML), bone marrow (BM) evaluation is recommended after starting induction chemotherapy at 14 to 21 days (mid-induction) and 30 to 35 days (postinduction). Timely assessment of residual morphologic and molecular disease is challenging at these time points, given the low cellularity, the lack of CD34 or CD117 expression by blasts in most NPM1-mutated (NPM1mut) AML, and the longer turnaround time for molecular testing. Methods NPM1 mut AML undergoing BM evaluation at mid- and postinduction with concurrent flow cytometry and NPM1 real-time polymerase chain reaction or next-generation sequencing was evaluated. Different cell types positive by NPM1 immunohistochemistry (IHC) were enumerated, and the results were compared with flow cytometry and molecular findings. Results NPM1 IHC demonstrated a sensitivity of 78% and 41% for detecting residual mutation at mid- and postinduction, respectively, with a positive predictive value ranging from 88% to 100%. Of 16 IHC-negative cases, 3 had no residual NPM1 mutation, 12 had very low-level mutation at a variant allele frequency of less than or equal to 21 transcripts, and only 1 had a high-level mutation in a markedly hypocellular BM. Of 24 IHC-positive cases, 22 had residual NPM1 mutation, and 2 showed false-positive staining in only a single cell with no residual NPM1 mutation. The level of IHC staining was mostly proportional to the level of residual mutation. Conclusions Mutation-specific NPM1 IHC is a valuable tool for a rapid assessment of residual morphologic and molecular disease in mid- and postinduction NPM1mut AML.

Abstract INTRODUCTION : Despite expanding use of plasma biomarkers for Alzheimer's disease (AD), minimal examination has been undertaken in early‐onset AD (EOAD). Prior analyses assessed criterion and convergent validity of common plasma biomarkers in a well‐characterized sample with sporadic EOAD. METHODS : Plasma amyloid beta (Aβ) 42/40, tau phosphorylated at threonine 231 (p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light change (NfL) levels were obtained for 189 EOAD, 52 early‐onset non‐AD (EOnonAD), and 83 cognitively normal (CN) participants. Diagnostic group differences, convergence with imaging biomarkers, and the capacity to predict specific cognitive domains were investigated. RESULTS : After controlling for cognitive status, EOAD participants exhibited more pathologic levels of Aβ42/40, p‐tau231, and GFAP relative to EOnonAD participants. However, NfL displayed the greatest sensitivity to non‐amnestic cognitive impairment across the sample. DISCUSSION : These results establish criterion and convergent validity of plasma biomarkers in sporadic EOAD and highlight complementary roles that AD‐specific and non‐specific plasma markers may play across the course of AD care.

Introduction Individuals with inborn errors of immunity (IEI) are increasingly reaching reproductive age, yet guidance on fertility preservation, genetic counseling, medication adjustments in pregnancy and breastfeeding, monitoring for complications, and multidisciplinary coordination is lacking. This joint effort between two committees of the Clinical Immunology Society (CIS), the Women of the Clinical Immunology Society (WCIS) and the Adult Immune Deficiency Committee (AID) survey aimed to characterize current reproductive care practices for IEI patients. Methods A survey was disseminated to 809 CIS members. The response rate was 6.43% (52 respondents). The 24-item questionnaire addressed management of pregnancy in IEI, medications adjustment, participation in hematopoietic stem cell transplant (HSCT) care and fertility preservation, and maternal/neonatal outcomes. Results Because survey items were optional, the number of respondents varies by question. Forty-two participants completed core items: 64% (27/42) allergists/immunologists, 71% (30/42) practicing at academic centers, and 48% (20/42) with &gt;50% immunology-focused practices. Most respondents (78%, 41/52) currently or previously cared for pregnant/planning IEI patients. Preconception counseling was common (90%, 37/41), yet only 2% (1/41) have access to a formal reproductive multidisciplinary team. Among clinicians involved in HSCT care, 45% (13/29) referred patients for fertility preservation. More than half, 52% (22/42), observed reduced fertility in IEI patients, and 56% (20/36) observed adverse maternal outcomes. Medication management varied: 61% (24/39) discontinued known teratogenic medications, and 64% (25/39) adjusted dosing during pregnancy. Regarding immunoglobulin replacement therapy, 79% adjusted dosing based on IgG levels and 42% increased dosing by trimester. Conclusions This CIS survey reveals practice variability and notable gaps in reproductive health support for individuals with IEIs. Due to the relatively low response rate, generalizability across providers and practice settings is challenging. However, the results of this survey suggest that although most clinicians provide preconception counseling and manage IgG and immunomodulatory therapy during pregnancy, formal multidisciplinary structures are rare. High rates of reported fertility concerns and maternal complications underscore the need for enhanced collaboration with obstetrics/gynecology and the development of structured, evidence-based, multidisciplinary guidelines for reproductive care in IEI. Tabular data are included as downloadable supplement files.