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Introduction Burnout among healthcare professionals remains a critical public health issue linked to impaired cognition, emotional exhaustion and diminished clinical performance. Structured breathing practices have demonstrated promise in improving autonomic regulation and cerebral oxygenation, yet their feasibility, acceptability and implementation in real-world healthcare settings remain underexplored. Objectives This single-arm pilot feasibility trial aims to evaluate the feasibility, acceptability and implementation appropriateness of a structured breathing-based intervention for healthcare professionals across community-based Mayo Clinic Health System (MCHS) sites. Secondary objectives include assessing usability and engagement with the mobile breathing platform, while exploratory analyses will describe magnitude of variability and feasibility of collecting psychological and cerebral haemodynamic measures. This study will commence in November 2025 and is expected to be completed by June 2026. Methods and analysis A total of 40 clinicians (MD/DO/MBBS/PA) and nurses reporting moderate or greater burnout will be enrolled across four MCHS sites. Participants will complete a 4-month structured breathing programme delivered primarily online, supported by a mobile application for practice tracking. Assessments will occur at baseline, 2 months and 4 months, with functional near-infrared spectroscopy (fNIRS) measures of cerebral oxygenation collected at baseline and 4 months in a population subset. Primary outcomes include (1) recruitment yield, retention and adherence rates; (2) acceptability and participant satisfaction (survey and qualitative feedback); and (3) implementation appropriateness measured by the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). Secondary outcomes include digital engagement and usability through mobile analytics and the System Usability Scale. Exploratory outcomes are psychological indicators (burnout, depression, anxiety, perceived stress, sleep, fatigue, professional fulfilment and resilience) and physiological endpoints (fNIRS). Analyses will be descriptive, summarising feasibility metrics with 95% CIs. Progression criteria (recruitment≥75%, retention≥80%, adherence≥70%, AIM/IAM/FIM≥4.0) will determine readiness for a definitive hybrid effectiveness–implementation trial. Ethics and dissemination The study is approved by the Mayo Clinic Institutional Review Board (IRB # 25-009320). All participants will provide informed consent. Study procedures ensure confidentiality, cultural sensitivity and participant safety. Data will be securely stored in REDCap and disseminated through peer-reviewed publications and scientific conference Trial registration number NCT07218458 .

BACKGROUND: Cerebral microbleeds (CMBs) are associated with dementia, but the impact of specific microbleed patterns (with distinct pathophysiologies) is unclear. Lobar CMBs commonly result from cerebral amyloid angiopathy (sometimes with cortical superficial siderosis [cSS]), while subcortical microbleeds indicate a hypertensive cause. This study investigates the association of CMB presence, patterns, and frequency with dementia risk. METHODS: Participants from the ARIC-NCS (Atherosclerosis Risk in Communities-Neurocognitive Study), a community-based longitudinal cohort, with a 3T research magnetic resonance imaging scan at visit 5 (2011–2013) and without prior intracerebral hemorrhage or dementia were included. CMB and cSS presence and location were evaluated using a T2* gradient-recalled echo sequence. Each individual’s pattern of CMBs was classified as no CMBs, subcortical only, mixed (subcortical and lobar±cSS), lobar±cSS only, or cSS. Dementia adjudication was determined by blinded review of cognitive testing, informant interviews, and hospital discharge codes or death certificates (from follow-up visits and ongoing surveillance). Cox proportional hazards models assessed associations between CMBs and incident dementia through 2020, adjusted for demographics, vascular risk factors, and white matter hyperintensities. RESULTS: Among 1583 participants (mean age, 76 years; 24.7% cumulative dementia incidence over a median of 23.6 follow-up years), 361 had CMBs. Compared with individuals without CMBs, those with mixed (hazard ratio, 1.99 [95% CI, 1.40–2.83]) or lobar±cSS (hazard ratio, 1.96 [95% CI, 1.30–2.97]) CMB patterns had increased dementia risk, whereas individuals with a subcortical-only pattern did not (hazard ratio, 1.04 [95% CI, 0.78–1.39]). cSS presence (n=21; versus absence) showed an increased risk of dementia (hazard ratio, 2.57 [95% CI, 1.36–4.89]). Greater numbers of microbleeds across all CMB subtypes exhibited an increased risk of dementia. CONCLUSIONS: Lobar and mixed CMB patterns and increasing numbers of CMBs are associated with incident dementia. Certain CMB patterns have differential associations with dementia, but severe enough disease burden, regardless of CMB distribution, is associated with increased dementia risk.

Dominant-inactivating mutations in the colony stimulating factor-1 receptor ( CSF1R ) cause CSF-1R–related leukoencephalopathy (CRL), an adult-onset neurodegenerative disease that is modeled in the Csf1r +/– mouse. CRL is caused by microglial dysfunction. However, the primary microglial deficit is unknown. To address this question, we employed single-nucleus RNA sequencing of brains from young Csf1r +/– mice without pathological or behavioral alterations. Reduction of CSF-1R signaling caused metal ion accumulation in brain macrophages, with concomitant activation of cell death and stress response pathways in oligodendrocytes and neuronal subpopulations. Reduction of metallothionein 1 ( Mt1 ) and 3 ( Mt3 ) gene expression was a common feature in glial and neuronal cells of Csf1r +/– mice. Overexpression of Mt1 restored metal ion homeostasis, normalized ROS production in microglia, and prevented the development of behavioral deficits, while Mt3 deletion had disease-enhancing effects. These findings demonstrate CSF-1R regulation of metal ion homeostasis via metallothioneins in the brain.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Purpose: Subcortical functional brain mapping is a valuable technique, especially involving lesions within or near white matter tracts. Motor and language deficits caused by intraoperative damage to these subcortical fibers are associated with worse outcomes. However, there are variable approaches to performing subcortical functional brain mapping. This systematic review was performed to better understand indications and optimal stimulation parameters. Methods: A systematic review was performed by PRISMA guidelines, using PubMed, Scopus, and Medline databases. Search dates ranged from inception to November 30th, 2024. Studies included adults who underwent subcortical electrical stimulation for functional brain mapping. Results: A total of 55 articles (249 patients, mean age 44.8 years, 114 female) were included. The most common pathology was brain tumor (96.3%), primarily gliomas and metastases, and 24.4% of all cases had a history of epilepsy. The most frequently mapped white matter tracts were the arcuate fasciculus, corticospinal/pyramidal tract, and inferior fronto-occipital fasciculus, involving motor, language, and cognitive functions. Bipolar stimulation (50–60 Hz, 0.5–1 millisecond, 1–10 mA) was preferred over monopolar stimulation. Among 147 patients with outcome data, 89.1% did not suffer permanent adverse outcomes including neurologic deficits, although long-term outcomes were inconsistently reported. Conclusions: The methodologic variability of subcortical functional brain mapping and lack of long-term follow-up reported limits determination of optimal parameter selection for electrical stimulation although common trends are reported. Functional brain mapping approaches may be guided by the tract and network involved. Further studies are needed to develop a standardized approach and more definitive guideline to its performance.

Abstract Objective: Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. Method: Former American football players ( n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ 1-42 , p-tau 181 , t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. Results: Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. Conclusions: SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

INTRODUCTION: The adjunctive use of p53 immunohistochemistry has been proposed as a potential tool to improve risk stratification in Barrett's esophagus (BE) with conflicting results. We performed a systematic review and meta-analysis to evaluate the performance of p53 in predicting progression to advanced neoplasia (high-grade dysplasia [HGD] and esophageal adenocarcinoma [EAC]) among patients with BE. METHODS: We searched multiple databases for studies that evaluated the use of aberrant p53 in esophageal biopsies among patients with BE and reported progression rates to HGD/EAC. The outcomes were p53 test characteristics and incidence and risk ratio (RR) for progression to HGD/EAC in patients with and without aberrant p53 using random effects models. RESULTS: Among the 27 included studies, the proportion of patients with aberrant p53 expression at baseline was 20% (95% CI: 14%, 27%). The rate of progression with and without aberrant p53 was 8 per 100 person-years (95% CI: 6, 11) and 0.3 per 100 person-years (95% CI: 0.1, 0.6), respectively. Compared with patients without aberrant p53 expression, those with aberrant p53 had a higher risk for progression to HGD/EAC in cohort studies (RR = 10.2 [95% CI: 6.9, 15.0]) and case control studies (RR = 3.3 [95% CI: 2.5, 4.4]). The sensitivity for progression for non-dysplastic Barrett's esophagus and low-grade dysplasia/indefinite for dysplasia was 42% and 77% and specificity was 96% and 76%, respectively. DISCUSSION: While aberrant p53 expression has been associated with an increased risk of progression to advanced neoplasia in patients with BE undergoing surveillance, the diagnostic characteristics are suboptimal precluding uniform clinical adoption. Prospective studies with standardized grading protocols are needed to determine whether p53-guided surveillance strategies can meaningfully improve patient outcomes.

Abstract Metabolic reprogramming is a fundamental determinant of immune cell fate and effector function during inflammation, yet how distinct metabolic pathways regulate pathogenic lung macrophage activity and contribute to fibrotic remodeling remains incompletely understood. Here, we integrated single-cell RNA sequencing, lineage-specific genetic mouse models, and fate-mapping approaches to define the metabolic pathways that regulate the pro-fibrotic activity of lung macrophages. We found that such cells undergo pronounced aerobic glycolysis in the bleomycin-induced mouse model of pulmonary fibrosis. Myeloid cell-specific depletion of lactate dehydrogenase A (Ldha), but not of mitochondrial pyruvate carrier (Mpc), markedly attenuated lung fibrosis and improved survival. Mechanistically, enhanced glycolytic flux increased lactate production, which promoted histone lysine lactylation and facilitated Arginase 1 (Arg1) expression in lung macrophages, thereby driving fibrotic progression. Using monocyte fate-mapping, we further demonstrated that Arg1 expression is largely restricted to recruited monocyte-derived macrophages rather than lung-resident macrophages. Notably, selective deletion of Ldha in granulocyte-monocyte progenitors and their progeny was sufficient to suppress Arg1 expression and reduce fibrosis severity. In human lung samples, we observed significantly elevated expression of ARG1 and key glycolytic enzymes in patients with idiopathic pulmonary fibrosis, despite species-specific differences in the immune cell types expressing ARG1. Together, these findings identify an aerobic glycolysis–lactate–histone lactylation axis that regulates pro-fibrotic myeloid cell function and represents a potential therapeutic target in pulmonary fibrosis.

ABSTRACT Meningiomas are the most common primary brain tumors and, despite their benign reputation, often behave aggressively. Meningiomas are morphologically heterogeneous, yet the full significance of their histologic diversity is unclear. This is in large part because many features are not readily quantifiable by traditional observer-based light microscopy. Molecular testing improves prognostic stratification, but is not universally accessible. We therefore sought to determine whether an artificial intelligence (AI)-trained program could predict specific genomic and epigenomic patterns in meningiomas, and whether it could extract more prognostic information out of standard hematoxylin and eosin (H&E) histopathology than the current WHO classification. To do this, we developed Morphologic Set Enrichment (MSE), an interpretable computational pathology framework that quantifies statistical enrichment of morphologic patterns, cells, and tissue architecture from H&E whole-slide images. The MSE meningioma histology program was able to accurately predict DNA methylation subtypes and concurrent chromosome 1p/22q losses, in the process identifying specific morphologic patterns associated with key genomic and epigenomic alterations. It also added prognostic value independent of standard clinical and pathological variables. These results demonstrate that AI-based quantitative morphologic profiling can capture clinically and biologically relevant information that redefines risk stratification for meningiomas, incorporating histological information not included in existing grading schemes.