Citations

Introduction Increasing publication of fraudulent clinical trials poses a serious threat to evidence-based medicine. In the VITALITY Study I, we demonstrated that contamination by retracted trials significantly distorts evidence synthesis. The upcoming VITALITY Study II will take a step further and investigate how such problematic evidence undermines the credibility of guideline recommendations. Methods and analyses The VITALITY Study II will adopt a retrospective cohort design and will be structured as three work packages (WPs). To start with, a cohort of clinical practice guidelines (CPGs) that were contaminated by retracted trials and/or meta-analyses that included retracted trials will be established based on forward citation searching (WP1). Then, recommendations from these CPGs that used evidence from retracted trials and/or meta-analyses that synthesised these retracted trials will be re-evaluated after removing such problematic evidence, in terms of both the direction and strength of effect sizes (WP2). Finally, the subsequent impact on patient outcomes attributable to distorted recommendations will be estimated on a hypothetical population, measured by the number of expected benefit loss and the number of expected harm increment per 100 000 patients (WP3). Ethics and dissemination Formal ethical approval is not necessary for this study as it does not involve human or animal participants, nor does it involve the collection of primary data. We will disseminate the findings through publication in peer-reviewed journals and, whenever possible, presentations at academic conferences.

ABSTRACT The normal adult male breast has not been characterized at single-cell resolution, leaving the cellular basis of male breast cancer (MBC) biology undefined. Here we present an integrated single-cell RNA sequencing atlas of the adult human breast comprising 174,471 cells from 17 donors (3 male, 14 female), including 18,117 male-derived cells. This revealed that the male breast retains all three epithelial populations, basal (BC), luminal progenitor (LP), and luminal committed cells (LC), but with an increase in LC at the expense of BC and LP across all three male donors. Male LC were distinguished from female by elevated ESR1 and PGR mRNA, enrichment of RNA processing and ribosome biogenesis programs, reduced inflammatory cytokine and growth factor signaling, elevated estradiol gene set enrichment scores, and higher inferred activity of developmental patterning transcription factors. This pattern was observed across differential expression, gene ontology, ligand profiling, and regulon-based analyses, and was not restricted to sex chromosome-linked gene expression. This is consistent with the near-universal estrogen receptor (ER) positivity that characterizes MBC clinically. This atlas provides the first cellular and transcriptional reference for the normal male breast and a resource for investigating sex differences in mammary biology, germline susceptibility variant interpretation, and modeling breast malignancies.

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

Background: Patients with primary sclerosing cholangitis (PSC) are at risk for developing gallbladder neoplasia (GBN) and biliary neoplasia, including cholangiocarcinoma (CCA), because of chronic inflammation and an underlying field effect. However, the risk of CCA after GBN detection in those with PSC remains poorly understood. We aimed to determine if the incidence of CCA is higher in those with GBN. Methods: We conducted a retrospective review of adult patients with large-duct PSC seen at Mayo Clinic between January 1, 1995, and December 31, 2019. Incidence rates for CCA development were calculated. Cox regression analyses were performed to determine features associated with CCA development beginning at the time of PSC diagnosis. Results: Our study included 1,829 patients with PSC. CCA and GBN developed in 334 (18.26%) and 71 individuals (3.88%), respectively. Among those with GBN, 14 (19.72%) developed CCA. The annual incidence of CCA was nearly twofold higher in patients with GBN (4.34% versus 2.21%). GBN was associated with CCA in an unadjusted analysis (hazard ratio 2.14 [95% CI 1.16–3.94]). When adjusting for other predictors of CCA, an association between GBN and CCA may remain. Conclusions: While few patients with PSC develop GBN, this subgroup is more likely to develop CCA. Consequently, once GBN is detected, clinicians should consider more intensive screening for CCA.

Background: There are limited oral treatment options available for resistant Gram-negative bacterial (GNB) infections. Minocycline, a second-generation tetracycline antibiotic, offers good bioavailability and broad-spectrum coverage that may be an option for GNB infections. Methods: We conducted a retrospective review of minocycline susceptibility testing performed on GNB isolates at the Mayo Clinic reference lab between 2013 and 2022. Minocycline susceptibility was evaluated with a focus on difficult-to-treat organisms and relevant anatomic source. Organisms included resistant isolates of Escherichia coli and Klebsiella pneumoniae ; high-risk ampC-derepressors, including Citrobacter freundii, Enterobacter cloacae, and K. aerogenes; and clinically challenging non-Enterobacterales, Acinetobacter species, Achromobacter species, and Stenotrophomonas maltophilia . Results: Of 217,206 GNB isolates, 18,148 Enterobacterales (EB) and 8,190 non- Enterobacter isolates were tested for minocycline susceptibility. Of these, 80% of all EB and 92% of non-EB isolates were susceptible. Among E. coli isolates with ceftriaxone, ciprofloxacin, meropenem, or multidrug resistance, minocycline susceptibility was 78%, 76%, 70%, and 70.9%, respectively. Among the K. pneumoniae isolates with ceftriaxone, ciprofloxacin, meropenem, or multidrug resistance, minocycline susceptibility was 46%, 38%, 37%, and 39.3%, respectively. 85% of C. freundii , 81% of E. cloacae, and 85% of K. aerogenes isolates were susceptible to Minocycline. 83.5% of Achromobacter species isolates, 66% of Acinetobacter species isolates, and 99.1% of S. maltophilia isolates were susceptible. Conclusions: Our study reports the largest collection of minocycline susceptibility findings in GNB. Minocycline showed in vitro activity against many difficult-to-treat GNB isolates, including ceftriaxone- and multidrug-resistant E. coli and some K. pneumoniae isolates, common Amp-C-producing species, and non-fermenting GNB, including Stenotrophomonas , Acinetobacter , and Achromobacter .

Human diseases are complex and arise from the coordinated action of multiple genes and their protein products. Genes’ behaviors extend beyond genetic variants, mutations, and differential expressions. Their coordinated activity across biological scales (molecules, cells, tissues, organs) produces emergent behaviors that shape health and disease. These emergent behaviors span time and space and are often hard to measure directly from observation when using standard experimental measurements. Yet these “hidden” or latent gene characteristics can be powerful drivers of disease. We propose a Mini-Galaxy Model (MGM), a systems-level AI-driven network framework that models cells as “mini-galaxies” composed of multilayered biological information, with each layer encoding a different dimension of genes’ behavior. Here, we delineate a strategy on how to construct and compare MGMs across health and disease and map their etiological relatedness. We also operationalize the MGM as a discovery platform for translational medicine, offering modules to allow target prioritization and editing. By reframing human diseases as the result of emergent behavior of multilayered multimode biological networks and their perturbations, the MGM yields actionable rules to streamline biomarker discovery, guide target selection and enable rational design of combinatorial interventions, and accelerate drug repurposing.

Background Oral anti-cancer treatment is commonly used, and non-adherence can negatively affect outcomes. The Oral Oncolytic Non-Adherence Estimator (ORACLE) was designed to prospectively categorize patients into risk levels by considering constructs such as self-efficacy, health literacy, perception of treatment, quality of life, social support, and regimen complexity. Validating this estimator is essential. Methods A content validation survey evaluated representativeness, clarity, and factor structure of each construct in ORACLE. A multidisciplinary panel of 8 content experts and 4 lay experts completed the survey. Results were analyzed to evaluate inter-rater agreement, content validity index (CVI), and factorial validity index (FVI). Post-survey workgroup discussions reviewed results and considered tool adjustments. Results All 12 invited experts completed the survey. The average CVI for content experts was 0.88 for representativeness and 0.98 for clarity. The average CVI for lay experts was 0.95 for clarity. The average FVI was 0.88, with self-efficacy and negative perception constructs yielding the lowest scores (0.63 and 0.75, respectively). ORACLE revisions addressed survey results and expert feedback on health literacy, social support, and regimen complexity. Conclusions Strong CVI for content and lay experts (94% and 95%) and strong FVI for content experts (98%) verify that the tool is understandable and addresses non-adherence issues, establishing validity of construct clarity and representativeness. Content validity of the first pre-treatment oral oncolytic non-adherence risk estimator was established, providing a reliable tool to identify patients at higher risk of non-adherence.

Opioids are often the first-line approach to treat moderate to severe cancer-related pain. However, opioids can cause conflict and distress to cancer survivors when prescribed for pain. The objective of this multi-methods study was to explore the psychosocial factors that affect the use or refusal of opioids among breast cancer survivors. We recruited 20 breast cancer survivors treated with opioids to participate in a free-listing exercise and semi-structured interview. Results revealed that survivors felt unprepared for the intensity of pain following cancer treatments, which contributed to the use of opioids. The adverse side effects often influenced their decision to discontinue them from their pain management strategy. Finally, the addictive properties of the medication affected survivors’ use of the medication. Findings identify and recognize clinicians and researchers can promote safer, more personalized approaches to pain management to inform interventions that integrate behavioral health support and improve patient-provider communication.