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Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

ABSTRACT Studies in humans and murine models have pointed towards a possible link between metabolic syndrome, which shows insulin resistance and metabolic dysregulation, and Alzheimer’s disease (AD) pathology marked by amyloid-beta (Aβ) accumulation at the BBB and hypometabolism in the brain. Yet, the underlying biological mechanisms by which metabolic syndrome affects these pathological changes in AD brain remain unknown. We hypothesized that insulin resistance is responsible for alterations in blood-brain barrier (BBB) transport of Aβ peptides and glucose. This hypothesis was tested by employing radiolabeled tracers ( 125 I-Aβ40, 125 I-Aβ42, and 18 F-FDG) in high-fat diet (HFD)-fed mouse models that manifest metabolic syndrome. Further, we assessed alterations in the expression of various molecular mediators within the brain microcapillaries harvested from both low-fat diet (LFD)-fed and HFD-fed mice. As expected, our studies show that HFD- fed mice developed peripheral insulin resistance and obesity. In addition, HFD-fed mice demonstrated an increase in the influx rate of Aβ peptides and a reduction in 18 F-FDG (a glucose surrogate) influx rate at the BBB compared to LFD-fed mice. These transport changes are associated with increase in the BBB endothelial expression of RAGE (receptor to traffic Aβ from plasma-to-brain) and a reduction of GLUT1 (glucose transporter) expression in HFD-fed mice compared to LFD-fed mice. Moreover, disruption in insulin signaling, as indicated by reduced pAKT and pERK expression, was observed in HFD-fed mice. Inhibiting AKT or ERK phosphorylation with specific inhibitors resulted in similar changes in Aβ and glucose uptake in polarized BBB endothelial cell monolayers in vitro. These results indicate that HFD induced metabolic syndrome may lead to BBB dysfunction, characterized by increased plasma-to-brain Aβ trafficking and diminished glucose transport at the BBB, thereby aggravating the expression of AD pathological hallmarks.

Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

Background: Staphylococcus aureus causes bloodstream and skin infections in humans. The prevalence of multidrug-resistant S. aureus strains means new antibiotics are needed. A novel antimicrobial drug named SK-03-92, a synthetic aromatic organic stilbenoid compound, kills S. aureus cells within 30 min, but an increase in both biofilm formation and persister cells occurs. SK-03-92 treatment downregulates transcription of the biofilm regulating protein regulator (brpR) gene and biofilm regulating protein sensor (brpS) gene in S. aureus. BrpR/BrpS system may be a LytTR regulatory system tied to biofilm formation, creation of persister cells, and late-stage competence in S. aureus. The aim of this study was to determine what biofilm, late-stage competence, and persister-associated genes were regulated in a brpR mutant compared to wild-type strains. Methods: In this study, involvement of BrpR in regulating other genes was assessed by comparing transcriptional changes in a brpR mutant strain to the S. aureus parent strain via RNA sequencing (RNA-Seq). Bioinformatic analysis was then performed on the RNA-Seq data to assess what biochemical pathways might be involved. Results: From these analyses, 440 genes were identified that had significant differences in transcript abundance when comparing the brpR mutant to wild-type strains. Quantitative reverse transcription polymerase chain reaction analysis confirmed bacA, icd, metE, and pdhA transcript levels were lower, whereas alr and mraY were higher in the brpR mutant versus wild-type strain. Furthermore, an enzymatic assay targeting NADH production from the pyruvate dehydrogenase complex showed lower levels in the mutant compared to wild-type strain. Conclusions: Overall, the study demonstrated several biosynthetic pathways tied to biofilm formation and late-stage competency may be regulated by BrpR and some potential leads for the mechanism of action of the SK-03-92 drug were uncovered.

ABSTRACT Bardet‐Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

Abstract Background Meningiomas lack effective therapies for recurrent or aggressive disease. NF2 inactivation, commonly in meningioma, may sensitize tumors to FAK inhibition and interact with MAPK signaling. This study investigated the therapeutic activity of defactinib (FAK inhibitor) and avutometinib (RAF/MEK inhibitor) alone and in combination in preclinical meningioma models. Methods MAPK-altered meningioma cell lines, IOMM-Lee (NF2 wild-type, BRAF p.V600E) and CH157-MN (NF2 mutant, NRAS p.Q61K), BenMen-1 (NF2 mutant, MAPK wild-type), and three patient-derived NF2 mutant cell lines were cultured in matrigel and treated with defactinib and avutometinib in 3D cell viability assays. In vivo, flank and intracranial xenograft models of IOMM-Lee and CH157-MN were treated with VS-4718 (FAK inhibitor, superior pharmokinetics in mice), avutometinib, or combination. Tumor growth, survival, and pharmacokinetic/pharmacodynamic properties were assessed. Results In vitro, combination therapy showed synergistic or additive effects in CH157-MN and IOMM-Lee cells, respectively. Defactinib alone demonstrated activity in NF2-mutant patient-derived and BenMen-1 cells, while avutometinib did not. In vivo, avutometinib monotherapy suppressed tumor growth and extended survival in both flank and intracranial xenograft models, with evidence of favorable pharmacokinetic properties and target pathway inhibition in intracranial tumors. Combination therapy provided enhanced and sustained control of flank CH157-MN meningioma compared to avutometinib alone but did not significantly improve survival over avutometinib alone in intracranial models. Conclusions Avutometinib demonstrated robust anti-tumor effects in flank and intracranial models of MAPK-altered meningioma. Combination benefits were context dependent. Defactinib activity in NF2-mutant patient-derived cells without targetable MAPK-kinase alterations highlights the importance of genomic biomarkers to guide personalized strategies.

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Abstract Cerebrospinal fluid (CSF) is the biofluid most proximal to the central nervous system (CNS), yet its proteomic organization across neurological disease remains unresolved. We assembled a meta-atlas of 35 CSF proteomic datasets (2016–2026) comprising 10,560 quality-controlled samples spanning neurodegenerative, neuroinflammatory, neuro-oncological, infectious and structural-injury contexts. Meta-analysis of cross-cohort detection defined a 747-protein core mass-spectrometry-accessible CSF proteome that generalizes to held-out cohorts. We derived thirteen consensus meta-programs that transfer across independent cohorts and span the major neural, barrier, immune and plasma compartments. Unexpectedly, these programs are dominated by a single axis of variation opposing complement- and plasma-associated inflammation against neuronal-synaptic homeostasis. This injury–homeostasis axis is diagnosis-spanning and tracks clinical severity and disease activity across diverse neurological conditions. We show that a two-protein C5–NRCAM model can approximate the injury–homeostasis axis, bridging deep proteomic profiling toward bedside assessment.