Citations

Purpose: To describe a case of locally invasive conjunctival squamous cell carcinoma (SCC) refractory to plaque radiotherapy. Case Description: A 69-year-old man presented with a recurrent conjunctival tumor after 6 previous cycles of topical 5-fluorouracil chemotherapy and excisional biopsy showing invasive SCC with positive margins. There was a mild anterior chamber reaction. By the time of repeat excisional biopsy, the conjunctiva had ulcerated with underlying scleralysis associated with histopathologic evidence of scleral involvement by SCC. After subsequent tectonic scleral patch grafting, plaque radiotherapy was applied after which the disease appeared to be controlled for 9 months. The eye then developed progressive conjunctival ulceration and scleralysis with progressive ectropion. Exenteration was performed, revealing locally invasive SCC into palpebral conjunctiva, ciliary body, and choroid. Conclusions: Conjunctival SCC can be locally invasive with destruction of the globe, despite plaque radiotherapy. Clinicians should be suspicious of invasive diseases in cases of ocular surface squamous neoplasia that are poorly responsive to topical chemotherapy. Associated anterior chamber cell and progressive scleralysis should also raise concern for invasive malignancy.

Background and Objectives: Normothermic regional perfusion (NRP) is an effective technique to improve recipient outcomes. However, no valid methods for determining liver viability exist. Identifying relevant biological markers with clinical correlation to liver viability and recipient clinical outcomes is imperative to improve decision-making. Materials and Methods: Fifty-four donors undergoing NRP and their recipients were included. FMN was measured at the start, 1 h, and end of NRP. Lactate was measured at the start, 30, 60, and 90 min of NRP. Primary outcomes were early allograft function using the early allograft dysfunction (EAD) criteria and the model for early allograft function (MEAF). Secondary outcomes included the association with donor warm ischemia time (DWIT), stratified by 30 min. Spearman’s rho assessed correlations. Results: Forty (74%) livers were transplanted, with 5 (12.5%) recipients developing EAD and the mean MEAF score was 3.13 (1.49). FMN at all time points was significantly greater in the EAD group compared to the non-EAD group and was significantly correlated with the MEAF score (Peak FMN: rho = 0.507, p = 0.001). FMN during perfusion did not differ between DWIT < and ≥30 min. Lactate levels were similar across all groups and did not discriminate for adverse allograft outcomes. However, lactate levels during perfusion were higher in the DWIT ≥ 30 min group. Conclusions: These findings suggest that during NRP, elevated FMN, but not lactate, is associated with early allograft function.

Adult optic nerve axon regeneration has traditionally been framed as a problem of limited intrinsic growth capacity in central nervous system neurons. However, growing evidence suggests that intrinsic factors alone cannot account for regenerative failure: restrictive extrinsic environmental factors largely govern optic nerve regeneration, dictating the intrinsic capacity axons can express. In this review, we frame the extrinsic optic nerve environment as a dynamic regenerative niche, in which vascular, immune, glial, matrix, and metabolic compartments are spatially co-localized and temporally coordinated rather than acting as independent barriers. These compartments follow a shared trajectory, broadly protective in the acute phase, then inhibitory once the underlying response fails to resolve, while also actively driving one another, such as reactive astrocytes promoting the matrix remodeling that subsequently restricts axon regrowth. Consequently, the niche’s overall permissiveness for regeneration reflects the aggregate and interdependent state of these compartments rather than the action of any single barrier. This review integrates current evidence on extrinsic barriers, intervention opportunities, and disease-specific variability relevant to RGC axon regeneration after injury. These interventions must incorporate the spatial, temporal, and metabolic factors that shape the goal of functional recovery and vision restoration.

Abstract High-frequency oscillations (HFOs) are clinically established biomarkers of epileptogenic tissue, yet their translation from hospital-based recording systems to implantable neural interfaces remains a major barrier to their utilization in adaptive neuromodulation in epilepsy. Here, we established a bedside translational framework using a benchtop implementation of a wireless implantable neural interface (Brain Interchange, BIC) to evaluate whether clinically meaningful HFO can be preserved under implant-grade sensing constraints. Ten patients with drug resistant epilepsy underwent simultaneous 24-hour intracranial EEG recordings using synchronized BICs and a clinical-grade amplifier. A sensitive detector identified candidate HFOs, while sparse signal processing and machine learning methods removed artifact related pseudo-HFOs. Despite its lower sampling rate, narrower analog bandwidth, and higher noise floor, the integrated sensing and computational intelligence framework preserved approximately 82% of clinical amplifier HFOs and maintained nearly identical spatial distribution of pathological activity. After pseudo-HFO elimination, BIC derived HFOs localized the seizure onset zone with 84% sensitivity and 90% specificity, comparable to the clinical amplifier despite lower fast ripple detection. These findings demonstrate that implant-grade neural sensing, when integrated with artifact resilient computational intelligence, can preserve clinically relevant HFO biomarkers and their spatial fidelity without reproducing every individual electrophysiological event. More broadly, this work establishes a translational framework for chronic tracking of evolving epileptogenic networks and future biomarker-guided adaptive neuromodulation.

Background: Several breast cancer (BC) risk prediction models have been developed to provide personal risk assessments. Though individually validated, their performance has not been systematically evaluated across a wide range of populations or ages. Methods: We harmonized individual-level baseline questionnaire data and incident BC diagnoses from 21 cohorts from North America, Europe, and Australia participating in the Breast Cancer Risk Prediction Project. Five-year absolute risk of invasive BC was estimated for five established risk prediction models using classical risk factors only. Discrimination was evaluated by area under the curve (AUC). Calibration was assessed using average and risk-decile specific expected to observed (E/O) ratios. Performance metrics were meta-analyzed across cohorts and models. Metaregression tested associations between cohort characteristics and performance metrics. Results: This analysis included 1,595,977 women aged 20-75 years, enrolled in studies between 1976-2015, with 19,062 (1.2%) invasive BC cases ascertained within 5 years from exposure assessment. Age-adjusted AUCs were similar across models and cohorts (pooled AUCs by model: 0.57-0.58), while E/O ratios varied substantially (pooled E/O ratios by model: 0.83-1.25). Overestimation was common among predicted high-risk individuals (>3%). No appreciable differences in model performance by cohort age, birth year, race, and variable missingness emerged. Calibration improved after assigning race-specific incidence rates. Conclusion: Existing BC risk prediction models provided similar risk discrimination across multiple cohorts, although there was overestimation of risk for high-risk individuals. Performance variation across cohorts was not driven by specific characteristics, which supports development of a unified risk model for diverse populations that leverages appropriate incidence rates.

ABSTRACT Objective To compare outcomes of phenobarbital‐based versus benzodiazepine‐based pathways for alcohol withdrawal syndrome (AWS) in critically ill adults and evaluate whether pathway design and timing of phenobarbital use affect treatment outcomes. Data Sources A librarian‐led search of MEDLINE, Embase, Cochrane Central, CINAHL, Web of Science, Scopus, ClinicalTrials.gov , and the World Health Organization International Clinical Trials Registry Platform was conducted through July 2024, with updates in December 2024, August 2025, and December 2025. Search concepts included phenobarbital, benzodiazepines, and alcohol withdrawal. Study Selection and Data Extraction Comparative studies of adults admitted or transferred to an intensive care unit (ICU) with AWS and treated with phenobarbital‐based versus benzodiazepine‐based pathways were included. Sixteen nonrandomized studies were included in the qualitative synthesis, and 12 treatment‐oriented studies were included in the primary meta‐analysis. Multiple reviewers independently screened studies, extracted data, and assessed risk of bias using Risk Of Bias In Non‐randomized Studies—of Interventions (ROBINS‐I). Data Synthesis Phenobarbital‐based pathways were not associated with significantly different intubation (11 studies; odds ratio (OR), 0.62; 95% confidence interval (CI), 0.20–1.87; I 2 = 73%) or hospital length of stay (five studies; mean differences [MD], −1.75 days; 95% CI, −5.07 to 1.56; I 2 = 63%) compared with benzodiazepine‐based pathways. ICU length of stay was shorter with phenobarbital‐based pathways (eight studies; MD, −0.60 days; 95% CI, −0.79 to −0.41; I 2 = 0%). In exploratory subgroup analyses, front‐loaded, protocolized phenobarbital‐first pathways were associated with lower intubation and shorter hospital length of stay, but certainty of evidence was very low. Relevance to Patient Care and Clinical Practice This review distinguishes phenobarbital‐first, protocolized ICU pathways from adjunctive or mixed phenobarbital strategies, suggesting that implementation design may influence outcomes. Conclusions Although evidence remains very low certainty, these findings suggest that phenobarbital's role in ICU AWS may be pathway dependent. Front‐loaded, protocolized phenobarbital‐first pathways may be associated with favorable outcomes in exploratory analyses, but these findings should be considered hypothesis‐generating and require confirmation in prospective randomized trials. Trial Registration: CRD42024595819

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.

The goal in selecting these recent articles was to help identify literature that may change the clinical practice of women’s health for practitioners in the primary care and general gynecology setting. Articles were identified by reviewing high-impact medical and women’s health journals, national guidelines, ACP JournalWise and NEJM Journal Watch. In this Clinical Update, we selected recent publications relevant to the sexual health of women. Specifically, we reviewed guidelines and consensus statements on hypoactive sexual desire disorder (HSDD) and genitourinary syndrome of menopause (GSM), as well as studies around the role of pelvic floor muscle training for GSM and psychological and behavioral health for sexual health in midlife women.

Low protein (LP) diets improve metabolic health in rodents and humans. In rodents, LP diets are typically implemented by replacing protein with carbohydrates like sucrose or cornstarch, keeping diets isocaloric. However, humans can choose from many different types of carbohydrate, and how dietary carbohydrate quality - the precise composition of the dietary sugars - impacts the response to dietary protein remains largely unexplored. Here, mice were fed control (21% protein) or LP (7% protein) diets with four different carbohydrate sources: sucrose, a 1:1 glucose/fructose mixture, glucose, or fructose. While LP diets improved metabolic health across all groups in male mice, carbohydrate quality also significantly altered specific health outcomes, with fructose-fed mice having the lowest body weight and adiposity of all control diets. In female mice, responses to LP diets were influenced by carbohydrate quality, with certain sugars inducing a stronger metabolic response to LP diets than previously seen. Finally, in female APP/PS1 mice, a model of Alzheimer's disease, we find that although LP diets reduce A-beta; plaque burden irrespective of carbohydrate type, dietary sugar type does influence spatial memory. Together, these results demonstrate that while dietary protein is a critical determinant of metabolic and neurological health, carbohydrate quality influences these outcomes in a sex-specific manner.

Alcohol-associated liver disease (ALD) is a growing global health concern, with alcohol-associated hepatitis (AH) leading to the highest morbidity and mortality. Available therapies are limited and often inadequate. Platelets contribute in a variety of ways to liver disease pathogenesis, but their role in AH remains largely unexplored. In this study, we addressed the hypothesis that platelets contribute to pathological inflammation in AH. Using patient samples and a multiomics approach, we found that platelets undergo proinflammatory transcriptomic and proteomic changes in AH, with 2 alarmins, S100A8 and S100A9, being among the top upregulated genes/proteins. Additionally, the abundance of platelet-derived microparticles containing S100A8 and S100A9 in AH patient plasma was increased and correlated with disease severity (assessed by model for end-stage liver disease sodium [MELD-Na]) and endotheliopathy (assessed by ICAM1, CXCL8, and vWF). We mechanistically linked S100A9 with endotheliopathy via crosstalk between primary human liver sinusoidal endothelial cells and primary human monocytes. We also demonstrated that IL-6 upregulates S100A9 in megakaryocytic cells in a JAK/STAT-dependent manner, modeling changes occurring in the bone marrow in patients with AH. Our studies establish proinflammatory platelets as important contributors to AH pathology. Moreover, antiplatelet agents — or, more specifically, S100A9 targeted drugs — are potential therapeutic strategies in AH.