Citations

Background & Aims: The clinical course and outcomes of alcohol-associated hepatitis (AH) remain poorly understood. Major adverse liver outcomes do not capture the added risk of return to drinking. We examined the natural history of AH and developed a composite endpoint using a contemporary observational cohort of AH. Approach & Results: A cohort of 1127 participants: 712 AH patients, 256 heavy drinking controls without clinically evident liver disease, and 159 healthy controls, were prospectively followed for 6 months at 8 United States centers as part of the Alcoholic Hepatitis Network (AlcHepNet) consortium. Outcomes included mortality and a composite endpoint (AlcHepNet composite index) that included death, liver transplantation, hepatic decompensation (new onset/worsening ascites, HE, variceal bleeding), liver-related hospital admission, MELD increase ≥5, and return to drinking. Of 712 AH patients (age 45±10.7 y; 59.1% male), 558 (79.0%) had severe and 148 (21.0%) had moderate AH, 232 (32.5%) died, and 86 (12.1%) underwent liver transplantation. Mortality rates in moderate AH and severe AH were 0.7% versus 17.2% (30 d), 3.4% versus 26.5% (90 d), and 8.8% versus 30.5% (180 d), respectively (all p <0.001). Composite liver/alcohol use events were noted in 459 (64.5%) AH patients. Higher MELD score, lower mean arterial pressure, and baseline leukocytosis were associated with higher 90-day mortality in AH (all p <0.05). College education and higher ALP were associated with lower mortality. Heavy drinking controls had low mortality (n=3; 1.2%). Conclusions: This large observational study showed a high incidence of composite liver and alcohol-use events within 6 months, reiterating the need for early interventions.

Abstract Background: Conventional null hypothesis significance testing, which relies heavily on p-values and confidence intervals, remains central to scientific research. However, both measures are subject to variability and may yield fragile or misleading conclusions. This has contributed to reproducibility concerns and the need for more informative inferential tools. Methods: We propose the Replicative Significance Index (RSI), a simulation-based metric that estimates the proportion of hypothetical replications that achieve statistical significance under identical design assumptions. The RSI directly models the stability of observed significance, in contrast to post hoc p-value interpretation or traditional power analysis. We further introduce a tail-augmented RSI (RSI*), which incorporates the depth of significant p-values through a tail-dominance adjustment. RSI and RSI* were implemented in R and demonstrated via conceptual examples, simulations under varying precision, and illustrative case scenarios of fragile significance and hidden robustness. Results: The simulations revealed that the RSI discriminates between superficially similar p-values that differ markedly in replicability and highlights cases where confidence intervals and p-values may overstate or understate robustness. RSI* further rewards distributions concentrated in the lower tail, distinguishing robustly reproducible findings from borderline significance. An R package and interactive Shiny web application are provided to facilitate implementation.

Abstract May-Thurner physiology (MTP) can lead to various congestion syndromes due to compression of the left common iliac vein (LCIV) by the right common iliac artery (RCIA). This compression may result in venous reflux through the lumbar vein, leading to congestion of the spinal epidural venous plexus (EVP), which could contribute to refractory headaches. This case report details the clinical course of a patient with severe refractory new daily persistent headache associated with MTP who underwent ascending lumbar vein (ALV) embolization. The patient is a 59-year-old female with a 3-year history of daily persistent headache which failed multiple migraine prevention therapies and minimally invasive procedures. Imaging studies revealed significant LCIV compression by the RCIA, retrograde ALV flow, and EVP congestion. The patient underwent ALV embolization, resulting in significant symptomatic relief. At the 22-month follow-up, headache severity reduced by 80%, with the patient no longer requiring routine headache medications. Additionally, treatment of associated pelvic congestion syndrome through gonadal vein embolization resolved longstanding associated pelvic pain and pressure. This case highlights the role of venous congestion in refractory headache syndromes and underscores the potential of targeted venous interventions, such as embolization, in their management. The findings expand on emerging evidence linking venous compression syndromes to headache pathophysiology and support exploring interventional strategies as viable treatment options for selected patients. Further research is needed to validate these findings and establish evidence-based guidelines for clinical practice.

Abstract Insulin resistance (IR) is a modifiable risk factor for dementia, yet its effects on brain metabolism and function remain unclear. In older adults, greater IR was associated with reduced cerebral glucose uptake (indicating impaired mitochondrial metabolism), atrophy, and weakened connectivity between brain regions critical for cognition. In neuron-specific insulin receptor knockout mice, brain IR produced deficits in hippocampal- and prefrontal-dependent tasks accompanied by reduced brain mitochondrial ATP and elevated reactive oxygen species. To evaluate reversibility of IR-induced brain deficits, forty older adults with IR were randomized to 40-weeks of metformin or placebo. Metformin improved insulin sensitivity, increased brain glucose uptake, strengthened cognitive network connectivity, and preserved whole-brain and regional volumes implicated in decision-making and learning. Metformin also improved processing speed and working memory. Collectively, these findings highlight IR as a driver of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.

Key Points ift140 -deficient zebrafish exhibited phenotypes observed in mammals, including skeletal defects and kidney cysts. Beyond ciliogenesis, ift140 also regulated cell polarity and intracellular microtubule stability, potentially contributing to cystogenesis. Microhomology-mediated end joining–induced mosaic ift140 crispants enabled evaluation of cystogenesis in adult fish and F0-based screening for modifiers of kidney cysts. Background Genetic modifiers are believed to play an important role in the onset and severity of polycystic kidney disease, but identifying these modifiers has been challenging due to the lack of effective methodologies. Methods We generated zebrafish mutants of IFT140 , a skeletal ciliopathy gene and newly identified autosomal dominant polycystic kidney disease gene, to examine skeletal development and kidney cyst formation in larval and juvenile mutants. In addition, we used ift140 crispants, generated through efficient microhomology-mediated end joining–based genome editing, to compare phenotypes with mutants and conduct a pilot genetic modifier screen. Results ift140 mutants developed kidney cysts and bone defects similar to those seen in mammalian models. ift140 crispants recapitulated mutant phenotypes while bypassing the early lethality of the mutants, enabling the analysis of kidney cyst formation in adult fish. In addition to cilia defects, we identified nonciliary phenotypes, including disrupted cell polarity and aberrant cytoplasmic microtubule stabilization in kidney epithelial cells, as potential contributors to ift140 -associated cystogenesis. The ability to detect ift140 -associated kidney cysts with ease allowed us to develop an F0-based genetic screen to identify potential protective modifiers. A pilot screen of 16 genes previously implicated in dysregulated signaling pathways in autosomal dominant polycystic kidney disease revealed both known and novel modifiers, including mtor and ulk1a . We further found that inhibition of mtor and ulk1a reversed both cilia-related and non–cilia-related abnormalities in the kidney. Conclusions By establishing a zebrafish model of ift140 -associated cystic kidney disease, we recapitulated ift140 ’s ciliary role and uncovered a nonciliary function in kidney cystogenesis. Importantly, we demonstrated the feasibility of using ift140 mosaic crispants to evaluate cystogenesis in adult fish and to perform F0-based screening for identifying genetic modifiers of kidney cysts.

ImportancePatients with kidney failure (KF) receiving long-term dialysis have increased incidence of atrial fibrillation (AF). Patients with KF and AF have increased risk of stroke, death, and bleeding compared with age-matched cohorts. In KF, the use of oral anticoagulants (OACs) increases hemorrhage risk, offsetting potential benefits and making left atrial appendage occlusion (LAAO) a potentially promising solution for risk reduction in AF.ObjectivesTo compare the outcomes and safety of OACs and LAAO for risk reduction of AF in patients with KF.Design, Setting, and ParticipantsThis retrospective cohort study assessed patients with KF enrolled in the US Renal Data System registry between January 1, 2015, and December 31, 2018, who were diagnosed with AF after initiation of long-term dialysis. On average, patients met inclusion criteria for 22 months. Data analysis was completed in May 2024.ExposureMedicare claims were used to identify patients who received OACs and LAAO after AF diagnosis. A propensity-matched cohort was created based on the CHA2DS2-VASc score and year of treatment.Main Outcomes and MeasuresDeath, nonfatal bleeds, and nonfatal strokes.ResultsThe final cohort included 2344 patients with KF and a new AF diagnosis (median [IQR] age, 66.0 [57.0-73.0] years; 1341 [57.2%] male). Of these patients, 293 received LAAO and 2051 received OACs. A total of 2194 patients (93.6%) were receiving hemodialysis, with the remaining 150 (6.4%) receiving peritoneal dialysis. In the LAAO group, 79 deaths (27.0%) and 21 nonfatal strokes (7.2%) occurred, and 117 patients (39.9%) experienced 234 bleeding events. In the OAC group, 729 deaths (35.5%) and 163 strokes (8.0%) occurred, and 687 patients (33.5%) experienced 1114 bleeding events. After accounting for correlation between bleeds and death, the joint frailty model showed evidence of a treatment association of LAAO compared with OACs on recurrent bleeding events (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98) and death (HR, 0.47; 95% CI, 0.30-0.72). There was a reduced risk of nonfatal stroke in the LAAO group (HR, 0.55; 95% CI, 0.32-0.94), but this finding was not significant after adjustment (HR, 1.18; 95% CI, 0.76-1.81).Conclusions and RelevanceIn this cohort study, LAAO compared with OACs was associated with improved survival and reduced bleeding risk in patients with KF and AF. These findings suggest that these data should be considered in shared decision-making in consideration of LAAO for patients with KF and AF.

The integration of mobile health (mHealth) technologies is transforming neurosurgery. Despite its potential, many uses remain unrealized due to the unique challenges and complexity of developing mHealth technology. While neurosurgeons bring invaluable clinical expertise and an understanding of patient needs, the technical intricacies of application development often require collaboration with developers and computer scientists, a process that can feel unfamiliar and difficult to navigate. The aim of this article was to demystify mHealth development by providing a guide for neurosurgeons seeking to develop disease-specific mHealth applications. We outline this process using the development of SynapTrack, an mHealth tool designed to provide objective assessments of degenerative cervical myelopathy, a chronic condition caused by symptomatic compression of the cervical spinal cord. This article offers neurosurgeons concrete guidance on navigating key considerations such as design decisions, algorithm integration, database architecture, and data security. By grounding these insights with SynapTrack, this guide offers a transparent view into the development process and provides a practical framework that can be adapted to the development of other mHealth tools. The aim of this work was to foster interdisciplinary collaboration and enable neurosurgeons to develop mHealth applications tailored to the specific needs of their specialty.