Citations

Abstract Provided herein are novel benzofuran derivatives as SARM1 inhibitors, pharmaceutical compositions, use of such compounds in treating axonal degeneration, and processes for preparing such compounds.

Understanding the complex interplay between electrical activity and neurochemical signaling is essential for advancing neuromodulation therapies, yet current technologies often measure these modalities in isolation and suffer from technical limitations such as stimulation artifacts. To address these challenges, we developed the Multifunctional Apparatus for Voltammetry, Electrophysiology, and Neuromodulation (MAVEN), a compact, battery-powered platform designed for high-resolution, concurrent multimodal data acquisition. Preclinical validation in both small- and large-animal models demonstrated that MAVEN provides stable, high-fidelity multimodal readouts while effectively minimizing stimulation artifacts during simultaneous programmable neurostimulation. By capturing phasic and tonic neurochemical changes, alongside real-time electrophysiological data, we established the system's feasibility for continuous monitoring. Beyond its utility in investigating the mechanisms of neurological and neuropsychiatric disorders, MAVEN has been engineered as a versatile analytical platform. Recent successful applications in monitoring pharmacological agents, such as vancomycin, further demonstrate its potential as a robust point-of-care device for real-time diagnostic and therapeutic monitoring. These results position MAVEN not only as a powerful tool for developing personalized, closed-loop neuromodulation strategies but also as a next-generation analytical device capable of broader clinical and bio-sensing applications.

Introduction: COVID-19, in addition to its direct detrimental respiratory infection, is associated with multiple systemic complications involving different organs, including the liver. COVID-19 has been associated with liver injury through multiple mechanisms, including direct viral effects on liver cells, immune-mediated injury, cytokine-driven inflammation, ischemic hepatitis, microvascular thrombosis, and sepsis-related multiorgan dysfunction. Acute liver failure (ALF) is the acute form of liver damage, which has a high mortality, and recovery is dependent on various factors. We studied the effect of COVID-19 on clinical outcomes such as mortality, length of stay, and need for non-invasive and invasive ventilation in patients with acute liver failure. Methods: We performed a retrospective cohort analysis using the Nationwide Inpatient Sample (NIS) database from 2020 to 2022. Adult patients admitted to the hospital with acute liver failure were divided into 2 groups based on their COVID-19 infection status. We analyzed differences in mortality, length of stay, need for non-invasive and invasive ventilation, acute kidney injury, need for renal replacement therapy, and total charges to evaluate the effects on outcomes, and the results were then adjusted for demographic and hospital factors. Results: Of 633,155 patients with acute liver failure, 66,785 had concurrent COVID-19 infection, while 566,370 did not. Patients with concurrent COVID-19 infection had significantly higher in-hospital mortality (63.9% vs. 36.0%) and greater utilization of noninvasive ventilation (14.9% vs. 6.4%), invasive mechanical ventilation (68.9% vs. 41.7%), higher incidence of acute kidney injury (81.4% vs. 70.3%) and higher need for renal replacement therapy (26.8% vs. 16.9%). They also experienced longer hospital stays (17.1 vs. 10.7 days) and higher total charges ($345,072 vs. $221,268). The findings were statistically significant after adjusting for demographics and clinical factors. Conclusions: Patients hospitalized with acute liver failure and concurrent COVID-19 infection experienced worse clinical outcomes, including higher in-hospital mortality, greater need for ventilatory support and renal replacement therapy, and higher hospital resource utilization. Notably, COVID-19 was independently associated with worse outcomes even among patients with fewer baseline comorbidities. These findings underscore the importance of early recognition of COVID-19 in patients presenting with acute liver failure, as well as prompt, multidisciplinary management to optimize clinical outcomes.

Background: Midfoot arthritis can cause debilitating dorsal midfoot pain and functional limitation. Deep peroneal nerve (DPN) neurectomy is a minimally invasive surgical option that addresses pain through selective denervation. Although favorable midterm outcomes have been reported, long-term durability remains unclear. The purpose of this study was to evaluate changes in patient-reported physical function and pain interference between midterm and long-term follow-up after DPN neurectomy using validated Patient-Reported Outcomes Measurement Information System (PROMIS) instruments. Methods: A retrospective review identified patients who underwent isolated DPN neurectomy for midfoot arthritis between 2017 and 2021 and completed PROMIS Physical Function (PF) and Pain Interference (PI) questionnaires at midterm and long-term follow-up. Mean follow-up was 2.9 years (midterm) and 6.1 years (long-term). PROMIS scores were compared using paired t tests. Clinically meaningful improvement was defined using established minimal clinically important difference (MCID) thresholds (+5.88 for PF, −5.49 for PI). Results: The final cohort included 32 patients (81.2% female, mean age 68.4 ± 7.3 year). PF improved from 37.7 ± 6.2 to 39.0 ± 7.5 (Δ = +1.3, 95% CI [−0.7 to +3.4], P = .188), whereas PI decreased from 62.6 ± 8.8 to 59.2 ± 9.0 (Δ = −3.4, 95% CI [−6.3 to −0.5], P = .020). Clinically meaningful improvement was achieved by 7 of 32 (21.9%) for PF and 15 of 32 (46.9%) for PI. Five patients experienced clinically meaningful worsening, including patients with stroke, chronic pain syndrome, or contralateral foot and ankle pathology or surgery. Conclusion: DPN neurectomy was associated with stable longitudinal PROMIS outcomes through extended follow-up, with a nonsignificant mean PF change of +1.3 points and a statistically significant but sub-MCID mean PI decrease of −3.4 points over approximately 6 years. Outcomes were heterogeneous; fewer than half of patients achieved clinically meaningful improvement in pain interference, and a subset experienced worsening. These findings suggest that DPN neurectomy may provide durable symptom stability in appropriately selected patients with refractory dorsal midfoot pain, although clinically meaningful benefit at the individual level is not universal. Level of Evidence: Level III, comparative series.

Abstract Objective To evaluate whether thyroid dysfunction, including hypothyroidism and hyperthyroidism, is associated with migraine across racial and age groups using a large, multinational electronic health record database. Background Thyroid disorders are highly prevalent worldwide, with hypothyroidism affecting over 200 million individuals and hyperthyroidism affecting approximately 2.5% of adults. Migraine is a leading cause of disability globally. Prior studies have suggested potential links between thyroid dysfunction and migraine, but evidence has been limited by small sample sizes, restricted population diversity, and inadequate control of confounding. Whether associations differ by thyroid subtype, race, or age remains unclear. Methods We performed two parallel retrospective cohort analyses within the TriNetX Global Collaborative Network, comprising over 200 million patients across 21 countries, using patient records from January 2004 to December 2024. Adults aged 18–100 years with hypothyroidism or hyperthyroidism, defined by ≥3 clinical encounters within 20 years, were identified. Individuals with psychiatric disorders (including mood, anxiety, and stress‐related disorders), sleep disorders, epilepsy or recurrent seizures, or known migraine‐related genetic mutations were excluded. Each thyroid cohort was compared with a control group without thyroid disease, with groups balanced on key demographic and clinical characteristics including age, sex, and hypertension; beta‐blocker use was additionally considered in the hyperthyroidism cohort. The primary outcome was diagnosis of migraine (International Classification of Diseases, 10th Revision, code G43) within 5 years of index date. Subgroup analyses were conducted by race (Caucasian, African American/Black, Asian) and age (18–40, 40–65, 65–100 years). Sensitivity analyses assessed robustness to alternative visit thresholds and expanded covariate adjustment. Results A total of 33,327,750 patients were included in the hypothyroidism analysis and 28,182,377 in the hyperthyroidism analysis. Baseline differences between groups were minimized after cohort balancing. Hypothyroidism was associated with higher odds of migraine across all racial groups, strongest among African American/Black (odds ratio [OR] 2.04; 95% confidence interval [CI] 1.91–2.17), followed by White (OR 1.93; 95% CI 1.89–1.96) and Asian (OR 1.83; 95% CI 1.69–1.98). Hyperthyroidism was similarly associated with increased migraine odds, most prominently among White (OR 1.64; 95% CI 1.59–1.70), with smaller but significant associations in African American/Black (OR 1.28; 95% CI 1.14–1.44) and Asian (OR 1.18; 95% CI 1.07–1.29). Elevated odds were observed across all age strata, generally increasing with age. Findings were consistent in sensitivity analyses. Conclusion In this large, multinational real‐world study, both hypothyroidism and hyperthyroidism were independently associated with increased migraine prevalence across diverse racial and age groups. These results highlight thyroid dysfunction as an important comorbid condition in migraine and support further prospective and mechanistic investigation.

Abstract Background Quality assurance (QA) in radiation therapy is a critical component of ensuring accurate and consistent patient treatments, but many tasks are time consuming and rely on human visual acuity, which limits their accuracy. Purpose We aimed to automate monthly mechanical QA tests, improve measurement accuracy and precision, and decrease inter‐user variability using a computer vision‐based quality assurance (CVQA) system. Methods A custom marker board incorporating four ArUco markers was created along with a custom camera holder that mounted onto the gantry head. OpenCV was utilized to automate tests for couch translation, collimator and table angles, collimator and table walkout, optical distance indicator (ODI), and field size detection. A GUI was created to guide users through the tests, determine passing status of measurements based on MPPG8.b criteria, and display image captures to allow users to troubleshoot if needed. Reproducibility tests were taken across four days. The system was tested against manual measurements by graph paper or digital level for each test. Field sizes and ODI were read by 12 different physicists to determine human variability and comparisons for CVQA. Results The CVQA system took 5 min to set up and 7 min to perform all tests. All field sizes, collimator/table angles, collimator/table walkout, and table translations were reproducible within 0.5 mm and 0.5°. ODI measurements were reproducible within 1 mm. Table travel, ODI, and walkout measurements agreed with manual measurements within 0.5 mm and 0.4°, except for vertical table motions that agreed within 0.9 mm due to the lens focus being optimized for the 100 cm SSD plane. The standard deviation between physicists for almost all symmetric and asymmetric jaws was larger than the reproducibility of CVQA. CVQA has been utilized for five years and has demonstrated ability to identify mechanical machine issues. Conclusions CVQA successfully automates mechanical QA tasks, providing an efficient and precise system. CVQA is open source and freely available for academic institutions. Its adoption can improve workflow efficiency and consistency in clinical environments.

ABSTRACT Stickler syndrome is most commonly caused by variants in COL2A1 and COL11A1 genes. The purpose of this study was to describe genetic variants and phenotypes in COL2A1 and COL11A1 Stickler syndrome. We performed a retrospective genotype–phenotype evaluation of COL2A1 and COL11A1 Stickler syndrome subjects. Thirty‐two subjects with COL2A1 and 13 subjects with COL11A1 Stickler syndrome were last seen in clinic at a mean age of 17.2 ± 13.1 and 12.6 ± 3.8 years, respectively ( p = 0.08). We found that 50% of COL2A1 subjects had lattice degeneration, whereas 8% of the COL11A1 subjects had lattice degeneration ( p = 0.015). The most common type of variant for COL2A1 Stickler syndrome was a premature termination codon (12 out of 18 families, 67%); and the most common types of variants for COL11A1 Stickler syndrome were glycine missense variants (4 out of 10 families, 40%) and splice site variants (4 out of 10 families, 40%). There was a higher rate of lattice degeneration in COL2A1 patients compared with COL11A1 patients, a finding that could be influenced by a trend towards older age at last follow‐up in the COL2A1 group.

Interleukin 33 (IL-33) is a cytokine of the IL-1 family that acts as an alarmin in both innate and adaptive immunity. IL-33 is constitutively nuclear in epithelial and endothelial cells, where its activity is limited by nuclear retention. Release of IL-33 in response to cellular stress or injury can mediate type 2 immune responses or tissue repair, depending on the local tissue environment. IL-33 activity is regulated at multiple levels, including nuclear retention, oxidation, proteolytic processing, and metabolic regulation. Following its release, oxidation rapidly suppresses IL-33 activity, while mast cell and neutrophil proteases can generate smaller active fragments that target cells expressing the IL-33 ST2 receptor. Simultaneously, tissue metabolic status influences cellular responsiveness through the mTORC1 and AMPK pathways, which link metabolic capacity to effector function. These conditions may explain why IL-33 can mediate an inflammatory response, but in other circumstances, it contributes to tissue repair. Such pleiotropic properties may also underline the variability in clinical responses to IL-33/ST2-targeted therapies across various diseases. The appreciation of IL-33 as a cytokine whose activity is conditioned by its structural, redox, and metabolic environment is critical to optimizing its therapeutic potential as a target.

Early-onset colorectal cancer is increasing, making reproductive health an increasingly relevant survivorship issue. While immune checkpoint inhibitors have altered the management of deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) colorectal cancer, their implications for reproductive-age women remain insufficiently defined. We performed a focused narrative review, structured in line with the SANRA framework, to clarify this specific clinical domain. Immunotherapy may reshape female oncofertility counseling through two distinct mechanisms: direct reproductive uncertainty, including established endocrine toxicities and hypothesized, but currently unproven, direct gonadal effects; and indirect pathway-modifying effects, such as the potential avoidance of pelvic radiotherapy or radical surgery in selected patients with locally advanced dMMR/MSI-H rectal cancer. Anatomical organ preservation should not be automatically equated with functional fertility preservation. The key clinical message is that reproductive counseling should not be restricted to historically gonadotoxic chemotherapy. Instead, early multidisciplinary guidance should explicitly distinguish CRC-specific evidence from extrapolated or theoretical concerns, integrate fertility preservation strategies when clinically feasible, and address pelvic and sexual health, contraception, washout, endocrine follow-up, and future pregnancy planning. Until prospective CRC-specific reproductive data become available, immunotherapy should not be presented as either reproductively neutral or fertility-preserving.