Citations

Background: Prostaglandin E2 (PGE2) suppresses perinatal breathing. Reducing antenatal PGE2 concentrations with paracetamol could stimulate spontaneous breathing in premature infants at birth. We aimed to assess feasibility and potential effects of antenatal paracetamol. Methods: In this randomised, placebo-controlled, triple-blind feasibility trial, pregnant women <31 weeks’ gestation were randomised to receive either intravenous paracetamol (intervention) or placebo (control). Multiple pregnancies were also eligible, and the number of infants could exceed the number of enrolled women. The primary outcome was feasibility of administering study medication within 30–120 min prior to birth. Secondary exploratory outcomes included measures of breathing and other physiological parameters of infants during the first 1–10 min after birth and were compared between infants from mothers who received paracetamol and infants from mothers who received a placebo irrespective of timing of administration. Planned enrolment was 40 women. Results: The trial enrolled 23 women before termination due to low recruitment. Five women did not receive study medication, while 18 did (9 per group). Overall, 11 of the 23 enrolled women (48%) received study medication within the specified timeframe. The nine women in the intervention group gave birth to 13 infants, while the nine women in the control group gave birth to 12 infants. Among infants, average minute volume did not differ significantly between groups (intervention (n = 13) vs. control (n = 12); mean ± SEM; 147 ± 12 vs. 114 ± 14 mL/kg/min, p = 0.093). However, the intervention group had a significantly higher area under the curve for minute volume, greater inspiratory drive, and a higher heart rate (1120 ± 410 vs. 707 ± 346 mL/kg, p = 0.020; 11.8 ± 1.0 vs. 8.4 ± 1.3 mL/kg/breath/s, p = 0.046; 137 ± 5 vs. 121 ± 5 beats/min, p = 0.037). Conclusions: Antenatal paracetamol administration 30–120 min prior to birth was feasible in only half of the women, below the pre-specified threshold of 80%, but the exploratory findings suggest that it may improve the breathing effort of premature infants.

ABSTRACT Drug‐induced QTc prolongation (diQTP) is a major risk factor for torsades de pointes and sudden cardiac death. This study evaluated whether carriers of the G allele of the NOS1AP rs10494366 T > G variant have greater risk for diQTP when prescribed high‐risk QT‐prolonging medications. A retrospective case‐control analysis was conducted using the Michigan Genomics Initiative (MGI) biobank, linking genotype and electronic health records for 5848 patients of European ancestry prescribed ≥ 1 CredibleMeds high‐risk drug for torsades de pointes between 2001 and 2022. QTc was Bazett‐corrected, and diQTP was defined as change of > 60 ms from the baseline QTc and/or QTc ≥ 500 ms. Associations between rs10494366 and diQTP were tested using unadjusted and propensity‐score‐adjusted logistic regression. The minor‐allele frequency (G) was 0.36, and genotype frequencies were in Hardy–Weinberg equilibrium ( p = 0.07). diQTP occurred in 12.2% of participants. The G allele was not significantly associated with risk of diQTP in either the unadjusted analysis (OR 0.94 [95% CI 0.84–1.05] p = 0.27) or the adjusted analysis (OR 0.94 [95% CI 0.83–1.06] p = 0.30). In this large, real‐world cohort of patients with European ancestry, the NOS1AP rs10494366 variant was not significantly associated with the risk of diQTP. These findings suggest that previously observed associations between this variant and baseline QTc may not extend to all drug‐induced settings.

ABSTRACT Background Alcohol‐associated hepatitis (AH) has high short‐term mortality, whereas current prognostic models mainly reflect liver and renal dysfunction. The Metabolic Vulnerability Index (MVX) is a nuclear magnetic resonance‐derived score comprising the Inflammation Vulnerability Index (IVX; small high‐density lipoprotein particles [S‐HDL‐P] and GlycA) and the Metabolic Malnutrition Index (MMX). We evaluated whether MVX, IVX, and IVX components improve 90‐day mortality prediction beyond Model for End‐Stage Liver Disease (MELD) in AH. Methods Serum samples from 196 patients with AH, 169 heavy‐drinking controls, and 351 healthy controls were analyzed by nuclear magnetic resonance spectroscopy. The primary outcome was 90‐day AH‐related mortality. Biomarkers were modeled continuously after standardization within the AH cohort; S‐HDL‐P was modeled per 1 SD decrease. Cox models were adjusted for MELD, age, sex, white blood cell count, and baseline antibiotic or corticosteroid use. Model performance was assessed using Akaike information criterion (AIC), likelihood‐ratio testing, and Harrell's C ‐statistic. Results Among patients with AH, 30 AH‐related deaths occurred within 90 days (15.3%). IVX and MVX were highest in AH cases and increased with AH severity, whereas MMX did not consistently differentiate severity. Lower S‐HDL‐P was independently associated with 90‐day mortality in fully adjusted models (HR, 1.84; 95% CI, 1.01–3.35; p = 0.045), whereas GlycA was not (HR, 0.86; 95% CI, 0.54–1.37; p = 0.527). Adding S‐HDL‐P improved fully adjusted MELD‐based model fit (AIC, 298.97 vs. 301.46; LR p = 0.034; C ‐statistic, 0.741 vs. 0.729). IVX showed supportive improvement in model fit and discrimination (AIC, 299.81; LR p = 0.056; C ‐statistic, 0.749). Continuous MELD interaction analyses supported risk separation for S‐HDL‐P (LR χ 2 = 6.20; p = 0.045) and IVX (LR χ 2 = 6.64; p = 0.036). Conclusions Lower S‐HDL‐P appears to be the principal short‐term prognostic component within the IVX domain in AH. S‐HDL‐P and IVX may refine MELD‐based 90‐day risk stratification, pending external validation.

siRNA delivery to target cellular processes is an appealing area in lung diseases such as asthma. To realize this potential requires efficient, targeted cytosolic delivery without cellular toxicity or siRNA degradation. We demonstrate the efficacy of PONI-Guan nanoparticles in accessing airway epithelial and smooth muscle cells with specific siRNA targeting of mRNAs of interest while maintaining barrier integrity and avoiding cellular toxicity.

ABSTRACT Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end‐organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin‐driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)‐protein associated with a clonal plasma or B‐cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein–induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M‐protein‐mediated mechanisms; however, direct evidence implicating the M‐protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M‐proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence‐based management strategies for this clinically important group of disorders.

Background: Diffuse axonal brain injury (DABI) is a major component of traumatic brain injury, but the optimal timing of magnetic resonance imaging and histologic assessment after isolated DABI remains unclear. Because each method captures a different phase of injury, defining time-dependent diagnostic windows may improve experimental design and reduce animal use. Methods: Sixty-four Sprague-Dawley rats were randomized to moderate DABI or sham operation. Neurological Severity Score (NSS), 3 T diffusion tensor imaging (DTI), and histologic assessment were performed at early and late time points. Hippocampal fractional anisotropy (FA) was measured at 48 h and 1 month. β-amyloid precursor protein (β-APP) immunohistochemistry assessed acute axonal injury at 48 h, and hematoxylin and eosin (H&E) staining quantified hippocampal neuronal density at 1 month. Results: At 48 h, DABI rats had higher NSS, lower hippocampal FA, and greater β-APP-positive axonal accumulation than sham-operated rats. By 1 month, NSS and hippocampal FA no longer differed between groups, whereas hippocampal neuronal density remained significantly reduced in DABI rats, indicating persistent structural injury. Conclusions: In this rat model of isolated DABI, hippocampal FA and β-APP immunohistochemistry identified acute axonal pathology at 48 h, whereas conventional histology detected a persistent reduction in neuronal density at 1 month. These findings support a time-optimized diagnostic strategy using early DTI for noninvasive injury detection and late histology for long-term structural assessment.

Abstract Introduction Cystoid macular edema (CME) is a recognized complication associated with penetrating keratoplasty (PK) and Endothelial Keratoplasty (EK). The purpose of this study was to determine the incidence of acute CME within the first 6 months after PK, Descemet stripping automated EK, or Descemet’s membrane EK. Methods A retrospective cohort analysis of the TriNetX United States collaborative database was conducted. Patients with a diagnosis of Fuchs dystrophy or keratoconus who underwent PK or EK between January 1, 2004 and August 30, 2024 were included. Those with a history of uveitis, retinal vascular occlusion, diabetic macular edema, or prior vitrectomy were excluded. Outcomes and diagnoses were defined using current procedural terminology and International Classification of Diseases, Tenth edition (ICD-10) codes. Cohorts were stratified based on a history of prior PK or EK with >6 months follow-up. Propensity score matching was performed on both cohorts to control for age at index, sex, race, ethnicity, and the diagnosis of Fuchs dystrophy and keratoconus. The incidence of acute CME during a 6-month postoperative follow-up period was assessed. Odds ratios were calculated between cohorts. Results A total of 2516 eyes were included in the study (PK: 1258; EK: 1258). At six months postoperatively, the incidence of acute CME in the EK cohort (46 of 1258) was significantly higher than in the PK cohort (20 of 1258) (P = 0.0012) (OR 0.426, 95% confidence interval 0.25–0.72). Conclusions Our findings suggest that the incidence of acute CME is higher in patients undergoing EK compared to PK.

Purpose To implement and evaluate a faculty mentorship skill development curriculum within a radiation oncology department at a single academic medical center. Methods A three-part faculty development curriculum consisting of three 45-minute facilitated workshops was implemented for physician faculty mentors. The curriculum was designed to support mentors in navigating mentoring relationships, aligning expectations, and fostering mentee independence. Content was informed by evidence-based mentorship frameworks and adult learning principles, including models developed by the Center for the Improvement of Mentored Experiences in Research, social cognitive theory, and principles of psychological safety and self-efficacy. Faculty participants representing a range of academic ranks and mentoring experience levels participated voluntarily. Pre- and post-curriculum self-assessment surveys evaluated participant understanding and implementation of mentorship skills, as well as perceptions of common mentorship challenges, using a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree). Descriptive statistics were used to analyze responses. Results Curriculum content progressed from foundational mentorship concepts, including mentor roles, mentoring networks, and stages of mentoring relationships, to communication strategies, expectation alignment, and promotion of mentee independence. Educational methods included brief didactic instruction, case-based discussion, guided reflection, and peer-to-peer learning. Survey data demonstrated improvement in participant self-assessment scores across all evaluated mentorship domains, including mentoring across differences, supporting mentee goal achievement, confidence as a mentor, providing constructive feedback, awareness of mentorship challenges, setting clear expectations, and understanding core mentorship competencies. Participants also reported reduced perceived challenges related to mentorship, with the largest improvements observed in setting boundaries, mentoring across differences, and addressing sensitive topics. Conclusions This faculty mentorship development curriculum was feasible to implement and demonstrated favorable early improvements in self-reported mentorship knowledge, confidence, and perceived ability to navigate common mentorship challenges. Further longitudinal evaluation is needed to assess sustained implementation of mentorship skills and longer-term impact on mentoring relationships.

Abstract TAR DNA‐binding protein 43 (TDP‐43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age‐related tauopathy (PART). TDP‐43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP‐43 are yet to be elucidated. We investigate relationships between TDP‐43 inclusions and the tangle maturation continuum in AD, PART, and co‐pathologies by multiplex immunostaining combined with artificial intelligence (AI)–based segmentation via object recognition, reconstruction, and quantification. We performed anti‐phosphorylated TDP‐43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP‐43 (PART‐TDP), five cases with high likelihood AD and TDP‐43 (AD‐TDP), and four cases of high likelihood AD with TDP‐43 and Lewy Body disease (AD‐TDP‐LBD). Confocal imaging was taken from eight regions: amygdala (amygdala‐BL and amygdala‐CM) and hippocampus (Cornu Ammonis (CA)‐1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP‐43 (TAT) inclusions. TATs, which were either identified by pTDP‐43 and AT8 or pTDP‐43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre‐TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre‐TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI‐based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP‐43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region‐specific dynamics in the neurodegenerative processes of PART and AD.

ABSTRACT Background and Aims Nonsystemic vasculitic neuropathy classically presents as a painful asymmetric axonal neuropathy, multiple mononeuropathies or radiculoplexus neuropathy. Demyelinating electrophysiologic features are rare and may lead to misdiagnosis. We describe a patient with biopsy‐proven vasculitic neuropathy presenting as a severe symmetric demyelinating polyradiculoneuropathy. Methods Clinical, electrophysiologic, imaging, laboratory, and histopathologic findings are presented. Results A 57‐year‐old man developed acute ascending weakness, sensory loss, facial weakness, and areflexia following a febrile illness, with initial improvement before developing recurrent neurological decline 6 weeks after initial symptom onset despite treatment with intravenous immunoglobulin and plasma exchange. Cerebrospinal fluid protein was elevated. Nerve conduction studies demonstrated prolonged distal motor latencies, slowed conduction velocities, conduction block, and prolonged blink reflex latencies, fulfilling 2021 European Academy of Neurology/Peripheral Nerve Society electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). MRI demonstrated mild but diffuse lumbosacral plexus enlargement and T2 hyperintensity. Sural nerve biopsy ultimately demonstrated evidence of epineurial inflammation and microvasculitis with ischemic nerve injury, accompanied by both increased rates of axonal degeneration (12%) and segmental demyelination (9%) on teased fiber analysis. Treatment with corticosteroids and rituximab resulted in complete neurological recovery. Interpretation Vasculitic neuropathy may closely mimic CIDP clinically, radiologically, and electrophysiologically. Clues to the vasculitis diagnosis were prominent neuropathic pain, dense denervation on electrophysiology, and poor response to typical CIDP treatment. Peripheral nerve biopsy remains a critical tool in the evaluation of atypical or treatment‐refractory inflammatory neuropathies.