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Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

ABSTRACTBackgroundThe carbon‐13 spirulina gastric emptying breath test (GEBT) is approved to identify delayed, but not accelerated, gastric emptying (GE). We compared the utility of the GEBT to scintigraphy for diagnosing abnormal GE in patients with diabetes mellitus.MethodsTwenty‐eight patients with diabetes ate a 230‐kcal test meal labeled with technetium 99 m and 13C‐spirulina, after which 10 scintigraphic images and breath samples (baseline, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min) were collected on 2 occasions 1 week apart. We assessed the accuracy of 13C‐spirulina GEBT excretion rate (percent dose multiplied by 1000 [kPCD] min−1) values to predict scintigraphic half‐life and distinguish between normal, delayed, and accelerated GE and the intraindividual reproducibility of the GEBT.Key ResultsScintigraphy revealed normal, delayed, and accelerated GE, respectively, in 17 (30%), 29 (52%), and 10 (18%) test results. GE T½ values measured with scintigraphy and GEBT were highly concordant within individuals; the intraindividual reproducibility was 34% (scintigraphy) and 15% (GEBT). Compared to current criteria, the kPCD150 (150 min) and kPCD180 values provided equally sensitive (90%) and more specific (81% vs. 67%) approach for distinguishing between delayed versus normal/accelerated GE. A new metric (kPCD60–kPCD15 min) was 90% sensitive and 83% specific for distinguishing between accelerated versus normal/delayed GE. These findings were used to create nomograms and an algorithm for interpreting GEBT results.Conclusions and InferencesAmong patients with poorly controlled diabetes, the 13C‐spirulina GEBT can accurately and precisely assess GE and effectively distinguish between normal, delayed, and accelerated GE.

ImportanceUnderstanding the interplay between diabetes risk factors and diabetes development is important to develop individual, practice, and population-level prevention strategies.ObjectiveTo evaluate the progression from normal and impaired fasting glucose levels to diabetes among adults.Design, Setting, and ParticipantsThis retrospective community-based cohort study used data from the Rochester Epidemiology Project, in Olmsted County, Minnesota, on 44 992 individuals with at least 2 fasting plasma glucose (FPG) measurements from January 1, 2005, to December 31, 2017. People who met criteria for diabetes on or before their first FPG measurement were excluded. Data were electronically retrieved in December 2019 with analyses finalized in November 2024.ExposuresThe exposure was baseline FPG level, with covariates including the following measures that are consistently recorded in the electronic health record: body mass index (BMI), age, and sex.Main Outcomes and MeasuresThe cumulative probability of freedom from diabetes was estimated and presented graphically using a Kaplan-Meier curve. Multivariable Cox proportional hazards regression modeling was used to estimate the partial hazard ratios (HRs) for variables of interest. Diabetes was defined as an FPG level greater than 125 mg/dL.ResultsA total of 44 992 individuals (mean [SD] age at baseline, 43.7 [11.8] years; 26 025 women [57.8%]) were included. The baseline mean (SD) BMI was 28.9 (6.6). Over a median follow-up of 6.8 years (IQR, 3.6-9.7 years), 3879 individuals (8.6%) developed diabetes. The Kaplan-Meier 10-year cumulative risk of incident diabetes was 12.8% (95% CI, 12.4%-13.2%). All initial FPG levels outside a range of 80 to 94 mg/dL were associated with increased risk for diabetes (ie, FPG <70 mg/dL: HR, 3.49 [95% CI, 2.19-5.57]; FPG 120-125 mg/dL: HR, 12.47 [10.84-14.34]). Other independent risk factors were male sex (HR, 1.31 [95% CI, 1.22-1.40]), older age (≥60 years: HR, 1.97 [95% CI, 1.71-2.28]), and any abnormal category of BMI, including underweight (BMI <18.5: HR, 2.42 [95% CI, 1.77-3.29]; BMI ≥40: HR, 4.03 [95% CI, 3.56-4.56]). There was a significant additive association of variables, particularly FPG level and BMI. For instance, a woman aged 55 to 59 years with a BMI of 18.5 to 24.9 and an FPG level of 95 to 99 mg/dL had an estimated 10-year diabetes risk of 7.0%. However, an almost doubling of risk to 13.0% was observed if the BMI was 30.0 to 34.9, and risk more than doubled again to 28.0% if FPG level also increased to 105 to 109 mg/dL. A nomogram was generated to facilitate individual classification into one of four 10-year risk categories.Conclusions and RelevanceThis retrospective cohort study of 44 992 individuals suggests that FPG level, age, BMI, and male sex were all associated with development of diabetes, with significant interaction between these variables. These data contribute to understanding the clinical course of diabetes and highlight the substantial individual variation in diabetes risk according to commonly measured clinical variables. The findings facilitate lifestyle and pharmacologic interventions to treat those at highest risk of diabetes to reduce future morbidity and mortality. Further work is needed to validate this risk categorization tool for different populations.

Abstract Translational large-animal models that can accommodate human-scale implantable devices are essential for advancing neuromodulation therapies in epilepsy. This study establishes a kainic acid (KA)-induced porcine model of mesial temporal lobe epilepsy (mTLE) using clinical imaging, stereotactic surgery, and a fully implantable neural stimulation and recording (INSR) device designed for humans. Seven pigs (six KA-treated and one saline control) underwent MRI-guided stereotactic implantation of electrodes targeting bilateral hippocampus (HPC) and anterior thalamus (ANT), followed by intra-hippocampal KA or saline infusion. Local field potentials (LFP) were recorded continuously with synchronized video monitoring. Seizures and LFP interictal epileptiform-like discharges (IEDs) were quantified using validated automated detectors. Histology was performed in the saline control and the longest surviving KA-treated pig. Intra-hippocampal KA infusion induced acute status epilepticus in all (6/6) treated pigs. Four animals survived to chronic monitoring with spontaneous seizures observed in three pigs (2,733 seizures; mean duration of 27.2 ± 17.6 seconds). IEDs were observed in bilateral HPC of all animals, including saline control, with higher rates in the lesioned HPC (p <0.0001). While the IED morphology is consistent with epileptiform activity; IEDs alone are not specific for epilepsy and physiological transients (e.g. sharp-wave ripples) and injury-related hyperexcitability or strain-specific hyperexcitability cannot be excluded. Histological analysis revealed patchy neuronal loss and cytoarchitectural changes in HPC. This porcine model reproduces electrophysiological features of human mTLE. This approach provides a powerful translational bridge for developing and testing next-generation INSR and neuromodulation strategies in freely behaving large animals.

Background: The relative advantages and disadvantages of 2-stage versus 1-stage management of infection following total hip arthroplasty (THA) are the current subject of intense debate. To understand the merits of each approach, detailed information on the short and, importantly, longer-term outcomes of each must be known. The purpose of the present study was to assess the long-term results of 2-stage exchange arthroplasty following THA in one of the largest series to date. Methods: We identified 331 periprosthetic joint infections (PJIs) that had been treated with a 2-stage exchange arthroplasty between 1993 and 2021 at a single institution. Patients were excluded if they had had prior treatment for infection. The mean age at the time of reimplantation was 66 years, 38% of the patients were female, and the mean body mass index (BMI) was 30 kg/m 2 . The diagnosis of PJI was based on the 2011 Musculoskeletal Infection Society criteria. A competing-risk model accounting for death was utilized. The mean duration of follow-up was 8 years. Results: The cumulative incidence of reinfection was 7% at 1 year and 11% at 5 and 10 years. Factors predictive of reinfection included BMI ≥30 kg/m 2 (hazard ratio [HR] = 2; p = 0.049) and the need for a spacer exchange (HR = 3.2; p = 0.006). The cumulative incidence of any revision was 13% at 5 and 10 years. The cumulative incidence of aseptic revision was 3% at 1 year, 7% at 5 years, and 8% at 10 years. Dislocation occurred in 33 hips (11% at 10 years); 15 (45%) required revision. Factors predictive of dislocation were female sex (HR = 2; p = 0.047) and BMI <30 kg/m 2 (HR = 3; p = 0.02). The mean Harris hip score (HHS) improved from 54 to 75 at 10 years. Conclusions: In this series of 331 two-stage exchange arthroplasties that were performed for the treatment of infection, we found a low rate of aseptic revision (8%) and a low rate of reinfection (11%) at 10 years. These long-term mechanical and infection data must be kept in mind when considering a paradigm shift to 1-stage exchanges. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin ( DCTN1 ). PS brains accumulate inclusions positive for ubiquitin, transactive‐response DNA‐binding protein of 43 kDa (TDP‐43), and to a lesser extent dynactin. Objectives Little is known regarding the contributions of TDP‐43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP‐43 dysfunction in two regions of PS brains. Methods We evaluated the levels of insoluble pTDP‐43 and TDP‐43‐regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology, and 11 cognitively healthy controls without TDP‐43 pathology. Results Insoluble pTDP‐43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP‐43‐regulated cryptic RNAs ( ACTL6B , CAMK2B , STMN2 , UNC13A , KCNQ2 , ATG4B , GPSM2 , and HDGFL2 ) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A , reached significance in the substantia nigra despite similar pTDP‐43 levels. Conclusion We detected TDP‐43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP‐43 dysfunction across different brain regions and determine the targets that are specific and common to TDP‐43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Context Defects in insulin secretion and action contribute to the progression of prediabetes to diabetes. However, the contribution of α-cell dysfunction to this process has been unclear. Objective This work aimed to understand the relative contributions of α-cell and β-cell dysfunction to declining glucose tolerance. Methods A longitudinal, community-based observational study was conducted at a clinical research unit at an academic medical center. We studied 96 individuals without diabetes (age 55 ± 1 years; body mass index 27.7 ± 0.4) on 2 occasions, 3 years apart using an oral 75-g glucose challenge. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Main outcome measures included glucose tolerance status (categorical variable) and then symmetrical percentage change in peak and 120-minute glucose (post oral glucose tolerance test) concentrations (continuous variables). Results A total of 32 individuals progressed from normal to impaired glucose tolerance (IGT) or from IGT to type 2 diabetes. The disposition index (DI) declined in the progressors (568 ± 98 vs 403 ± 65 10−4 dL/kg/min per μU/mL, baseline vs 3 years; P = .04). α-Cell suppression by glucose (δGSR/δglucose) did not change in the nonprogressors (1.5 ± 0.1 vs 1.3 ± 0.1 nmol/min/L; P = .37) but decreased (1.0 ± 0.2 vs 0.8 ± 0.2 nmol/min/L; P &lt; .01) in those who progressed. Analysis of the entire cohort showed that DI and δGSR/δglucose were independently and inversely correlated with an increase in glycemic excursion. Conclusion These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.

AbstractBackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder involving pathological deposition of tau that includes glial inclusions and specific regional vulnerability patterns. Therapeutic developments are hampered by incomplete understanding of disease mechanisms. Few studies have examined its cell type‐specific effects. We performed RNA‐sequencing in a large cohort of PSP patients and controls to understand molecular pathways disrupted across prefrontal cortex and caudate nucleus in PSP. We also performed multi‐omic single‐nucleus sequencing to deconvolute cell type‐specific changes.MethodRNA‐sequencing was conducted in 250 PSP patients and age‐ and sex‐matched controls, with a subset (N = 23) undergoing multi‐omic single‐nucleus RNA‐sequencing and ATAC‐sequencing (10x Genomics). Sequencing data was aligned to GRCh38 and quantified using STAR and RSEM (RNA‐seq) and CellRanger (single‐nucleus) and corrected for technical and biological covariates. Differential expression was calculated with Dream (RNA‐seq) and Dreamlet (single‐nucleus sequencing), and co‐expression network analysis (WGCNA) used to extract disease‐relevant gene modules.ResultRNA‐sequencing analysis identified ∼4000 differentially expressed genes in both brain regions. Despite differences in cellular composition and degree of disease impact, both regions share patterns of dysregulation related to protein folding and processing, indicating common pathological mechanisms. Differences between the regions includes disruption of cellular homeostasis and intracellular trafficking in caudate, while prefrontal cortex shows suppression of metabolic processes and immune response. Preliminary findings from the single cell genomic analyses suggest the greatest changes occur in neurons of both regions, where there is a shared pattern of protein processing dysregulation and a distinct enrichment in metabolic processing within prefrontal cortex interneurons.ConclusionWe identified thousands of dysregulated genes in two impacted brain regions in PSP and show that this dysregulation is reflected in specific neuronal populations in these regions. Identifying regional and specific cell type‐specific mechanisms related to PSP will further our understanding of causative disease mechanisms and provide new avenues for therapeutic developments.

ABSTRACT Background: Neutrophil extracellular traps (NETs), and its formation and release, known as NETosis, may play a role in the initiation of thrombin generation (TG) in trauma. The objective of this study was to assess whether trauma patients, who develop symptomatic venous thromboembolism (VTE), have increased levels of plasma citrullinated histone H3 (CitH3) and accelerated TG kinetics. Methods: Patients presenting to a level I trauma center as trauma activations had samples collected within 12 h of time of injury, alongside healthy volunteers (HV). CitH3 was measured by enzyme-linked immunosorbent assay, and TG data were measured using a TG analyzer, comparing results between patients developing symptomatic VTE versus those who did not, within 90 days of injury. Data were expressed as median and quartiles (Q1, Q3), and tested using Wilcoxon rank-sum or Fisher’s exact test, or 1-sample test of Spearman’s correlation, P < 0.05 considered significant. Results: 39 trauma patient samples were analyzed (10 with and 29 without VTE), and compared to 15 HV samples. CitH3 levels in patients who developed VTE were significantly greater as compared to those who did not (12.8 ng/mL [7.1, 30.8]; 3.0 ng/mL [1.8,6.8], P = 0.024), with levels in both groups greater compared to HV (1.2 [0.3, 4.1], P = 0.003, P = 0.012), respectively. TG profiles were accelerated in patients developing VTE, with differences in peak height (337.6 nM [304.4, 356.0]; 231.8 nM [180.2, 281.8], P = 0.008), endogenous thrombin potential (1718.5 nM*min [1,500, 1794]; 1208.5 nM*min [1,072, 1,417], P = 0.003) and velocity index (213.2 nM/min [162.3, 260.5]; 124.3 nM/min [93.2, 223.1], P = 0.03), respectively. Conclusion: Trauma patients developing VTE exhibit increased NETosis, measured by increased CitH3 levels and accelerated TG early after injury, outlining an area for further understanding VTE after trauma.