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Background: Although patients often aim to lose weight after total hip arthroplasty (THA) or total knee arthroplasty (TKA), long-term changes in body mass index (BMI) are unknown. We analyzed BMI at 2, 5, and 10 years after primary THA and TKA and determined predictors of BMI change. Methods: We identified patients who underwent primary THA or TKA for osteoarthritis between 2001 and 2011 and had a BMI at surgery and at 2, 5, and 10 years postoperatively. This resulted in 763 patients (310 who underwent THA and 453 who underwent TKA). The mean patient age was 66 years, and 60% of patients were female. BMI changes were analyzed with repeated-measures analysis of variance. Multinomial logistic regression determined predictors of BMI change. Results: Following THA, the mean BMI increased from 30.3 kg/m 2 at surgery to 30.9 kg/m 2 at both 2 years (p = 0.003) and 5 years (p = 0.002). Following TKA, the mean BMI increased from 32.7 kg/m 2 at surgery to 33.1 kg/m 2 at both 2 years (p = 0.053) and 5 years (p = 0.040). By 10 years, the mean BMI was 30.6 kg/m 2 (p = 0.453) for patients undergoing THA and 32.6 kg/m 2 (p = 0.947) for patients undergoing TKA, similar to the BMIs at surgery. At 10 years, 27% of patients who underwent THA and 30% of patients who underwent TKA had a BMI decrease of >5%, whereas 30% of patients who underwent THA and 32% of patients who underwent TKA had a BMI increase of >5%. Female sex among patients who underwent THA increased the odds of a >5% BMI increase at 10 years (odds ratio [OR], 2.1; p = 0.006). Older age among patients who underwent TKA decreased the odds of a >5% BMI increase at 10 years (OR per year, 0.95; p < 0.001). Conclusions: Although most patients experienced a BMI change of >5% at 10 years, the mean BMI did not meaningfully change 2, 5, or 10 years after THA or TKA. Arthroplasty should not be viewed as a gateway to BMI improvement for patients overall, but female sex and older age may predict clinically important weight changes 10 years after arthroplasty. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Surgeons often recommend weight loss for patients with obesity before total knee arthroplasty (TKA). However, it is unknown whether preoperative weight loss affects outcomes. The goals of this study were to determine how many patients with obesity lost weight before TKA, to identify weight loss predictors, and to evaluate if preoperative weight loss affected postoperative outcomes. Methods: Among 23,726 primary TKAs performed between 2002 and 2019, we identified 3,665 patients who had a body mass index (BMI) of ≥30 kg/m 2 measured 1 to 24 months before surgery and had a weight measured at surgery. The mean patient age was 68 years, and 59% of patients were female. The mean patient BMI was 36 kg/m 2 . Univariable linear regressions evaluated weight loss predictors. Univariable and multivariable logistic regressions and Cox proportional hazards models evaluated the impact of preoperative weight change on discharge, operative time, periprosthetic joint infections (PJIs), complications, revisions, and reoperations. The mean follow-up was 6 years. Results: Overall, 20% of patients gained ≥5 pounds (1 pound = 0.45 kg), 39% maintained weight, 17% lost 5 to <10 pounds, 15% lost 10 to <20 pounds, and 9% lost ≥20 pounds before TKA. Male patients lost slightly more weight (−4.6 pounds) than female patients (−4.3 pounds) (p = 0.05). In univariable analyses, gaining >5 pounds was associated with increased odds of extended hospital length of stay (odds ratio [OR], 1.4; p = 0.01) and risk of complications (hazard ratio [HR], 1.7; p < 0.01). Losing 10 to <20 pounds was associated with increased risks of revision (HR, 2.0; p = 0.01), PJI (HR, 3.1; p < 0.01), and complications (HR, 1.6; p = 0.03). In multivariable analyses, compared with maintaining weight, losing 10 to <20 pounds was associated with an increased risk of PJI (HR, 2.6; p = 0.01), whereas gaining >5 pounds was associated with an increased risk of complications (HR, 1.5; p = 0.03). Conclusions: Few patients with obesity lost substantial weight before primary TKA, and reaching common preoperative weight loss goals was not associated with improved outcomes. Although a healthy weight is important for general health, weight loss before TKA may not be sufficient to improve postoperative outcomes for most patients with obesity. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Many surgeons recommend weight loss for patients with obesity before total joint arthroplasty (TJA), but few studies have evaluated weight loss interventions. This study compared weight loss using a remote dietitian and a mobile application (app) with weight loss using standard care for patients with severe obesity before TJA. Methods: This multicenter randomized controlled trial included 60 subjects with a body mass index (BMI) of 40 to 47 kg/m 2 who had been scheduled for primary total hip or knee arthroplasty from September 2019 to January 2023. The mean age was 61 years, 67% were women, and the mean BMI was 44 kg/m 2 . The control subjects (n = 29) received standard care; the intervention subjects (n = 31) completed video calls with dietitians and used a mobile app for 12 weeks preoperatively. Weights and surveys were collected at baseline and 12 weeks, with 87% follow-up. Weight loss, patient-reported outcomes, complications, revisions, and reoperations were compared. The mean follow-up was 1.8 years. Results: The intervention subjects lost more weight (−4.1 versus −2.1 kg, p = 0.22) and had larger decreases in BMI (−1.4 versus −0.9 kg/m 2 , p = 0.36 than the controls, but not significantly so. The intervention subjects had higher odds of achieving a BMI of <40 kg/m 2 (odds ratio = 1.9, p = 0.44), but not significantly so. There were no significant differences in the mean change in the Hip disability and Osteoarthritis Outcome Score, the Knee injury and Osteoarthritis Outcome Score, or the Lower Extremity Activity Scale score. At baseline, only 11% had seen a dietitian in the last 3 months. Most subjects (83%) felt that video calls were helpful. There were no differences in complications between the groups; there was a patellar fracture in the control group and a deep venous thromboembolism in the intervention group. Conclusions: A preoperative weight loss intervention using a dietitian and a mobile app was feasible and viewed favorably among patients. Remote dietitians and mobile apps may address gaps in access to obesity treatment before TJA. While the intervention subjects lost more weight and were more likely to achieve a BMI of <40 kg/m 2 , the differences were not significant. More intensive interventions may be needed to achieve enough weight loss for clinically important improvements in TJA. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Background: Many surgeons use body mass index (BMI) cutoffs when offering total hip arthroplasty (THA). However, little is known about who loses weight before THA, and if weight loss improves outcomes. This study determined how many patients lost weight before primary THA, identified predictors of preoperative weight loss, and evaluated whether preoperative weight loss was associated with improved outcomes. Methods: Among 53,038 primary THAs that were performed between 2002 and 2019, we identified 2,463 patients who had a BMI of ≥30 kg/m 2 (measured 1 to 24 months before surgery) and had their weight measured at the time of surgery. The mean age was 66 years; 47% were women. The mean BMI was 35 kg/m 2 . Nonparametric models evaluated potential associations with weight loss. Univariable and multivariable logistic regression and Cox proportional hazards models evaluated the impact of preoperative weight change on hospital length of stay, discharge disposition, operative time, periprosthetic joint infection (PJI), complications, revision, and reoperation. The mean follow-up was 5 years. Results: Overall, 17% of the patients gained >5 pounds (2.27 kg), 38% maintained their weight, 16% lost 5 to <10 pounds (4.54 kg), 17% lost 10 to <20 pounds (9.07 kg), and 12% lost ≥20 pounds before THA. Only 28% of patients with a preoperative BMI of ≥40 kg/m 2 achieved a BMI of <40 kg/m 2 by the time of surgery; those who did required a mean of 1.3 years to lose the weight. In multivariable analyses, there were no significant improvements in operative time, length of stay, and discharge disposition, or survivorship free of PJI, complication, revision, or reoperation for any weight-loss category when compared with those who maintained their weight. Conclusions: Only 12% of patients lost ≥20 pounds, and only 28% of patients with a BMI of ≥40 kg/m 2 achieved a BMI of <40 kg/m 2 before primary THA. There was no decrease in complications, revisions, or reoperations for any preoperative weight-loss category when compared with those who maintained their weight. While weight loss benefits overall health, the results of this study call into question whether preoperative weight loss alone is enough to reduce postoperative complications for most patients. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine 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 January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR &amp;lt;1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

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; &amp;lt;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 &amp;lt;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

Introduction Current evidence suggests that abnormal ventriculo-vascular coupling may contribute to the development of atrial fibrillation (AF) by increasing ventricular filling pressures and consequently, left atrial pressure. Recent investigations have also suggested that inflammation might have a role in the pathophysiology of AF. We hypothesize that autoimmune vasculitis plays a significant role in the pathogenetic mechanism of AF. Methods In this longitudinal cohort study, residents of Olmsted County, MN with first- time diagnosed AF during 1980-2000 and a reference age- and sex-matched control group from the same underlying population and time period were identified and followed until death, or 2000. The relationship between autoimmune vasculitis and first documented AF was analyzed. Results Of a total of 8766 patients (mean age 61.1+14.9 years; 56% women), 691 (7.9%) were diagnosed with autoimmune vasculitis during the 20 year period. The prevalence of autoimmune vasculitis in the AF group was 9.9% and 5.9% in the control group; p <0.001, respectively. After adjusting for CAD and LV dysfunction, the odds of autoimmune vasculitis in AF was 1.7 times higher than in controls (OR 1.69, 95%; CI 1.42 - 2.01, p < 0.0001). AF patients with autoimmune vasculitis had a worse survival compared to controls; p=.0114 (log-rank test). Conclusion Autoimmune vasculitis strongly increases the risk of atrial fibrillation and portends shorter survival in the AF population. These observations may represent one mechanism linking increased arterial stiffness and inflammation in the pathogenesis and prognosis of AF as an age-related disorder.