Citations

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

Abstract Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8–negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm–driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have “oligocentric” lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.

Abstract To propose a novel entity of possible intraosseous pseudoprogression in clival chordoma following proton radiation therapy (PRT). A total of 38 consecutive patients who underwent surgical resection followed by PRT for clival chordoma between January 2015 and December 2023 were analyzed retrospectively. Follow-up magnetic resonance imaging (MRI) suggesting recurrence or progression was evaluated for validity. Apparent diffusion coefficient (ADC) and tumor-to-brainstem signal intensity ratio on contrast-enhanced T1-weighted imaging (Rce) were assessed. Pseudoprogression was defined as (1) MRI signs of recurrence or progression with no pathological confirmation despite obtaining a specimen, or (2) MRI signs of recurrence or regression with spontaneous resolution/regression. Of the 11 patients with MRI findings suggestive of recurrence or progression, 3 were diagnosed with recurrence, 5 with progression, and 3 with pseudoprogression. Patients with pseudoprogression were significantly younger than those with progression (p = 0.04), and all were female. The median time to recurrence, progression, and pseudoprogression was 31, 29, and 21 months, respectively. The three pseudoprogression cases were managed with gross-total resection followed by stereotactic radiosurgery, extensive biopsy, and observation, respectively. Although statistical significance was not reached, ADC (p = 0.33) and Rce (p = 0.13) tended to be higher in pseudoprogression cases. After PRT for clival chordoma, intraosseous pseudoprogression should be considered in the differential diagnosis, particularly in relatively young female patients, although the role of ADC and Rce on MRI remains inconclusive. Multidisciplinary teams managing chordomas should take this into account when determining the aggressiveness of treatment in such cases.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity and mortality and are associated with acute cardiac events in the peripartum period, as well as cardiovascular disease later in life. Despite the robust association between hypertension and atrial fibrillation (AFib), comparatively little is known about HDP and its subtypes as sex-specific risk factors for AFib. METHODS: A population-based retrospective cohort study was conducted, including 771 521 nulliparous women discharged for obstetrical delivery of their first live or stillborn singleton infant between 2002 and 2017 in Ontario, Canada. Data were obtained from record-level, coded, and linked population-based administrative databases housed at ICES. Using competing risks Cox proportional hazards regression, we estimated crude and multivariable-adjusted cause-specific hazard ratios and 95% CIs for associations between history of any HDP (and its 6 subtypes), and AFib before death, as well as all-cause mortality without a previous AFib diagnosis. RESULTS: Approximately 8% of women were diagnosed with HDP during the 16-year exposure accrual period. The total person-time of follow-up was 7 380 304 person-years, during which there were 2483 (0.3%) incident AFib diagnoses and 2951 (0.4%) deaths. History of any HDP was associated with an increased cause-specific hazard ratios of incident AFib and death without a previous AFib diagnosis (adjusted cause-specific hazard ratios, 1.45 [95% CI, 1.28–1.64] and 1.31 [95% CI, 1.16–1.47], respectively). These associations were observed in relatively young women (median time to event, 7 years postpartum). Associations suggestive of a dose-response relationship were observed, with more severe HDP subtypes and prepregnancy chronic hypertension associated with a 1.5 to 2.2 times higher cause-specific rate of AFib, and a 1.4 to 2.1 times higher cause-specific rate of death compared with no hypertension in pregnancy. CONCLUSIONS: Women exposed to HDP in their first delivery have a significantly increased cause-specific hazard ratios of incident AFib compared to their unexposed counterparts, with higher rates observed in subjects exposed to more severe de novo HDP diagnoses as well as chronic hypertension in pregnancy. These findings underscore the need to consider HDP history in risk calculation/stratification for arrhythmic and nonarrhythmic cardiovascular diseases, improve surveillance of traditional and female-specific cardiovascular disease risk factors, and develop targeted prevention strategies to reduce the occurrence and burden of HDP.

Abstract The prevalence of steatotic liver disease (SLD) is rising globally, presenting a significant public health challenge. While non-contrast computed tomography (CT) scans hold promise for the opportunistic detection of SLD, their full potential has not been systematically explored. Clinical indicators, such as serum data, are crucial for monitoring the progression of SLD. We introduce a novel Multimodal AI for Opportunistic Steatotic Liver Disease Screening (MAOSS), which integrates demographic data, serum tests, conventional CT biomarkers, and deep learning-derived CT image features to enhance model performance and explainability. MAOSS employs an innovative learning strategy, trained on a large-scale dataset (n = 1,783) encompassing both histopathologically-confirmed SLD and radiologically-reported steatosis cases. The model underwent extensive retrospective validation using steatosis grades derived from both histology and MRI-PDFF across internal and external datasets (n = 913), as well as real-world patient data (n = 18,504). It accurately detected mild to severe steatosis (≥ S1) with AUCs ranging from 0.903 to 0.929. Notably, MAOSS significantly improved the overall AUC for radiologists (n = 11) from 0.709 to 0.798 (p < 0.001). Furthermore, MAOSS was applied to optimize the standard clinical pathway for a simulated primary risk screening of SLD patients (n = 1,192), resulting in the identification of 31% more patients at risk of steatohepatitis and liver fibrosis progression, highlighting its potential to enhance SLD detection and management.

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.