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

Purpose: Fatigue is one of the most common and disabling symptoms experienced by people with inflammatory bowel disease; however, interventions to treat fatigue are limited. The purpose of this systematic review is to examine the relationship between sleep deficiency and fatigue in adults with inflammatory bowel disease and to describe the demographic and clinical factors associated with fatigue to inform future intervention work. Methods: We conducted a systematic review and reported the results using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search was conducted using MEDLINE, EMBASE, PsycINFO, CINAHL, and CENTRAL on 3/7/24. We included studies with adults (≥18 years of age) who had a diagnosis of inflammatory bowel disease (Crohn’s disease, ulcerative colitis, or indeterminate colitis) and measured fatigue and sleep using a validated self-report questionnaire or objective measurement. Results: Twenty-two studies met inclusion criteria for a total sample of 16 927, of whom 58.7% (n = 9937) had Crohn’s disease, and 66.3% (n = 11 226) were female. 56.1% of the participants experienced fatigue and 66.3% experienced sleep deficiency. Sleep quality and insomnia were consistently associated with fatigue. Baseline poor sleep quality was associated with persistent and worsening fatigue over 12 to 24 months. Clinical but not objective assessment of disease activity, anxiety, depression, female gender/sex, and younger age were also associated with more severe fatigue. Conclusions: Sleep quality and insomnia represent important modifiable contributors to fatigue. Future research should explore whether sleep interventions can improve fatigue in this population.

Abstract Background and Aims Individuals with inflammatory bowel disease (IBD) experience a high symptom burden, including abdominal pain, fatigue, anxiety, depression, and sleep disturbances; yet, little is known regarding the relationship between sex and gender on symptoms. We sought to report symptom severity for cisgender men, cisgender women, and transgender and gender-diverse (TGD) individuals. In addition, we used network analysis to identify core symptoms and explore if symptoms and their relationships differ between cisgender men and cisgender women. Methods This was a cross-sectional study. We recruited adults with IBD online through ResearchMatch. Individuals responded to Patient-Reported Outcomes Measurement Information symptom questionnaires, as well as demographic and clinical questionnaires. Network analysis was used to identify the core symptoms driving the symptom structure. Results One-hundred and fifty-seven (63.3%) participants identified as cisgender women, 84 (33.9%) as cisgender men, and 7 (2.8%) as TGD. Cisgender men (M = 61.8) and TGD (M = 61.3) groups reported higher abdominal pain levels compared with cisgender women (M = 57.8; P = .02). Transgender and gender-diverse individuals reported higher depression levels (M = 64.8) compared with cisgender men (M = 56.7) and cisgender women (M = 54.4; P = .01). Using a network analysis approach, anxiety and fatigue emerged as core symptoms for the entire sample (clinically active and inactive disease), and among only those with active clinical disease. Fatigue was a top core symptom for cisgender women; anxiety emerged as a top core symptom for cisgender men. Conclusions This study highlights that fatigue and anxiety are core symptoms among individuals with IBD and demonstrates a potential sex and/or gender difference in core symptoms. Replication of this study is needed with further consideration of inclusion of TGD patients.

Abstract Introduction Inflammatory Bowel Disease (IBD) is a chronic, immune-mediated condition, encompassing Crohn's disease (CD) and ulcerative colitis (UC). Up to 80% of individuals with IBD report poor sleep quality. However, there is limited information on factors that predict sleep characteristics in this population. This study aims to explore the associations between demographic, clinical, and psychological factors with sleep characteristics in adults with IBD. Methods We conducted a retrospective analysis of two IBD sleep studies. Participants aged 18-64 years old with a diagnosis of IBD were recruited from two academic medical centers and completed Patient-Reported Outcomes Measure Information System (PROMIS) depression and anxiety questionnaires and wore a wrist actigraph for 10 days continuously. We employed Independent T-Tests and Pearson’s correlation to assess the association of biologic treatment, IBD type, sex, depression, and anxiety on sleep efficiency (SE), total sleep time (TST), and sleep onset latency (SOL). Results We included 58 participants with a mean age of 35.6 years (SD=12.1). 60.3% were female, and 60.3% were diagnosed with CD. The mean depression score was 51.3 (SD = 10.2) and the anxiety score was 52.2 (SD = 15.5). The mean SOL was 19.3 minutes (SD = 15.5), TST was 413.3 minutes (SD = 53.2), and SE was 83.5% (SD = 5.7). TST was significantly longer in females compared to males (427.4 vs. 391.9 minutes , p< 0.05). SE was significantly higher among females compared to males (85.1% vs. 81.0%, p< 0.001) and among individuals with Crohn's disease compared to Ulcerative colitis ((85.1% vs. 81.0%, p< 0.01). SOL was longer among individuals with Ulcerative colitis compared to Crohn's disease (15.6 vs.25.0minutes , p< 0.05). Depression and anxiety scores were not significantly correlated with any sleep characteristic. Conclusion Sleep continuity was poor in people with IBD. Given that we found sex and IBD type impacted sleep continuity, these factors should be considered in future precision sleep health interventions for this population. Support (if any) This study was funded by the University of Washington School of Nursing, NINR (K23 NR020044) (Kendra Kamp, and the American Nurses Foundation (Samantha Conley).

Abstract Introduction Inflammatory bowel disease (IBD) is a chronic immune-mediated disease that includes Crohn’s disease and ulcerative colitis. People with IBD experience poor sleep health, including short and highly fragmented sleep and extraintestinal manifestations including alterations to cognitive functioning; however, the relationships between sleep health and cognitive symptoms have not been evaluated in this population. The purpose of this study was to identify the associations between sleep health and perceived cognitive impairments in adults with IBD. Methods We conducted a descriptive, correlational study of adults (18 to 59 years old) with IBD. We used the Pittsburgh Sleep Quality Index (PSQI) to obtain self-reported data on sleep health, the FACT-Cog Perceived Cognitive Impairments questionnaire to elicit cognitive symptoms, and the Manitoba IBD Index to describe IBD disease activity. Descriptive statistics, point-biserial correlations, and Pearson’s correlations were used to describe relationships. Results Of the 59 participants [Mean age 40.8 (SD 10.5), 71.2% female, 94.9% white], 67.8% (n=40) had clinically active IBD. 79.7% (n=47) had a PSQI total score >5, indicating poor sleep health. The most common cognitive symptoms, occurring two or more times a week, were trouble concentrating (55.9%), walking into a room and forgetting an intended task (44.1%), and forgetting the names of people soon after being introduced (44.0%). PSQI total score was positively and significantly correlated with 12 of 13 questions on the FACT-Cog. The strongest correlations included trouble concentrating (r = .497, P<.001), slower thinking (r = .450, p<.001), trouble forming thoughts (r=.550, p<.001), and difficulty finding the right words to express oneself (r=.546, p<.001). Longer self-reported sleep latency was associated with higher frequency of 12 out of 13 cognitive symptoms, while sleep efficiency was associated with 4 and sleep duration was associated with 2. Having clinically active IBD was associated with trouble forming thoughts (r=-.261, p=.046), slower thinking (r=-.307, p=.018), and trouble concentrating (r=-.346, p=.007). Conclusion Cognitive symptoms are common among people with IBD, highly correlated with sleep health, and not fully explained by IBD disease activity. Future studies should include objective measures of sleep health and cognition to further elucidate these relationships. Support (if any) Mayo Clinic Bonner Fund

Background The objective of this international multicenter study was to investigate both early and late outcomes of cardiac resynchronization therapy (CRT) in patients with a systemic right ventricle (SRV) and to identify predictors for congestive heart failure readmissions and mortality. Methods and Results This retrospective international multicenter study included 13 centers. The study population comprised 80 adult patients with SRV (48.9% women) with a mean age of 45±14 (range, 18–77) years at initiation of CRT. Median follow‐up time was 4.1 (25th–75th percentile, 1.3–8.3) years. Underlying congenital heart disease consisted of congenitally corrected transposition of the great arteries and dextro‐transposition of the great arteries in 63 (78.8%) and 17 (21.3%) patients, respectively. CRT resulted in significant improvement in functional class (before CRT: III, 25th–75th percentile, II–III; after CRT: II, 25th–75th percentile, II–III; P =0.005) and QRS duration (before CRT: 176±27; after CRT: 150±24 milliseconds; P =0.003) in patients with pre‐CRT ventricular pacing who underwent an upgrade to a CRT device (n=49). These improvements persisted during long‐term follow‐up with a marginal but significant increase in SRV function (before CRT; 30%, 25th–75th percentile, 25–35; after CRT: 31%, 25th–75th percentile, 21–38; P =0.049). In contrast, no beneficial change in the above‐mentioned variables was observed in patients who underwent de novo CRT (n=31). A quarter of all patients were readmitted for heart failure during follow‐up, and mortality at latest follow‐up was 21.3%. Conclusions This international experience with CRT in patients with an SRV demonstrated that CRT in selected patients with SRV dysfunction and pacing‐induced dyssynchrony yielded consistent improvement in QRS duration and New York Heart Association functional status, with a marginal increase in SRV function.

ObjectiveSystemic lupus erythematosus (SLE) is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study sought to identify optimal immune mediators informing an empirically refined flare risk index (FRI) reflecting altered immunity prior to clinical disease flare.MethodsThirty‐seven SLE‐associated plasma mediators were evaluated by microfluidic immunoassay in 46 samples obtained in SLE patients with an imminent clinical disease flare (preflare) and 53 samples obtained in SLE patients without a flare over a corresponding period (pre‐nonflare). SLE patients were selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting the American College of Rheumatology 1997 revised criteria for SLE or the Systemic Lupus International Collaborating Clinics 2012 revised criteria for SLE). Autoantibody specificities, hybrid SLE Disease Activity Index (hSLEDAI) scores, clinical features, and medication usage were also compared at preflare (mean ± SD 111 ± 47 days prior to flare) versus pre‐nonflare (99 ± 21 days prior to nonflare) time points. Variable importance was determined by random forest analysis with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI.ResultsPreflare versus pre‐nonflare differences were not associated with demographics, autoantibody specificities, hSLEDAI scores, clinical features, nor medication usage. Forward selection and backward elimination of mediators ranked by variable importance resulted in 17 plasma mediator candidates differentiating preflare from pre‐nonflare visits. A final combination of 11 mediators best informed a newly refined FRI, which achieved a maximum sensitivity of 97% and maximum specificity of 98% after applying decision curve analysis to define low, medium, and high FRI scores.ConclusionWe verified altered immune mediators associated with imminent disease flare, and a subset of these mediators improved the FRI to identify SLE patients at risk of imminent flare. This molecularly informed, proactive management approach could be critical in prospective clinical trials and the clinical management of lupus.

Leucine-rich repeat containing (LRR) proteins facilitate protein-protein interactions critical in a number of cellular functions including ion channel regulation. Leucine-rich repeat containing protein 10 (LRRC10), a cardiac-specific protein expressed in zebrafish, mice and humans, is essential for normal cardiac physiology with loss of Lrrc10 in Lrrc10 -/- mice resulting in dilated cardiomyopathy (DCM). However, the mechanism by which LRRC10 contributes to DCM is unknown. Further, the functional role of LRRC10 in the regulation of ion channels in the heart has not been explored. Here we recorded L-type Ca 2+ channel currents (I Ca,L ) from isolated ventricular myocytes of WT and Lrrc10 -/- mice, demonstrating a significant reduction in I Ca,L in Lrrc10 -/- myocytes (-4.9 ± 0.19 pA/pF, n=10) compared to WT (-6.5 ± 0.24 pA/pF, n=8). Co-immunoprecipitation (co-IP) experiments showed an association between LRRC10 and Ca v 1.2 in WT, but not Lrrc10 -/- mouse lysates, with immunocytochemistry studies further demonstrating colocalization of LRRC10 and Ca v 1.2 in isolated ventricular myocytes from wild-type (WT) mice. Additionally, whole exome sequencing revealed a novel homozygous recessive missense variant in LRRC10 , I195T, found in a pediatric DCM patient. To determine whether the I195T variant impacts Ca v 1.2 L-type Ca 2+ channels, whole-cell patch clamp experiments were performed using HEK293 cells transiently expressing the L-type Ca 2+ channel complex (LTCC) alone or with WT or I195T LRRC10. These electrophysiology experiments demonstrated a significant increase in I Ca,L with WT LRRC10 coexpression (-81 ± 5.3 pA/pF, n=12), but a decrease in I Ca,L when I195T (-18.2 ± 3.3 pA/pF, n=9) was coexpressed compared to the LTCC alone (-34.1 ± 2.2 pA/pF, n=17). Parallel surface biotinylation experiments demonstrated that WT and I195T LRRC10 did not alter L-type Ca 2+ channel expression on the plasma membrane, while co-IP experiments using lysates prepared from the transiently transfected HEK293 cells showed the association between Ca v 1.2 and I195T LRRC10 variant. Overall, these findings newly identify LRRC10 as a cardiac-specific component of the Ca v 1.2 macromolecular complex and demonstrate dysregulation of I Ca,L by the DCM associated I195T LRRC10 variant.