Citations

Abstract Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2-4 weeks. A wrist-worn activity monitor (ActiGraph's Insight Watch) or an ankle-worn activity monitor (Modus' StepWatch) was used continuously by each participant. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcomes development.

Abstract Purpose: To explore the role of NBN as a pan-cancer susceptibility gene. Experimental Design: Matched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and presumed pathogenic germline variants (PGV) identified. Allele-specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation. Results: We identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4–5.5; P = 0.0024; pan-cancer], including lung and pancreatic tumors compared with breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR = 2.22; CI: 1.3–3.6; P = 0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared with controls in the European population (OR = 1.9; CI: 1.3–2.7; P = 0.0004), a finding confirmed in the replication cohort (OR = 1.8; CI: 1.2–2.6; P = 0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation. Conclusions: Burden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.

AbstractBackgroundDisruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function.MethodsColon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites.ResultsColitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre).ConclusionsDisruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota–derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (<18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

AbstractIntroductionThere is some evidence that social media interventions can promote smoking cessation. This randomized controlled pilot study is the first to evaluate the feasibility and potential efficacy of a Facebook smoking cessation intervention among Alaska Native (AN) adults.Aims and MethodsRecruitment and data collection occurred from December 2019 to March 2021. Participants were recruited statewide in Alaska using Facebook advertisements with a targeted sample of 60 enrolled. Participants were stratified by gender, age, and rural or urban residence and randomly assigned to receive referral resources on evidence-based cessation treatments (EBCTs) (control, n = 30) or these resources plus a 3-month, closed (private), culturally tailored, Facebook group (intervention, n = 31) that connected participants to EBCT resources and was moderated by two Alaska Native Trained Tobacco Specialists. Assessments were conducted online post-randomization at 1, 3, and 6 months. Outcomes were feasibility (recruitment, retention, and intervention engagement), self-reported use of EBCTs, and biochemically confirmed seven-day point-prevalence smoking abstinence.ResultsOf intervention participants, 90% engaged (eg posted, commented) more than once. Study retention was 57% at 6 months (no group differences). The proportion utilizing EBCTs was about double for intervention compared with the control group participants at 3 and 6 months. Smoking abstinence was higher for intervention than control participants at 3 months (6.5% vs. 0%, p = .16) but comparable at 6 months (6.4% vs. 6.7%, p = .97).ConclusionsWhile additional research is needed to promote long-term cessation, this pilot trial supports recruitment feasibility during the Coronavirus Disease 2019 (COVID-19) pandemic, consumer uptake, and a signal for intervention efficacy on the uptake of cessation treatment and short-term smoking abstinence.ImplicationsThis study is the first evaluation of a social media intervention for smoking cessation among Indigenous people. We learned that statewide Facebook recruitment of AN adults who smoke was feasible and there was a signal for the efficacy of a Facebook intervention on the uptake of EBCT and short-term (3 months) biochemically verified smoking abstinence. Clinically, social media platforms may complement current care models by connecting AN individuals and others living in hard-to-reach communities to cessation treatment resources.

7006 Background: Measurable residual disease (MRD) prior to allogeneic hematopoietic cell transplantation (alloHCT) is associated with increased relapse and death in patients with acute myeloid leukemia (AML) in cytomorphological complete remission (CR). We recently demonstrated AML MRD detected in pre-alloHCT blood by DNA-sequencing was associated with increased relapse and decreased overall survival in patients randomized to reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC). The clinical utility of such ultra-deep next-generation sequencing (NGS-MRD) had not yet been reported in a large multi-center cohort. Methods: Patients aged 18 or older who underwent first alloHCT between 2013-2017 for AML in first CR (CR1), reported to be FLT3, NPM1, IDH1, IDH2 and/or Kit mutated at diagnosis, with a pre-conditioning remission blood sample available in the CIBMTR biobank were eligible for this study. Ultra-deep anchored multiplex PCR-based NGS-MRD for the above mutations was performed on 500ng gDNA with error-corrected variant calling as previously described. The pre-specified statistical analysis plan was registered on OSF. Results: Of 457 patients with a sample available, 448 had sufficient clinical annotation and DNA for analysis. 147 of these 448 patients (33%) experienced relapse at a median of 5.6 months post-alloHCT. NGS-MRD was positive in 129 pre-alloHCT patient samples (29%), averaging 1.35 mutation(s)/patient (range: 1-4). 173 mutations were detected with a median VAF of 0.18% (range: 0.0054-62%), most frequently FLT3-ITD (n = 43 patients), NPM1 (n = 48), and IDH2 (n = 46). Testing positive by NGS-MRD prior to alloHCT was associated with a 3yr RFS of 36% (95% CI: 28-45%) compared with 56% (51-62%) in those testing negative (p < 0.001). Detection of NPM1 and/or FLT3-ITD mutations prior to alloHCT was associated with a 3yr relapse probability of 55% (43-67%) and RFS of 26% (16-37%). NGS-MRD impact was modified by conditioning intensity: positive patients receiving RIC/NMA had the highest relapse of 57% at 3yr, testing negative followed by RIC/NMA had the same relapse rate at 3yr (35%) as those who tested positive but received MAC (p < 0.001). At three years, those positive for FLT3-ITD and/or NPM1 mutations prior to RIC/NMA alloHCT had a relapse probability of 67% (50-83%) with a RFS of 19% (8-33%). HR for relapse if NGS-MRD positive pre-alloHCT in CR1 was 2.3 (p < 0.001, 95% CI 1.6-3.1) when adjusting for conditioning intensity and age group. Conclusions: In this largest cohort of NGS-MRD testing prior to alloHCT for AML reported to date, we confirm the ability to identify patients in CR1 but at high-risk of subsequent relapse. This evidence provides the foundation for future precision medicine approaches to reduce post-transplant AML relapse.

Background: Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, although it is unclear whether this reduction occurs due to blood pressure control or class-specific pleiotropic effects, such as improved beat-to-beat arterial pressure variability with calcium channel blockers. The goal of this study was to investigate the influence of antihypertensive medication class, particularly with calcium channel blocker, on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. Methods: We completed an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), a large randomized controlled trial of participants who completed a baseline and 4-year follow-up brain magnetic resonance image with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the magnetic resonance images. A percentage of follow-up time participants were prescribed each of the 11 classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between 2 scans and, to address skew, dichotomized into a top tertile of the distribution compared with the remaining. Results: Among 448 individuals, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 versus 65.7±7.3 years; P <0.001) and systolic blood pressure (128.3±11.0 versus 126.2±9.4 mm Hg; P =0.039). Seventy-two (48.3%) of the top tertile cohort and 177 (59.2%) of the remaining cohort were in the intensive blood pressure arm. Those within the top tertile of progression had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL ( P <0.001). Use of angiotensin-converting enzyme inhibitors (odds ratio, 0.36 [95% CI, 0.16–0.79]; P =0.011) and dihydropyridine calcium channel blockers (odds ratio, 0.39 [95% CI, 0.19–0.80]; P =0.011) was associated with less WMH progression, although dihydropyridine calcium channel blockers lost significance when WMH was treated as a continuous variable. Conclusions: Among participants of SPRINT-MIND trial, angiotensin-converting enzyme inhibitor was most consistently associated with less WMH progression independent of blood pressure control and age.

In America, Black adults are 30% more likely to die from cardiovascular disease (CVD) compared to White adults, and more than half of this racial disparity in CVD‐related mortality may be attributed to the substantially greater prevalence of high blood pressure (BP) in Black adults. Furthermore, compared to White adults with hypertension, Black adults with hypertension are less likely to exhibit a nocturnal reduction in BP (i.e., “dipping”). Importantly, non‐dipping BP is associated with target organ damage and increased CVD risk. However, it is unclear whether young and apparently healthy Black adults exhibit reduced BP dipping compared to their White peers. PURPOSE Therefore, the purpose of this preliminary investigation was to determine whether there are racial differences in BP dipping using ambulatory BP monitoring (ABPM), including 24‐hour‐, daytime‐, and nighttime‐BP, in young and apparently healthy Black and White adults. METHODS We obtained clinical BP and 24‐hour ABPM readings in 10 self‐identified White adults (5M/5F; age: 21.6±4.4 yrs; BMI: 23.8±2.9 kg/m 2 ; Mean±SD) and 7 self‐identified Black adults (3M/4F; age: 21.7±3.5 yrs; BMI: 25.1±2.8 kg/m 2 ). The ABPM monitors were programmed to record BP every 20 and 30 minutes during each participants daytime‐ and nighttime‐period, respectively. True daytime‐ and nighttime‐BP periods were adjusted during analysis based upon participant activity logs. We defined “non‐dipping” as a failure to achieve a dipping ratio of <0.90 (night‐to‐day BP ratio). BP data were compared using independent t‐tests and the Fisher’s exact test was used to compare dipping frequency between races (α=0.05). RESULTS Clinically measured BP (systolic/diastolic) was not different (P>0.05) between White (117±9/67±6 mmHg) and Black (124±12/70±9 mmHg) adults. There was also no difference (P>0.05) in 24‐hour‐BP between White (117±11/66±7 mmHg) and Black (114±14/63±7 mmHg) adults. Likewise, daytime‐BP was not different (P>0.05) between White (122±12/71±8 mmHg) and Black (116±14/66±8 mmHg) participants, nor was there a difference in nighttime‐BP (P>0.05) between White (102±9/51±4 mmHg) and Black (105±13/54±7 mmHg) adults. However, systolic BP dipping was attenuated (P=0.04) in Black (0.90±0.05) compared to White (0.84±0.07) adults. Non‐dipping of systolic BP was observed in 5 of 7 Black participants and 2 of 10 White participants (P=0.06). Diastolic BP dipping in Black adults was 0.79±0.06 and White adults was 0.73±0.09 (P=0.05). Non‐dipping of diastolic BP was observed in 1 of 7 Black participants and 1 of 10 White participants (P=1.00). CONCLUSIONS These preliminary data suggest that despite similar clinical and 24‐hour ambulatory BP compared to White adults, young and apparently healthy Black adults exhibit impaired BP dipping, which may contribute to increased likelihood of CVD.

Insufficiency or irregularity in sleep is associated with high blood pressure (BP) and aortic stiffness, both of which are independent predictors of all‐cause and cardiovascular mortality. The cardiovascular ramifications of short and irregular sleep are well documented in shift workers, but the health implications of possible differences between sleep duration on workdays (WD) and free days (FD) in non‐shift workers is less clear. PURPOSE We sought to examine associations between WD and FD sleep duration, and then to inspect for relationships between WD and FD sleep duration, as well as the difference between WD and FD sleep duration (i.e., sleep irregularity), with BP and indices of arterial stiffness in apparently healthy young adults. We hypothesized 1) participants would sleep less on WD than FD, and 2) that participants with short WD sleep duration would exhibit higher BP and arterial stiffness, and 3) those with greater sleep irregularity would exhibit higher BP and arterial stiffness. METHODS 16 apparently healthy young adults (21.8±4.0 yrs; 24.4±2.9 kg/m 2 ; Mean±SD) participated in this study. All participants completed the Munich ChronoType Questionnaire to assess self‐described WD and FD sleep‐wake behavior. WD and FD sleep duration were determined, and sleep irregularity was quantified as the absolute value of the difference between WD and FD sleep duration. Following 10‐min of supine rest, we used an automated oscillometric device (SphygmoCor XCEL) to measure BP and augmentation index (AIx), an indirect measure of arterial stiffness. Aortic stiffness was then assessed using carotid‐femoral pulse wave velocity (cf‐PWV). WD and FD sleep duration were compared using a paired t‐test and associations between sleep with BP and indices of arterial stiffness were assessed using Pearson correlations, or the non‐parametric equivalent for sleep irregularity. RESULTS WD sleep duration was 492±85 min, FD sleep duration was 480±83 min, and sleep irregularity was 53±49 min. Systolic BP was 120±10 mmHg, diastolic BP was 68±7 mmHg, AIx was 10.9±9.8 %, and cf‐PWV was 5.8±0.7 m/s. WD sleep duration was significantly greater (P<0.01) than FD sleep duration, and WD sleep duration was not associated (P>0.05) with systolic BP (r=0.10), diastolic BP (r=0.10), AIx (r=0.07), or cf‐PWV (r=‐0.18). FD sleep duration was inversely correlated with cf‐PWV (r=‐0.65; P=0.01), but was not associated (P>0.05) with systolic BP (r=‐0.12), diastolic BP (r =‐0.08), or AIx (r=0.25). Sleep irregularity was not associated (P>0.05) with systolic BP (r=0.37), diastolic BP (r=0.45), AIx (r=0.08), or cf‐PWV (r=0.14). CONCLUSIONS Contrary to our hypothesis, FD, but not WD, sleep duration was associated with aortic stiffness in apparently healthy young adults. Average sleep duration of our cohort exceeded the recommended minimum of 7 hours per night and sleep irregularity was small (i.e., <60 min on average), thus potentially masking elevations in BP and arterial stiffness seen with short and/or irregular sleep such as in shift workers.