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ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

Background: Clinical management guidelines (CMGs) are decision support tools for patient care used by professionals, patients, and family caregivers. Since clinical experts develop numerous CMGs, their technical language hinders comprehension and access by nonmedical stakeholders. Additionally, the views of affected individuals and their families are often not incorporated into treatment guidelines. We developed an adequate methodology for addressing the needs and preferences of family and professional stakeholders regarding CMGs, a recently developed protocol for managing congenital disorders of glycosylation (CDG), a family of rare metabolic diseases. We used the CDG community and phosphomannomutase 2 (PMM2)-CDG CMGs as a pilot to test and implement our methodology. Results: We listened to 89 PMM2-CDG families and 35 professional stakeholders and quantified their CMG-related needs and preferences through an electronic questionnaire. Most families and professionals rated CMGs as relevant (86.5% and 94.3%, respectively), and valuable (84.3% and 94.3%, respectively) in CDG management. The most identified challenges were the lack of CMG awareness (50.6% of families) and the lack of plain language CMG (39.3% of professionals). Concordantly, among families, the most suggested solution was involving them in CMG development (55.1%), while professionals proposed adapting CMGs to include plain language (71.4%). Based on these results, a participatory framework built upon health literacy principles was created to improve CMG comprehension and accessibility. The outputs are six complementary CMG-related resources differentially adapted to the CDG community’s needs and preferences, with a plain language PMM2-CDG CMG as the primary outcome. Additionally, the participants established a distribution plan to ensure wider access to all resources. Conclusions: This empowering, people-centric methodology accelerates CMG development and accessibility to all stakeholders, ultimately improving the quality of life of individuals living with a specific condition and raising the possibility of application to other clinical guidelines.

Abstract Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.

Abstract Background Obesity, defined by the World Health Organization (WHO) as a BMI greater than 30k g/m2, has reached epidemic proportions worldwide, related to approximately 2.8 million deaths/year as of June 2021. WHO sub-classifies obesity based on BMI in Class 1: 30–34.9 kg/m2, Class 2: 35–39.9 kg/m2, and Class 3: ≥40 kg/m2. This state of increased body weight is associated with an increased risk of cardiovascular disease. Cardiac remodeling can be affected by obesity and/or other cardiovascular risk factors (CVRF) as an adaptive physiological response. The remodeling patterns, Normal Geometry (NG), Concentric Remodeling (CR), Concentric Hypertrophy (CH), and Eccentric Hypertrophy, are classified by changes in Relative Wall Thickness (RWT), ≤ or >0.42, and/or Left Ventricular Mass Index (LVMI g/m2), ≤ or >88 for women and ≤ or >102 for men. Left Ventricular Ejection Fraction (LVEF) can remain within normal limits in patients with obesity with multiple CVRF and cardiac remodeling. Left Ventricular Global Longitudinal Strain (LV-GLS) and Right ventricular free wall strain (RV-FWS) can be useful to detect subclinical myocardial dysfunction. The aim of this study was to evaluate if these strain variables are affected in patients with obesity associated to other CVRF in relation to cardiac remodeling type when compared to controls. Methods 2859 patients with BMI ≥30 kg/m2 and 2616 normal-weight controls (BMI between 18.5 and 24.9 kg/m2), with normal and abnormal cardiac geometry, and normal ejection fraction by echocardiography performed between 01/01/2008 and 12/31/2018, were compared. Obesity was classified based on the World Health Organization. CVRF included were Hypertension (HTN), Diabetes Mellitus (DM), Dyslipidemia, history of Vascular Event (myocardial infarction and/or stroke), and Obstructive sleep apnea (OSA). Results BMI, cardiac geometry, CVRF, and the number of comorbidities independently affected GLS and RV-FWS (Figure 1 and Figure 2). LV-GLS and RV-FWS values [mean (SD)] in obesity classes 1, 2, and 3 were −19 (2.9), −18.9 (2.9), −18.7 (2.9) & −24.2 (5.2), −23.8 (6.2), −24.5 (5.9), respectively. In the control group LV-GLS and RV-FWS values [mean (SD)] were −20.1 (3.0) & −27 (5.6), respectively. CH was associated with the greatest decrease in LV-GLS and RV-FWS in males and females, regardless of BMI (Figure 2). LV-GLS values [mean (SD)] associated to CH for obesity class 1, 2, and 3, and controls in females were −18.4 (3.4), −18 (3.1) −17.6 (3.6), and −17.8 (4), respectively, and for obesity class 1, 2, and 3, and controls in males were −16.1 (3.5), 16.5 (3.2), −14.4 (2.7), and −16.6 (4.7), respectively (Figure 1). Conclusion Obesity associated to CVRF and CH have the lowest values of GLS in patients with normal ejection fraction. These values were exceedingly below average compared to other groups. These parameters should be used as reference values for this population. Funding Acknowledgement Type of funding sources: None.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase ( IDH) –mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1 R132H -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

419 Background: The patient portal is part of an electronic health record (EHR) that allows patients to communicate with their healthcare team. The portal also provides a platform for patients to receive and complete symptom surveys that can be directly integrated into the EHR, allowing clinical care teams to monitor symptoms and provide cancer symptom management. The Improving Management of symPtoms during And following Cancer Treatment (IMPACT) consortium, supported by the National Cancer Institute’s Cancer MoonshotSM, aims to improve symptom control for cancer patients through assessment and symptom management interventions deployed via the EHR. This initiative presents an opportunity to examine portal enrollment and variation in use, factors critical to successful implementation, especially among groups that have high cancer symptom burden. To this end, we examine: 1) relationships between portal enrollment prior to the launch of IMPACT interventions and neighborhood broadband access, demographic, and social characteristics; and 2) frequency of pre-intervention portal use for any purpose among enrollees. Methods: Data are derived from two of three IMPACT research centers. Enrollment in and frequency of portal use, mode of accessing the portal (web vs. phone), social, demographic, and cultural factors were extracted from the EHR. Rural Urban Commuting Area (RUCA) codes were used to classify population density and degree of rurality. Broadband access was estimated using 2015-2019 American Community Survey estimates matched to zip codes from enrolled IMPACT patients and classified as a patient’s residence being in a community with high (≥85% of households) or low (< 85% of households) access. Bivariate comparisons and adjusted odds ratios were used to describe all associations. Results: Forty-seven percent of patients (22,596/48,034) were enrolled in the portal prior to the intervention. Patients in zip codes with low broadband access and those who were men, > 65 years old, not White, of Hispanic ethnicity, or disabled or not employed had significantly lower odds of being enrolled in the portal. If enrolled, 21% (n = 4825) used the portal at least once a week. Less variation was found in the average frequency of portal use, but patients younger than 40, and those who were Black, disabled, unemployed, or those who used a mobile device to access the portal had the lowest odds of accessing it at least once a week. Conclusions: Significant disparities in portal enrollment exist across demographic groups and among those with limited broadband access. Among those enrolled, most used the portal less than once a week. Fewer differences in frequency of use were observed by sociodemographic factors. Improving portal enrollment and frequency of use may be critical for symptom management interventions deployed via patient portals.