Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.

The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial.

Background New York City (NYC) bore the greatest burden of COVID-19 in the United States early in the pandemic. In this case series, we describe characteristics and outcomes of racially and ethnically diverse patients tested for and hospitalized with COVID-19 in New York City’s public hospital system. Methods We reviewed the electronic health records of all patients who received a SARS-CoV-2 test between March 5 and April 9, 2020, with follow up through April 16, 2020. The primary outcomes were a positive test, hospitalization, and death. Demographics and comorbidities were also assessed. Results 22254 patients were tested for SARS-CoV-2. 13442 (61%) were positive; among those, the median age was 52.7 years (interquartile range [IQR] 39.5–64.5), 7481 (56%) were male, 3518 (26%) were Black, and 4593 (34%) were Hispanic. Nearly half (4669, 46%) had at least one chronic disease (27% diabetes, 30% hypertension, and 21% cardiovascular disease). Of those testing positive, 6248 (46%) were hospitalized. The median age was 61.6 years (IQR 49.7–72.9); 3851 (62%) were male, 1950 (31%) were Black, and 2102 (34%) were Hispanic. More than half (3269, 53%) had at least one chronic disease (33% diabetes, 37% hypertension, 24% cardiovascular disease, 11% chronic kidney disease). 1724 (28%) hospitalized patients died. The median age was 71.0 years (IQR 60.0, 80.9); 1087 (63%) were male, 506 (29%) were Black, and 528 (31%) were Hispanic. Chronic diseases were common (35% diabetes, 37% hypertension, 28% cardiovascular disease, 15% chronic kidney disease). Male sex, older age, diabetes, cardiac history, and chronic kidney disease were significantly associated with testing positive, hospitalization, and death. Racial/ethnic disparities were observed across all outcomes. Conclusions and relevance This is the largest and most racially/ethnically diverse case series of patients tested and hospitalized for COVID-19 in New York City to date. Our findings highlight disparities in outcomes that can inform prevention and testing recommendations.

Introduction:Electronic health records (EHRs) offer potential for population health surveillance but EHR-based surveillance measures require validation prior to use. We assessed the validity of obesity, smoking, depression, and influenza vaccination indicators from a new EHR surveillance system, the New York City (NYC) Macroscope. This report is the second in a 3-part series describing the development and validation of the NYC Macroscope. The first report describes in detail the infrastructure underlying the NYC Macroscope; design decisions that were made to maximize data quality; characteristics of the population sampled; completeness of data collected; and lessons learned from doing this work. This second report, which addresses concerns related to sampling bias and data quality, describes the methods used to evaluate the validity and robustness of NYC Macroscope prevalence estimates; presents validation results for estimates of obesity, smoking, depression and influenza vaccination; and discusses the implications of our findings for NYC and for other jurisdictions embarking on similar work. The third report applies the same validation methods described in this report to metabolic outcomes, including the prevalence, treatment and control of diabetes, hypertension and hyperlipidemia.Methods:NYC Macroscope prevalence estimates, overall and stratified by sex and age group, were compared to reference survey estimates for adult New Yorkers who reported visiting a doctor in the past year. Agreement was evaluated against 5 a priori criteria. Sensitivity and specificity were assessed by examining individual EHR records in a subsample of 48 survey participants.Results:Among adult New Yorkers in care, the NYC Macroscope prevalence estimate for smoking (15.2%) fell between estimates from NYC HANES (17.7 %) and CHS (14.9%) and met all 5 a priori criteria. The NYC Macroscope obesity prevalence estimate (27.8%) also fell between the NYC HANES (31.3%) and CHS (24.7%) estimates, but met only 3 a priori criteria. Sensitivity and specificity exceeded 0.90 for both the smoking and obesity indicators. The NYC Macroscope estimates of depression and influenza vaccination prevalence were more than 10 percentage points lower than the estimates from either reference survey. While specificity was > 0.90 for both of these indicators, sensitivity was < 0.70.Discussion:Through this work we have demonstrated that EHR data from a convenience sample of providers can produce acceptable estimates of smoking and obesity prevalence among adult New Yorkers in care; gained a better understanding of the challenges involved in estimating depression prevalence from EHRs; and identified areas for additional research regarding estimation of influenza vaccination prevalence. We have also shared lessons learned about how EHR indicators should be constructed and offer methodologic suggestions for validating them.Conclusions:This work adds to a rapidly emerging body of literature about how to define, collect and interpret EHR-based surveillance measures and...

Background New York City (NYC) has borne the greatest burden of COVID-19 in the United States, but information about characteristics and outcomes of racially/ethnically diverse individuals tested and hospitalized for COVID-19 remains limited. In this case series, we describe characteristics and outcomes of patients tested for and hospitalized with COVID-19 in New York City's public hospital system. Methods We reviewed the electronic health records of all patients who received a SARS-CoV-2 test between March 5 and April 9, 2020, with follow up through April 16, 2020. The primary outcomes were a positive test, hospitalization, and death. Demographics and comorbidities were also assessed. Results 22254 patients were tested for SARS-CoV-2. 13442 (61%) were positive; among those, the median age was 52.7 years (interquartile range [IQR] 39.5-64.5), 7481 (56%) were male, 3518 (26%) were Black, and 4593 (34%) were Hispanic. Nearly half (4669, 46%) had at least one chronic disease (27% diabetes, 30% hypertension, and 21% cardiovascular disease). Of those testing positive, 6248 (46%) were hospitalized. The median age was 61.6 years (IQR 49.7-72.9); 3851 (62%) were male, 1950 (31%) were Black, and 2102 (34%) were Hispanic. More than half (3269, 53%) had at least one chronic disease (33% diabetes, 37% hypertension, 24% cardiovascular disease, 11% chronic kidney disease). 1724 (28%) hospitalized patients died. The median age was 71.0 years (IQR 60.0, 80.9); 1087 (63%) were male, 506 (29%) were Black, and 528 (31%) were Hispanic. Chronic diseases were common (35% diabetes, 37% hypertension, 28% cardiovascular disease, 15% chronic kidney disease). Male sex, older age, diabetes, cardiac history, and chronic kidney disease were significantly associated with testing positive, hospitalization, and death. Racial/ethnic disparities were observed across all outcomes. Conclusions and Relevance This is the largest and most racially/ethnically diverse case series of patients tested and hospitalized for COVID-19 in the United States to date. Our findings highlight disparities in outcomes that can inform prevention and testing recommendations.

OBJECTIVES: To evaluate the impact of ICU surge on mortality and to explore clinical and sociodemographic predictors of mortality. DESIGN: Retrospective cohort analysis. SETTING: NYC Health + Hospitals ICUs. PATIENTS: Adult ICU patients with coronavirus disease 2019 admitted between March 24, and May 12, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hospitals reported surge levels daily. Uni- and multivariable analyses were conducted to assess factors impacting in-hospital mortality. Mortality in Hispanic patients was higher for high/very high surge compared with low/medium surge (69.6% vs 56.4%; p = 0.0011). Patients 65 years old and older had similar mortality across surge levels. Mortality decreased from high/very high surge to low/medium surge in, patients 18–44 years old and 45–64 (18–44 yr: 46.4% vs 27.3%; p = 0.0017 and 45–64 yr: 64.9% vs 53.2%; p = 0.002), and for medium, high, and very high poverty neighborhoods (medium: 69.5% vs 60.7%; p = 0.019 and high: 71.2% vs 59.7%; p = 0.0078 and very high: 66.6% vs 50.7%; p = 0.0003). In the multivariable model high surge (high/very high vs low/medium odds ratio, 1.4; 95% CI, 1.2–1.8), race/ethnicity (Black vs White odds ratio, 1.5; 95% CI, 1.1–2.0 and Asian vs White odds ratio 1.5; 95% CI, 1.0–2.3; other vs White odds ratio 1.5, 95% CI, 1.0–2.3), age (45–64 vs 18–44 odds ratio, 2.0; 95% CI, 1.6–2.5 and 65–74 vs 18–44 odds ratio, 5.1; 95% CI, 3.3–8.0 and 75+ vs 18–44 odds ratio, 6.8; 95% CI, 4.7–10.1), payer type (uninsured vs commercial/other odds ratio, 1.7; 95% CI, 1.2–2.3; medicaid vs commercial/other odds ratio, 1.3; 95% CI, 1.1–1.5), neighborhood poverty (medium vs low odds ratio 1.6, 95% CI, 1.0–2.4 and high vs low odds ratio, 1.8; 95% CI, 1.3–2.5), comorbidities (diabetes odds ratio, 1.6; 95% CI, 1.2–2.0 and asthma odds ratio, 1.4; 95% CI, 1.1–1.8 and heart disease odds ratio, 2.5; 95% CI, 2.0–3.3), and interventions (mechanical ventilation odds ratio, 8.8; 95% CI, 6.1–12.9 and dialysis odds ratio, 3.0; 95% CI, 1.9–4.7) were significant predictors for mortality. CONCLUSIONS: Patients admitted to ICUs with higher surge scores were at greater risk of death. Impact of surge levels on mortality varied across sociodemographic groups.

The over-expression of NF-κB signalling in both muscle and immune cells contribute to the pathology in dystrophic muscle. The anti-inflammatory properties of glucocorticoids, mediated predominantly through monomeric glucocorticoid receptor inhibition of transcription factors such as NF-κB (transrepression), are postulated to be an important mechanism for their beneficial effects in Duchenne muscular dystrophy. Chronic glucocorticoid therapy is associated with adverse effects on metabolism, growth, bone mineral density and the maintenance of muscle mass. These detrimental effects result from direct glucocorticoid receptor homodimer interactions with glucocorticoid response elements of the relevant genes. Compound A, a non-steroidal selective glucocorticoid receptor modulator, is capable of transrepression without transactivation. We confirm the in vitro NF-κB inhibitory activity of compound A in H-2Kb-tsA58 mdx myoblasts and myotubes, and demonstrate improvements in disease phenotype of dystrophin deficient mdx mice. Compound A treatment in mdx mice from 18 days of post-natal age to 8 weeks of age increased the absolute and normalized forelimb and hindlimb grip strength, attenuated cathepsin-B enzyme activity (a surrogate marker for inflammation) in forelimb and hindlimb muscles, decreased serum creatine kinase levels and reduced IL-6, CCL2, IFNγ, TNF and IL-12p70 cytokine levels in gastrocnemius (GA) muscles. Compared with compound A, treatment with prednisolone, a classical glucocorticoid, in both wild-type and mdx mice was associated with reduced body weight, reduced GA, tibialis anterior and extensor digitorum longus muscle mass and shorter tibial lengths. Prednisolone increased osteopontin (Spp1) gene expression and osteopontin protein levels in the GA muscles of mdx mice and had less favourable effects on the expression of Foxo1, Foxo3, Fbxo32, Trim63, Mstn and Igf1 in GA muscles, as well as hepatic Igf1 in wild-type mice. In conclusion, selective glucocorticoid receptor modulation by compound A represents a potential therapeutic strategy to improve dystrophic pathology.

In Duchenne muscular dystrophy (DMD) patients and the mouse model of DMD, mdx, dystrophin deficiency causes a decrease and mislocalization of muscle-specific neuronal nitric oxide synthase (nNOSμ), leading to functional impairments. Previous studies have shown that nitric oxide (NO) donation associated with anti-inflammatory action has beneficial effects in dystrophic mouse models. In this study, we have systematically investigated the effects of naproxcinod, an NO-donating naproxen derivative, on the skeletal and cardiac disease phenotype in mdx mice. Four-week-old mdx and C57BL/10 mice were treated with four different concentrations (0, 10, 21 and 41 mg/kg) of naproxcinod and 0.9 mg/kg of prednisolone in their food for 9 months. All mice were subjected to twice-weekly treadmill sessions, and functional and behavioral parameters were measured at 3, 6 and 9 months of treatment. In addition, we evaluated in vitro force contraction, optical imaging of inflammation, echocardiography and blood pressure (BP) at the 9-month endpoint prior to sacrifice. We found that naproxcinod treatment at 21 mg/kg resulted in significant improvement in hindlimb grip strength and a 30% decrease in inflammation in the fore- and hindlimbs of mdx mice. Furthermore, we found significant improvement in heart function, as evidenced by improved fraction shortening, ejection fraction and systolic BP. In addition, the long-term detrimental effects of prednisolone typically seen in mdx skeletal and heart function were not observed at the effective dose of naproxcinod. In conclusion, our results indicate that naproxcinod has significant potential as a safe therapeutic option for the treatment of muscular dystrophies.