Adrenal suppression from vamorolone and prednisone in Duchenne muscular dystrophy: results from the phase 2b clinical trial.

CONTEXT: Vamorolone, a novel "dissociative" steroid, demonstrated similar efficacy in muscle function relative to prednisone 0.75 mg/kg/day but improved linear growth and bone turnover markers in a randomized trial of pediatric Duchenne muscular dystrophy (DMD). OBJECTIVES: To determine the frequency of adrenal suppression (AS) induced by vamorolone and prednisone in pediatric DMD, and to assess cortisol thresholds using a monoclonal antibody immunoassay. METHODS: Post-hoc analysis of cortisol levels was performed on data from a randomized, double-blind, placebo- and prednisone-controlled 24-week trial of vamorolone with a 24-week crossover extension. Morning and ACTH-stimulated cortisol levels were measured using the Elecsys II immunoassay, with AS defined as a stimulated cortisol of <500nmol/L ("historical threshold") and <400nmol/L ("revised threshold"). RESULTS: Mean age at enrolment was 5.41±0.86 years (N=118). At Week 24, proportion of participants with AS using the historical and revised cortisol thresholds, respectively, were as follows: prednisone 0.75 mg/kg/day=100% (25/25) and 92.0% (23/25); vamorolone 6 mg/kg/day=95.2% (20/21) and 90.5% (19/21); vamorolone 2 mg/kg/day=84.2% (16/19) and 47.5% (9/19); and placebo=20.0% (4/20) and 0% (0/20). Morning and peak ACTH-stimulated cortisol were strongly correlated in steroid-treated boys (Spearman correlation week 48=0.83). CONCLUSIONS: AS after vamorolone and prednisone was frequent and vamorolone-associated AS appeared dose-dependent. A lower stimulated cortisol threshold may be appropriate when using a monoclonal assay. We recommend hydrocortisone for glucocorticoid stress dosing in patients receiving vamorolone.

Modelling lifespan reduction in an exogenous damage model of generic disease.

We model the effects of disease and other exogenous damage during human aging. Even when the exogenous damage is repaired at the end of acute disease, propagated secondary damage remains. We consider both short-term mortality effects due to (acute) exogenous damage and long-term mortality effects due to propagated damage within the context of a generic network model (GNM) of individual aging that simulates a U.S. population. Across a wide range of disease durations and severities we find that while excess short-term mortality is highest for the oldest individuals, the long-term years of life lost are highest for the youngest individuals. These appear to be universal effects of human disease. We support this conclusion with a phenomenological model coupling damage and mortality. Our results are consistent with previous lifetime mortality studies of atom bomb survivors and post-recovery health studies of COVID-19. We suggest that short-term health impact studies could complement lifetime mortality studies to better characterize the lifetime impacts of disease on both individuals and populations.

Rapid implementation of virtual clinics due to COVID-19: report and early evaluation of a quality improvement initiative.

BACKGROUND: The COVID-19 outbreak has placed the National Health Service under significant strain. Social distancing measures were introduced in the UK in March 2020 and virtual consultations (via telephone or video call) were identified as a potential alternative to face-to-face consultations at this time. LOCAL PROBLEM: The Royal National Orthopaedic Hospital (RNOH) sees on average 11 200 face-to-face consultations a month. On average 7% of these are delivered virtually via telephone. In response to the COVID-19 crisis, the RNOH set a target of reducing face-to-face consultations to 20% of all outpatient attendances. This report outlines a quality improvement initiative to rapidly implement virtual consultations at the RNOH. METHODS: The COVID-19 Action Team, a multidisciplinary group of healthcare professionals, was assembled to support the implementation of virtual clinics. The Institute for Healthcare Improvement approach to quality improvement was followed using the Plan-Do-Study-Act (PDSA) cycle. A process of enablement, process redesign, delivery support and evaluation were carried out, underpinned by Improvement principles. RESULTS: Following the target of 80% virtual consultations being set, 87% of consultations were delivered virtually during the first 6 weeks. Satisfaction scores were high for virtual consultations (90/100 for patients and 78/100 for clinicians); however, outside of the COVID-19 pandemic, video consultations would be preferred less than 50% of the time. Information to support the future redesign of outpatient services was collected. CONCLUSIONS: This report demonstrates that virtual consultations can be rapidly implemented in response to COVID-19 and that they are largely acceptable. Further initiatives are required to support clinically appropriate and acceptable virtual consultations beyond COVID-19. REGISTRATION: This project was submitted to the RNOH's Project Evaluation Panel and was classified as a service evaluation on 12 March 2020 (ref: SE20.09).

Plant identity and shallow soil moisture are primary drivers of stomatal conductance in the savannas of Kruger National Park.

Our goal was to describe stomatal conductance (gs) and the site-scale environmental parameters that best predict gs in Kruger National Park (KNP), South Africa. Dominant grass and woody species were measured over two growing seasons in each of four study sites that represented the natural factorial combination of mean annual precipitation [wet (750 mm) or dry (450 mm)] and soil type (clay or sand) found in KNP. A machine-learning (random forest) model was used to describe gs as a function of plant type (species or functional group) and site-level environmental parameters (CO2, season, shortwave radiation, soil type, soil moisture, time of day, vapor pressure deficit and wind speed). The model explained 58% of the variance among 6,850 gs measurements. Species, or plant functional group, and shallow (0-20 cm) soil moisture had the greatest effect on gs. Atmospheric drivers and soil type were less important. When parameterized with three years of observed environmental data, the model estimated mean daytime growing season gs as 68 and 157 mmol m-2 sec-1 for grasses and woody plants, respectively. The model produced here could, for example, be used to estimate gs and evapotranspiration in KNP under varying climate conditions. Results from this field-based study highlight the role of species identity and shallow soil moisture as primary drivers of gs in savanna ecosystems of KNP.