Spirometry Correlates with Physical Activity in Patients with Duchenne Muscular Dystrophy

Background: Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness and respiratory decline. To date, studies have focused on respiratory decline and loss of ambulation as a metric of loss of skeletal muscle strength. However, new functional measures can assess skeletal muscle disease regardless of ambulatory status. The relationship between these tests and concurrent lung function is currently unexplored. Objective: To assess the correlation between spirometry measurements and functional muscle assessments such as accelerometry and quantitative muscle testing (QMT). Methods: Enrolled patients with DMD underwent accelerometry and QMT at study clinic visits. Any pulmonary function testing within 6 months of visit was obtained from the electronic medical record. The Spearman correlation coefficient was used to assess the relationship between spirometry and functional muscle testing. Results: Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 ) demonstrated the strongest correlation with accelerometry. Both FVC and FEV1 showed a similar relationship to accelerometry when activity was divided into intensity categories, with low intensity and moderate-to-vigorous activity categories showing the strongest correlation. Maximal expiratory pressure (MEP) and FVC showed the most robust correlations with total QMT (p < 0.001 and p < 0.01, respectively). Conclusion: Lung function, specifically FVC percent predicted and FEV1 %p, shows a good correlation with upper and lower extremity skeletal muscle functional testing such as accelerometry and QMT

Leveraging Cardiac Magnetic Resonance Imaging to Assess Skeletal Muscle Progression in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is characterized by muscle deterioration and progressive weakness. As a result, patients with DMD have significant cardiopulmonary morbidity and mortality that worsens with age and loss of ambulation. Since most validated muscle assessments require ambulation, new functional measures of DMD progression are needed. Despite several evaluation methods available for monitoring disease progression, the relationship between these measures is unknown. We sought to assess the correlation between imaging metrics obtained from cardiac magnetic resonance imaging (CMR) and functional assessments including quantitative muscle testing (QMT), spirometry, and accelerometry. Forty-nine patients with DMD were enrolled and underwent CMR, accelerometry and QMT at baseline, 1-year and 2-year clinic visits with temporally associated pulmonary function testing obtained from the medical record. Imaging of the upper extremity musculature (triceps and biceps) demonstrated the most robust correlations with accelerometry (p<0.03), QMT (p<0.02) and spirometry (p<0.01). T1-mapping of serratus anterior muscle showed a similar, but slightly weaker relationship with accelerometry and QMT. T2-mapping of serratus anterior demonstrated weak indirect correlation with aspects of accelerometry. These images are either routinely obtained in standard CMR or can be added to a protocol and may allow for a more comprehensive assessment of a patient’s disease progression

Prescribing cholinesterase inhibitors in mild cognitive impairment-Observations from the Alzheimer's Disease Neuroimaging Initiative

Introduction: Analyses of off-label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI-treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI-) subjects while accounting for baseline differences. Methods: We selected 121 ADNI MCI AChEI+ subjects and 151 AChEI- subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI- also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI-) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI- FDG PET and MRI data. Results: At baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI- subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI- subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid-positive and have lower GMD and FDG standardized uptake value ratio than AChEI- at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status. Discussion: Our data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects

Longitudinal profiling of the intestinal microbiome in children with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor

ABSTRACTThe intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores the function of the pathogenic mutated CF transmembrane conductance regulator (CFTR) channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in body mass index and percent predicted forced expiratory volume in one second, and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus, the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.IMPORTANCECystic fibrosis (CF) is an autosomal recessive disease with significant gastrointestinal symptoms in addition to pulmonary complications. Recently approved treatments for CF, CF transmembrane conductance regulator (CFTR) modulators, are anticipated to substantially improve the care of people with CF and extend their lifespans. Prior work has shown that the intestinal microbiome correlates with health outcomes in CF, particularly in children. Here, we study the intestinal microbiome of children with CF before and after the CFTR modulator, ELX/TEZ/IVA. We identify promising improvements in microbiome diversity, reduced measures of intestinal inflammation, and reduced antibiotic resistance genes. We present specific bacterial taxa and protein groups which change following ELX/TEZ/IVA. These results will inform future mechanistic studies to understand the microbial improvements associated with CFTR modulator treatment. This study demonstrates how the microbiome can change in response to a targeted medication that corrects a genetic disease

Improving rural health care reduces illegal logging and conserves carbon in a tropical forest.

Tropical forest loss currently exceeds forest gain, leading to a net greenhouse gas emission that exacerbates global climate change. This has sparked scientific debate on how to achieve natural climate solutions. Central to this debate is whether sustainably managing forests and protected areas will deliver global climate mitigation benefits, while ensuring local peoples' health and well-being. Here, we evaluate the 10-y impact of a human-centered solution to achieve natural climate mitigation through reductions in illegal logging in rural Borneo: an intervention aimed at expanding health care access and use for communities living near a national park, with clinic discounts offsetting costs historically met through illegal logging. Conservation, education, and alternative livelihood programs were also offered. We hypothesized that this would lead to improved health and well-being, while also alleviating illegal logging activity within the protected forest. We estimated that 27.4 km2 of deforestation was averted in the national park over a decade (∼70% reduction in deforestation compared to a synthetic control, permuted P = 0.038). Concurrently, the intervention provided health care access to more than 28,400 unique patients, with clinic usage and patient visitation frequency highest in communities participating in the intervention. Finally, we observed a dose-response in forest change rate to intervention engagement (person-contacts with intervention activities) across communities bordering the park: The greatest logging reductions were adjacent to the most highly engaged villages. Results suggest that this community-derived solution simultaneously improved health care access for local and indigenous communities and sustainably conserved carbon stocks in a protected tropical forest

Climate and urbanization drive changes in the habitat suitability of Schistosoma mansoni competent snails in Brazil

Abstract Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Schistosoma are obligate parasites of freshwater Biomphalaria and Bulinus snails, thus controlling snail populations is critical to reducing transmission risk. As snails are sensitive to environmental conditions, we expect their distribution is significantly impacted by global change. Here, we used machine learning, remote sensing, and 30 years of snail occurrence records to map the historical and current distribution of forward-transmitting Biomphalaria hosts throughout Brazil. We identified key features influencing the distribution of suitable habitat and determined how Biomphalaria habitat has changed with climate and urbanization over the last three decades. Our models show that climate change has driven broad shifts in snail host range, whereas expansion of urban and peri-urban areas has driven localized increases in habitat suitability. Elucidating change in Biomphalaria distribution—while accounting for non-linearities that are difficult to detect from local case studies—can help inform schistosomiasis control strategies