Real-world outcomes of long-term prednisone and deflazacort use in patients with Duchenne muscular dystrophy: experience at a single, large care center

Aim: To assess outcomes among patients with Duchenne muscular dystrophy receiving deflazacort or prednisone in real-world practice. Methods: Clinical data for 435 boys with Duchenne muscular dystrophy from Cincinnati Children\u27s Hospital Medical Center were studied retrospectively using time-to-event and regression analyses. Results: Median ages at loss of ambulation were 15.6 and 13.5 years among deflazacort- and prednisone-initiated patients, respectively. Deflazacort was also associated with a lower risk of scoliosis and better ambulatory function, greater % lean body mass, shorter stature and lower weight, after adjusting for age and steroid duration. No differences were observed in whole body bone mineral density or left ventricular ejection fraction. Conclusion: This single center study adds to the real-world evidence associating deflazacort with improved clinical outcomes

An ultra-sensitive biosensor based on surface plasmon resonance and weak value amplification

An ultra-sensitive phase plasmonic sensor combined with weak value amplification is proposed for the detection of IgG, as a model analyte. Phase detection is accomplished by self-interference between the p-polarization and the s-polarization of the light. With the principles of weak value amplification, a phase compensator is used to modulate the coupling strength and enhance the refractive index sensitivity of the system. On a simple Au-coated prism-coupled surface plasmon resonance (SPR) structure, the scheme, called WMSPR, achieves a refractive index sensitivity of 4.737 × 104 nm/RIU, which is about three times higher than that of the conventional phase-based approach. The proposed WMSPR biosensor gives great characteristics with a high resolution of 6.333 × 10−8 RIU and a low limit of detection (LOD) of 5.3 ng/mL. The results yield a great scope to promote the optimization of other SPR biosensors for high sensitivity

Transcriptomics of Gabra4 knockout mice reveals common NMDAR pathways underlying autism, memory, and epilepsy

Autism spectrum disorder (ASD) is a neuronal developmental disorder with impaired social interaction and communication, often with abnormal intelligence and comorbidity with epilepsy. Disturbances in synaptic transmission, including the GABAergic, glutamatergic, and serotonergic systems, are known to be involved in the pathogenesis of this disorder, yet we do not know if there is a common molecular mechanism. As mutations in the GABAergic receptor subunit gene GABRA4 are reported in patients with ASD, we eliminated the Gabra4 gene in mice and found that the Gabra4 knockout mice showed autistic-like behavior, enhanced spatial memory, and attenuated susceptibility to pentylenetetrazol-induced seizures, a constellation of symptoms resembling human high-functioning autism. To search for potential molecular pathways involved in these phenotypes, we performed a hippocampal transcriptome profiling, constructed a hippocampal interactome network, and revealed an upregulation of the NMDAR system at the center of the converged pathways underlying high-functioning autism-like and anti-epilepsy phenotypes

Case-control study on fragility fractures in coal miners: A comparison between surface and underground workers

BackgroundThe prevalence of osteoporosis and osteopenia is higher among underground coal miners than surface workers. The special underground work environment and unhealthy habits such as smoking, drinking, and a high-salt diet may lead to changes in bone metabolism, increasing the risk of fragility fractures and placing a heavy economic burden on individuals and society. ObjectiveTo identify potential factors influencing fragility fractures among coal miners in different working environments and to provide a basis for targeted preventive measures to reduce the occurrence of fragility fractures.MethodsMale participants who attended at least one of the physical examinations in Kailuan Group between June 2006 and December 2020 were included in the study. The participants were divided into two groups based on their working environment: surface or underground. A case-control study was conducted, where patients with new fragility fractures served as the case group and participants without fragility fractures served as the control group. The two groups were matched with a case:control ratio of 1:4 by age (±1 year) and the same year of physical examination. The matching process was repeated twice, once for the surface working population and once for the underground working population. The analysis of risk factors was conducted using conditional logistic regression models.ResultsAmong a total of 113138 employees in Kailuan Group, 82631 surface workers and 30507 underground workers were included, respectively. The number of individuals who suffered fragility fractures was 1375, accounting for 1.22% of the total population. The incidence of fragility fractures in underground workers was significantly higher than that in surface workers (1.63%>1.07%, P<0.001). The results of conditional logistic regression model showed that current smoking (OR=1.26, 95%CI: 1.05, 1.51), manual labor (OR=1.37, 95%CI: 1.06, 1.78), diabetes (OR=1.26, 95%CI: 1.04, 1.54), sinus tachycardia (OR=1.81, 95%CI: 1.23, 2.66), history of stroke (OR=1.51, 95%CI: 1.09, 2.09), education at college and above (OR=0.65, 95%CI: 0.45, 0.95), high income level (OR=0.69, 95%CI: 0.54, 0.90), elevated hemoglobin (OR=0.91, 95%CI: 0.85, 0.98), and elevated total cholesterol (OR=0.90, 95%CI: 0.82, 0.99) were associated with fragility fractures in the surface working population of coal mines; current smoking (OR=1.48, 95%CI: 1.17, 1.87), current drinking (OR=1.26, 95%CI: 1.01, 1.56), manual labor (OR=2.64, 95%CI: 1.41, 4.94), history of dust exposure (OR=1.28, 95%CI: 1.03, 1.58), and obesity (OR=0.72, 95%CI: 0.52, 0.96) were associated with fragility fractures in the underground working population of coal mines.ConclusionIn preventing fragility fractures, special attention should be paid to the bone health of underground workers engaged in manual labor or having a history of dust exposure. It is important to correct their unhealthy behaviors in a timely manner, such as smoking and drinking, and to appropriately increase body weight to prevent fragility fractures. For surface workers, particular attention should be given to the high-risk group for fragility fractures, such as low family income per capita, manual labor, and having a history of stroke or diabetes; in addition, close monitoring of their resting heart rate, hemoglobin levels, and total cholesterol levels may help prevent fragility fractures

Molecular characterization of methicillin-resistant and -susceptible Staphylococcus aureus recovered from hospital personnel

Introduction Methicillin resistant Staphylococcus aureus (MRSA) is one of the major causes of hospital acquired infections. Over the past two decades MRSA has become ‘epidemic’ in many hospitals worldwide. However, little is known about the genetic background of S. aureus recovered from hospital personnel in China. Aim The aim of this study was to determine the genetic diversity of MRSA and methicillin susceptible S. aureus (MSSA) recovered from hospital personnel in Tianjin, North China. Methodology Three hundred and sixty-eight hand or nasal swabs were collected from 276 hospital personnel in four tertiary hospitals in Tianjin, North China between November 2017 and March 2019. In total, 535 gram-positive bacteria were isolated, of which 59 were identified as S. aureus. Staphylococcal cassette chromosome mec (SCCmec) typing, multi-locus sequence typing (MLST) and spa typing were performed to determine molecular characteristics of S. aureus. Results Thirty-one out of 276 (11%) hospital personnel were S. aureus carriers, whereas 11/276 (4%) carried MRSA. Fifty out of 59 (85%) of S. aureus isolates were resistant or intermediate resistant to erythromycin. The dominant genotypes of MRSA recovered from hospital personnel were ST398-t034-SCCmecIV/V, and ST630-t084/t2196, whereas major genotypes of MSSA included ST15-t078/t084/t346/t796/t8862/ t8945/t11653 and ST398-t189/t034/ t078/t084/t14014. Conclusion Although, the predominant genotypes of MRSA recovered from hospital personnel in this study were different from those main genotypes that have previously been reported to cause infections in Tianjin and in other geographic areas of China, the MRSA ST398-t034 genotype has previously been reported to be associated with livestock globally. The dominant MSSA genotypes recovered from hospital personnel were consistent with those previously reported MSSA genotypes recovered from the clinic. The diversity of S. aureus genotypes warrantee further surveillance and genomic studies to better understand the relatedness of these bacteria with those recovered from patients and community

Dual-energy X-ray absorptiometry measures of lean body mass as a biomarker for progression in boys with Duchenne muscular dystrophy

We evaluated whether whole-body dual-energy X-ray absorptiometry (DXA) measures of lean body mass can be used as biomarkers for disease progression and treatment effects in patients with Duchenne muscular dystrophy. This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD. DXA measures of lean body mass were obtained from the whole body (excluding head), arms, legs and appendicular skeleton at baseline and every 16 weeks. Treatment effects on DXA measures for domagrozumab versus placebo were assessed at Week 49. At Week 49, domagrozumab statistically significantly increased lean body mass versus placebo in the appendicular skeleton (p = 0.050) and arms (p < 0.001). The relationship between lean body mass at Week 49 and functional endpoints at Week 97 was evaluated. Changes in lean body mass at Week 49 in all regions except arms were significantly correlated with percent change from baseline in 4-stair climb (4SC) at Week 97. DXA-derived percent lean mass at Week 49 also correlated with 4SC and North Star Ambulatory Assessment at Week 97. These data indicate that whole-body DXA measures can be used as biomarkers for treatment effects and disease progression in patients with DMD, and warrant further investigation.Trial registration: ClinicalTrials.gov, NCT02310763; registered 8 December 2014

Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014

DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials

BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients to untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. METHODS: Over 1,600 patient-years of follow-up (>700 patients) were studied from six real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51 or 53, other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-meter walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. RESULTS: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for non-genotypic prognostic factors. DISCUSSION: These findings suggest viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multi-genotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in the present study

Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls

Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean ΔNSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0 -0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ΔNSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD