Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy

Aim: Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials and methods: Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] \u3e /=300- \u3c 400 or \u3c 400 m). Meta-analyses examined 6MWD change from baseline to week 48. Results: Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2-34.1) m, p = 0.0473; \u3e/=300- \u3c 400 m (n = 143), +43.9 (18.2-69.6) m, p = 0.0008; \u3c 400 m (n = 216), +27.7 (6.4-49.0) m, p = 0.0109. Conclusion: These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD \u3e /=300- \u3c 400 m (the ambulatory transition phase), thereby informing future trial design

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

Clinical Study Socioeconomic Factors Affect Disparities in Access to Liver Transplant for Hepatocellular Cancer

Objective. The incidence/death rate of hepatocellular cancer (HCC) is increasing in America, and it is unclear if access to care contributes to this increase. Design/Patients. 575 HCC cases were reviewed for demographics, education, and tumor size. Main Outcome Measures. Endpoints to determine access to HCC care included whether an eligible patient underwent liver transplantation. Results. Transplant patients versus those not transplanted were younger (55.7 versus 61.8 yrs, P < 0.001), males (89.3% versus 74.4%, P = 0.013), and having completed high school (10.1% versus 1.2%, P = 0.016). There were differences in transplant by ethnicity, insurance, and occupation. Transplant patients with HCC had higher median income via census classification ($54,383 versus$49,383, P = 0.046) and self-reported income ($48,948 versus$38,800, P = 0.002). Differences in access may be related to exclusion criteria for liver transplant, as Pacific Islanders were more likely to have tumor size larger than 5 cm compared to Whites and have BMI > 35 (20.7%) compared to Whites (6.4%) and Asians (4.7%). Conclusions. Ethnic differences in access to transplant are associated with socioeconomic status and factors that can disqualify patients (advanced disease/morbid obesity). Efforts to overcome educational barriers and screening for HCC could improve access to transplant

Empirical Bayes accomodation of batch-effects in microarray data using identical replicate reference samples: application to RNA expression profiling of blood from Duchenne muscular dystrophy patients

<p>Abstract</p> <p>Background</p> <p>Non-biological experimental error routinely occurs in microarray data collected in different batches. It is often impossible to compare groups of samples from independent experiments because batch effects confound true gene expression differences. Existing methods can correct for batch effects only when samples from all biological groups are represented in every batch.</p> <p>Results</p> <p>In this report we describe a generalized empirical Bayes approach to correct for cross-experimental batch effects, allowing direct comparisons of gene expression between biological groups from independent experiments. The proposed experimental design uses identical reference samples in each batch in every experiment. These reference samples are from the same tissue as the experimental samples. This design with tissue matched reference samples allows a gene-by-gene correction to be performed using fewer arrays than currently available methods. We examine the effects of non-biological variation within a single experiment and between experiments.</p> <p>Conclusion</p> <p>Batch correction has a significant impact on which genes are identified as differentially regulated. Using this method, gene expression in the blood of patients with Duchenne Muscular Dystrophy is shown to differ for hundreds of genes when compared to controls. The numbers of specific genes differ depending upon whether between experiment and/or between batch corrections are performed.</p

The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation

We thank Cowen lab members for helpful discussions. We also thank David Rogers (University of Tennessee) for sharing microarray analysis of the CAS5 homozygous mutant, and Li Ang (University of Macau) for assistance in optimizing the ChIP-Seq experiments. J.L.X. is supported by a Canadian Institutes of Health Research Doctoral award and M.D.L. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust 096072). B.T.G. holds an Ontario Graduate Scholarship. C.B. and B.J.A. are supported by the Canadian Institutes of Health Research Foundation Grants (FDN-143264 and -143265). D.J.K. is supported by a National Institute of Allergy and Infectious Diseases grant (1R01AI098450) and J.D.L.C.D. is supported by the University of Rochester School of Dentistry and Medicine PREP program (R25 GM064133). A.S. is supported by the Creighton University and the Nebraska Department of Health and Human Services (LB506-2017-55). K.H.W. is supported by the Science and Technology Development Fund of Macau S.A.R. (FDCT; 085/2014/A2). L.E.C. is supported by the Canadian Institutes of Health Research Operating Grants (MOP-86452 and MOP-119520), the Natural Sciences and Engineering Council (NSERC) of Canada Discovery Grants (06261 and 462167), and an NSERC E.W.R. Steacie Memorial Fellowship (477598).Peer reviewedPublisher PD

Motifs, themes and thematic maps of an integrated Saccharomyces cerevisiae interaction network

BACKGROUND: Large-scale studies have revealed networks of various biological interaction types, such as protein-protein interaction, genetic interaction, transcriptional regulation, sequence homology, and expression correlation. Recurring patterns of interconnection, or 'network motifs', have revealed biological insights for networks containing either one or two types of interaction. RESULTS: To study more complex relationships involving multiple biological interaction types, we assembled an integrated Saccharomyces cerevisiae network in which nodes represent genes (or their protein products) and differently colored links represent the aforementioned five biological interaction types. We examined three- and four-node interconnection patterns containing multiple interaction types and found many enriched multi-color network motifs. Furthermore, we showed that most of the motifs form 'network themes' – classes of higher-order recurring interconnection patterns that encompass multiple occurrences of network motifs. Network themes can be tied to specific biological phenomena and may represent more fundamental network design principles. Examples of network themes include a pair of protein complexes with many inter-complex genetic interactions – the 'compensatory complexes' theme. Thematic maps – networks rendered in terms of such themes – can simplify an otherwise confusing tangle of biological relationships. We show this by mapping the S. cerevisiae network in terms of two specific network themes. CONCLUSION: Significantly enriched motifs in an integrated S. cerevisiae interaction network are often signatures of network themes, higher-order network structures that correspond to biological phenomena. Representing networks in terms of network themes provides a useful simplification of complex biological relationships

Electrical impedance myography for reducing sample size in Duchenne muscular dystrophy trials

OBJECTIVE: To evaluate the sensitivity of electrical impedance myography (EIM) to disease progression in both ambulatory and non-ambulatory boys with DMD. METHODS AND PARTICIPANTS: A non-blinded, longitudinal cohort study of 29 ambulatory and 15 non-ambulatory boys with DMD and age-similar healthy boys. Subjects were followed for up to 1 year and assessed using the Myolex((R)) mView(TM) EIM system as part of a multicenter study. RESULTS: In the ambulatory group, EIM 100 kHz resistance values showed significant change compared to the healthy boys. For example, in lower extremity muscles, the average change in EIM 100 kHz resistance values over 12 months led to an estimated effect size of 1.58. Based on these results, 26 DMD patients/arm would be needed for a 12-month clinical trial assuming a 50% treatment effect. In non-ambulatory boys, EIM changes were greater in upper limb muscles. For example, biceps at 100kHz resistance gave an estimated effect size of 1.92 at 12 months. Based on these results, 18 non-ambulatory DMD patients/arm would be needed for a 12-month clinical trial assuming a 50% treatment effect. Longitudinal changes in the 100 kHz resistance values for the ambulatory boys correlated with the longitudinal changes in the timed supine-to-stand test. EIM was well-tolerated throughout the study. INTERPRETATION: This study supports that EIM 100 kHz resistance is sensitive to DMD progression in both ambulatory and non-ambulatory boys. Given the technology\u27s ease of use and broad age range of utility it should be employed as an exploratory endpoint in future clinical therapeutic trials in DMD. TRIAL REGISTRATION: Clincialtrials.gov registration #NCT02340923

Prognostic factors for changes in the timed 4-stair climb in patients with Duchenne muscular dystrophy, and implications for measuring drug efficacy: A multi-institutional collaboration

The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children\u27s Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls

Moving Beyond the 2018 Minimum International Care Considerations for Osteoporosis Management in Duchenne Muscular Dystrophy (DMD)

Individuals living with Duchenne muscular dystrophy (DMD) are at significant risk of bone fragility due to osteoporosis, with the most potent drivers of fragility fractures in this context stemming from the aggressive myopathy and long term oral glucocorticoid therapy. Young people with DMD have a high fracture burden, with reported total and vertebral fracture rates that are four [1, 2] and 535 times [1] higher than those of healthy growing boys, respectively. Vertebral fractures can occur as early as six months following daily glucocorticoid initiation [3]. Up to 75% of young people with DMD sustain at least one fracture after eight years of glucocorticoid therapy [4]. Fractures in DMD can lead to devastating outcomes, including steeper rates of functional decline, premature and permanent loss of ambulation, chronic pain, and even death from fat embolism syndrome or adrenal crisis following long bone fractures [2, 5–8]. The potential for serious consequences and medical complications linked to fractures has driven efforts to develop effective guidelines for timely bone health surveillance and treatment with more recent efforts to develop fracture prevention strategies.To guide clinicians in the management of DMD and its related co-morbidities (including skeletal health), the first internationally-endorsed, minimum standards of care were published in 2010 under the moniker “Clinical Care Considerations” [9, 10]. This document recommends that osteoporosis monitoring include spine x-rays if back pain or kyphosis is present, followed by initiation of intravenous bisphosphonate therapy if vertebral fractures are identified [10]. In the years following the inaugural 2010 Clinical Care Considerations, studies were published showing that vertebral fractures, a key manifestation of bone fragility among children and adults living with glucorticoid-treated chronic conditions, were frequently asymptomatic, necessitating routine surveillance for early detection [3, 11]. It was also better appreciated that even a single long bone fracture can signal osteoporosis in a persistently high-risk setting such as DMD, and prompt initiation of bone protection therapy is important.With this new knowledge, the latest international, minimum standards of clinical care for DMD published in 2018, known as Care Considerations [12–14], recommended routine, standardized spine imaging for early detection of vertebral fractures, combined with more timely bone-targeted (bisphosphonate) intervention in the presence of vertebral or low trauma long bone fractures [12]. At the same time, the ever-changing therapeutic landscape for the treatment of the underlying condition calls for ongoing examination of the intimate relationship between muscle and bone development in DMD, including the effect of different DMD treatment approaches on the skeletal and endocrine systems. The overall goal of such focus is to harvest discussions about optimal management that will foster bone strength and prevent fractures in this high-risk setting across all underlying disease-targeted treatment paradigms for people with DMD

Moving beyond the 2018 minimum international care considerations for osteoporosis management in duchenne muscular dystrophy (DMD): Meeting report from the 3rd International Muscle-Bone Interactions Meeting 7th and 14th November 2022

This current manuscript summarizes the proceedings of the “Third Muscle-bone interactions in Duchenne Muscular Dystrophy Symposium: Moving Beyond the 2018 Minimum International Standards of Care for Osteoporosis Management”, an event co-organized by the World Duchenne Organization (www.worldduchenne.org) and the International Conference on Children’s Bone Health (www.theiscbh.org). This virtual symposium, held on November 7th and 14th 2022, brought together a total of 385 delegates representing 55 countries registered for the symposium, which included 239 clinicians, 70 researchers, 40 patient representatives and others from pharmaceutical companies and regulators. This symposium aimed to review the evidence base that informed the 2018 international minimum Care Considerations, best practices for implementation of these Care Considerations, and emerging knowledge that has arisen from research since the 2018 Care Considerations that shines light on the path forward. The online symposium and this report cover the following areas: 1. Current understanding of the bone morbidity in DMD, especially in relation to conventional glucocorticoid therapy. 2. The published, 2018 minimum international Care Considerations for osteoporosis monitoring and management in DMD. 3. Real world initiatives and challenges in the implementation of the 2018 minimum international Care Considerations for osteoporosis monitoring and management in DMD. 4. The need to consider strategies to move beyond the 2018 minimum international Care Considerations to prevent first fractures in DMD. 5. New therapies in DMD with potential impact on skeletal outcomes