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

Connexins in leukocytes: shuttling messages?

Gap junctions, formed by the connexin (Cx) protein family, are intercellular channels that permit the cytoplasmic exchange of ions and small metabolites between neighboring cells, a process called gap junction intercellular communication (GJIC). These channels possess unique properties, including distinctive permeabilities for various signaling molecules, which depend on the connexin member(s) that form them. Importantly, GJIC must be properly controlled as its misregulation might contribute to diseases. Morphological and functional studies have revealed ‘gap junction-like' structures and cell-to-cell communication involving cells of the immune system. The connexins involved in such contacts have been partially identified in recent years. This review focuses on the potential physiological roles of gap junctions in the development and recruitment of leukocytes as well as in the regulation of the immune response. Furthermore, the importance of GJIC in immuno-inflammatory pathologies is illustrated in atherosclerosi

Characterizing Range Anxiety in Electric Vehicle Users

Range Anxiety is the fear of running out of fuel for your car before arriving at a refueling point or final destination. While usually absent or low in gas-powered vehicles, this anxiety is a salient consideration when buying electric vehicles (EVs). This and the fact that there are fewer charging stations available compared to gas stations have been offered as hypotheses for why EV sales are low. Previous research has found that those with more experience driving EVs, felt less range anxiety as they can when and where to charge their vehicle in their daily lives. EVs are more environmentally friendly and safer for the driver, so it important to better understand range anxiety and find ways to mitigate it in order to lift one of the barriers for greater adoption of electric cars. In this study, we plan to provide EV drivers with an EV on low charge. They will be asked to drive around for as long as they feel comfortable, up to 30 minutes. As they are driving, their heart rate and galvanic skin response (a measure of emotional arousal) will be monitored to measure their anxiety as they watch the battery percentage of the electrical vehicle decrease. After driving around in the vehicle, participants will be asked to complete a survey evaluating their habits and their daily use of the vehicle. Some of the questions asked will query the type of electric vehicle they usually drive, their perception of etiquette around unplugging another person’s charging electrical vehicle in a public location if their own battery is low, and how comfortable the person is driving at a low percentage in their electric vehicle. We anticipate seeing an increase in heart rate and galvanic skin response, and therefore range anxiety, as the battery percentage gets lower

Perturbing the Sense of Agency

The goal of this experiment is to test a model of the sense of agency, intention, volition, and causality in order to examine the time course of the sense of agency associated with voluntary and involuntary movements. We examine the roles of context, expectation, and sensory feedback in the feeling of agency as well as examining the aspects of volition in different kinds of decisions. This experiment is thought to be very novel as it stimulates an internal signal for movement from an external source which is why the participant can find it hard to decipher if they are fully in control of their actions or not. The project explores the participants\u27 self-reported level of agency, to see the range and types of precept that emerge among the individuals. It will examine the role of context and expectation and compare different forms of volition and decision. The non-invasive, transcranial magnetic stimulation (TMS) stimulates the motor cortex, intermixing the resultant motor movements with motor movement of the participant’s own volition. TMS is a method of brain stimulation that relies on electromagnetic induction using an insulated coil placed on the scalp, to elevate brain function. The TMS coil will be placed above the scalp in a position that triggers a slight hand movement, the subject will then be instructed to make the same movement at will. It is expected that the participant will report ambiguity when asked whether the movement was due to them or the TMS. There should be an effect on the sense of agency by the TMS especially when it is close to the voluntary movement

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

Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons.

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in the most common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions

Une Perú

Une Perú es un proyecto que se creó con la finalidad de unir a padres de familia con especialistas y profesores que se quedaron sin empleo durante la pandemia. Tenemos el propósito de difundir talleres para niños en temas educativos, artísticos y recreativos para que lleguen a los padres y madres peruanos. El proyecto cuenta con una página web, la cual muestra a detalle los talleres que se brindan y tiene presencia en las redes sociales Facebook e Instagram, ya que son los medios que contribuyen a la difusión y al alcance de nuestro público objetivo. A través de estas se busca establecer una relación cercana y de confianza, que beneficie tanto a los niños y niñas como a los especialistas.Une Perú is a project that was created with the purpose of connecting parents with specialists and teachers who lost their jobs during the pandemic. Our purpose is to spread workshops for children on educational, recreational and artistic topics to reach peruvian parents. The project has a website, which shows in detail the workshops that are offered and has a presence on social networks Facebook and Instagram, as they are the media that contribute to the dissemination and reach of our target audience. Through these we seek to establish a close and trusting relationship that benefits both children and specialists

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

Ataluren treatment of patients with nonsense mutation dystrophinopathy

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double-blind, placebo-controlled study; males ≥5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need

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