The humanistic burden of Pompe disease: are there still unmet needs? A systematic review

Background: Humanistic burden considers the impact of an illness on a patient's health-related quality of life (HRQoL), activities of daily living (ADL), caregiver health, and caregiver QoL. Humanistic burden also considers treatment satisfaction and adherence to treatment regimens. Pompe disease is an autosomal recessive, progressive, multisystemic neuromuscular disease. Approval of enzyme-replacement therapy (ERT) markedly improved prognosis for patients, but considerable morbidity and a substantial humanistic burden remain. This article characterizes the humanistic burden of Pompe disease through a systematic literature review. Methods: A systematic search of MEDLINE (R) and Embase (R) with back-referencing and supplementary literature searches was performed to retrieve data from interventional and non- interventional studies on the humanistic burden of Pompe disease. Publications were screened according to predefined criteria, extracted, and assessed for quality. Extracted data were narratively synthesized. Results: No publications on the humanistic burden of infantile-onset Pompe disease (IOPD) were identified. As such, of 17 publications included here, all are in patients with late-onset Pompe disease (LOPD). Thirteen publications were initiated after approval of ERT, two were initiated before, and two overlapped the approval of ERT. The review shows that LOPD patients have a significantly lower HRQoL than the general population, even if treated with ERT. On transitioning to ERT, treatment was associated with improvement in the physical component score of the SF-36 and fatigue, although the SF-36 mental component score remained stable. Physical HRQoL remained below population norms after 4 years of ERT. Significantly more ERT-treated patients reported pain than controls, and bodily pain worsened in later years following ERT initiation. Treatment-naive LOPD patients had significantly poorer ADL functioning compared with the general population, although ERT stabilized deteriorating functioning impairment. ERT studies showed caregivers provide 17.7 h/week informal care on average. Fifty percent, 40% and <20% of caregivers reported mental health, physical health, and financial/relational problems, respectively. In ERT-naive patients, wheelchair use and home ventilatory support was associated with lower physical HRQoL and ADL functioning. In ERT-treated patients, key factors predicting worse HRQoL and ADL functioning were higher respiratory distress, poorer sleep quality, greater pain, and more fatigue. Conclusions: Pompe disease has a substantial humanistic burden, with strong inter-relationships among and between humanistic burden parameters and clinical progression

Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review With Cross-Species Comparisons

X-linked myotubular myopathy (XLMTM) is a devastating, rare, congenital myopathy caused by mutations in the MTM1 gene, resulting in a lack of or dysfunction of the enzyme myotubularin. This leads to severe perinatal weakness and distinctive muscle pathology. It was originally thought that XLMTM was related to developmental arrest in myotube maturation; however, the generation and characterization of several animal models have significantly improved our understanding of clinical and pathological aspects of this disorder. Myotubularin is now known to participate in numerous cellular processes including endosomal trafficking, excitation-contraction coupling, cytoskeletal organization, neuromuscular junction structure, autophagy, and satellite cell proliferation and survival. The available vertebrate models of XLMTM, which vary in severity from complete absence to reduced functional levels of myotubularin, recapitulate features of the human disease to a variable extent. Understanding how pathological endpoints in animals with XLMTM translate to human patients will be essential to interpret preclinical treatment trials and translate therapies into human clinical studies. This review summarizes the published animal models of XLMTM, including those of zebrafish, mice, and dogs, with a focus on their pathological features as compared to those seen in human XLMTM patients

Baseline values from the electrocardiograms of children and adolescents with ADHD

<p>Abstract</p> <p>Background</p> <p>An important issue in pediatric pharmacology is the determination of whether medications affect cardiac rhythm parameters, in particular the QT interval, which is a surrogate marker for the risk of adverse cardiac events and sudden death. To evaluate changes while on medication, it is useful to have a comparison of age appropriate values while off medication. The present meta-analysis provides baseline ECG values (i.e., off medication) from approximately 6000 children and adolescents with attention-deficit/hyperactivity disorder (ADHD).</p> <p>Methods</p> <p>Subjects were aged 6–18 years and participated in global trials within the atomoxetine registration program. Patients were administered a 12-lead ECG at study screening and cardiac rhythm parameters were recorded. Baseline QT intervals were corrected for heart rate using 3 different methods: Bazett's, Fridericia's, and a population data-derived formula.</p> <p>Results</p> <p>ECG data were obtained from 5289 North American and 641 non-North American children and adolescents. Means and percentiles are presented for each ECG measure and QTc interval based on pubertal status as defined by age and sex. Prior treatment history with stimulants and racial origin (Caucasian) were each associated with significantly longer mean QTc values.</p> <p>Conclusion</p> <p>Baseline ECG and QTc data from almost 6000 children and adolescents presenting with ADHD are provided to contribute to the knowledge base regarding mean values for pediatric cardiac parameters. Consistent with other studies of QT interval in children and adolescents, Bazett correction formula appears to overestimate the prevalence of prolonged QTc in the pediatric population.</p

Recommendations for the use of sapropterin in phenylketonuria

Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. Until recently, the only treatment for PKU was a Phe-restricted diet. Increasing evidence of suboptimal outcomes in diet-treated individuals, inconsistent PKU management practices, and the recent availability of tetrahydrobiopterin (BH(4)) therapy have fueled the need for new management and treatment recommendations for this metabolic disorder. BH(4), now available as sapropterin dihydrochloride (sapropterin), may offer the potential for improved metabolic control as well as enhanced dietary Phe tolerance in some PKU patients. A group of metabolic dietitians from North America convened in June 2011 to draft recommendations for the use of sapropterin therapy in PKU. Physicians with extensive experience in PKU management were invited at a later date to contribute to the development of these recommendations. Based on extensive clinical experience and current evidence, the present recommendations provide guidance from patient selection and determination of sapropterin response to the long-term management of patients on sapropterin therapy. Target Phe levels, nutritional adequacy, neurocognitive screening and adherence to treatment are addressed to optimize patient outcomes

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Fake News Detection using Machine Learning

Everyone depends upon various online resources for news in this modern age, where the internet is pervasive. As the use of social media platforms such as Facebook, Twitter, and others has increased, news spreads quickly among millions of users in a short time. The consequences of Fake news are far-reaching, from swaying election outcomes in favor of certain candidates to creating biased opinions. WhatsApp, Instagram, and many other social media platforms are the main source for spreading fake news. This work provides a solution by introducing a fake news detection model using machine learning. This model requires prerequisite data extracted from various news websites. Web scraping technique is used for data extraction which is further used to create datasets. The data is classified into two major categories which are true dataset and false dataset. Classifiers used for the classification of data are Random Forest, Logistic Regression, Decision Tree, KNN and Gradient Booster. Based on the output received the data is classified either as true or false data. Based on that, the user can find out whether the given news is fake or not on the webserver

Population status and factors influencing the distribution of Critically Endangered gharial (Gavialis gangeticus) in a regulated unprotected river system in India

Gharial (Gavialis gangeticus), the last surviving crocodilian member of the genus Gavialis, is endemic to the Indian subcontinent and is listed as one of the priorities species under the Evolutionary Distinct and Globally Endangered framework. Historically, the gharial used to occur in all major river systems of the Indian Subcontinent, now found in isolated stretches, mostly within the boundaries of Protected Areas. The gharial population decreased by over 80 % between the 1950s and 1960s due to habitat degradation, poaching, and mortality from passive fishing. The gharial population is, however, rebounding due to concerted conservation efforts launched in the mid-1970s. One of the largest gharial populations outside of the Protected Area is in the Gandak River, a transboundary northern tributary of the Ganga. However, the habitat association of gharial in relation to the rising anthropogenic stressors is not well-documented from an ecological standpoint in the Gandak River. The present study assessed the population status and factors influencing the gharial distribution in the Gandak River. Boat-based visual encounter surveys were conducted for data collection, and generalized linear models (GLMs) were employed to evaluate the factors influencing gharial distribution. The encounter rate fluctuated along the surveyed river stretches, peaking in the upstream. We observed a positive association with channel depth while a negative one with channel width, livestock presence, fishing nets, and fishing boats. The observed pattern of encounter rate and negative association with anthropogenic variables indicate spatial avoidance of these factors. Overall, conservation interventions, such as adaptive management strategies to reduce and remove these factors, are required for long-term gharial persistence in the regulated unprotected riverscape