537 research outputs found
Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity.
To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number.
A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines.
The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation.
The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process
Meta-analyses of deflazacort versus prednisone/prednisolone in patients with nonsense mutation Duchenne muscular dystrophy
Aim: Compare efficacies of deflazacort and prednisone/prednisolone in providing clinically meaningful delays in loss of physical milestones in patients with nonsense mutation Duchenne muscular dystrophy. Materials & methods: Placebo data from Phase IIb (ClinicalTrials.gov Identifier: NCT00592553) and ACT DMD (ClinicalTrials.gov Identifier: NCT01826487) ataluren nonsense mutation Duchenne muscular dystrophy clinical trials were retrospectively combined in meta-analyses (intent-to-treat population; for change from baseline to week 48 in 6-min walk distance [6MWD] and timed function tests). Results: Significant improvements in change in 6-min walk distance with deflazacort versus prednisone/prednisolone (least-squares mean difference 39.54 m [95% CI: 13.799, 65.286; p = 0.0026]). Significant and clinically meaningful improvements in 4-stair climb and 4-stair descend for deflazacort versus prednisone/prednisolone. Conclusion: Deflazacort provides clinically meaningful delays in loss of physical milestones over 48 weeks compared with prednisone/prednisolone for patients with nonsense mutation Duchenne muscular dystrophy
Ozone anomalies in the free troposphere during the COVID-19 pandemic
Using the CAM-chem Model, we simulate the response of chemical species in the free troposphere to scenarios of primary pollutant emission reductions during the COVID-19 pandemic. Zonally averaged ozone in the free troposphere during Northern Hemisphere spring and summer is found to be 5%-15% lower than 19-yr climatological values, in good agreement with observations. About one third of this anomaly is attributed to the reduction scenario of air traffic during the pandemic, another third to the reduction scenario of surface emissions, the remainder to 2020 meteorological conditions, including the exceptional springtime Arctic stratospheric ozone depletion. For the combined emission reductions, the overall COVID-19 reduction in northern hemisphere tropospheric ozone in June is less than 5 ppb below 400 hPa, but reaches 8 ppb at 250 hPa. In the Southern Hemisphere, COVID-19 related ozone reductions by 4%-6% were masked by comparable ozone increases due to other changes in 2020
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Clinical and genetic characterization of AP4B1-associated SPG47.
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated
HTAP_v2.2: a mosaic of regional and global emission grid maps for 2008 and 2010 to study hemispheric transport of air pollution
The mandate of the Task Force Hemispheric Transport of Air Pollution (TF HTAP) under the Convention on Long-Range Transboundary Air Pollution (CLRTAP) is to improve the scientific understanding of the intercontinental air pollution transport, to quantify impacts on human health, vegetation and climate, to identify emission mitigation options across the regions of the Northern Hemisphere, and to guide future policies on these aspects.
The harmonization and improvement of regional emission inventories is imperative to obtain consolidated estimates on the formation of global-scale air pollution. An emissions data set has been constructed using regional emission grid maps (annual and monthly) for SO2, NOx, CO, NMVOC, NH3, PM10, PM2.5, BC and OC for the years 2008 and 2010, with the purpose of providing consistent information to global and regional scale modelling efforts.
This compilation of different regional gridded inventories - including that of the Environmental Protection Agency (EPA) for USA, the EPA and Environment Canada (for Canada), the European Monitoring and Evaluation Programme (EMEP) and Netherlands Organisation for Applied Scientific Research (TNO) for Europe, and the Model Inter-comparison Study for Asia (MICS-Asia III) for China, India and other Asian countries - was gap-filled with the emission grid maps of the Emissions Database for Global Atmospheric Research (EDGARv4.3) for the rest of the world (mainly South America, Africa, Russia and Oceania). Emissions from seven main categories of human activities (power, industry, residential, agriculture, ground transport, aviation and shipping) were estimated and spatially distributed on a common grid of 0.1 degree W 0.1 degree longitude-latitude, to yield monthly, global, sector-specific grid maps for each substance and year.
The HTAP_v2.2 air pollutant grid maps are considered to combine latest available regional information within a complete global data set. The disaggregation by sectors, high spatial and temporal resolution and detailed information on the data sources and references used will provide the user the required transparency. Because HTAP_v2.2 contains primarily official and/or widely used regional emission grid maps, it can be recommended as a global baseline emission inventory, which is regionally accepted as a reference and from which different scenarios assessing emission reduction policies at a global scale could start.
An analysis of country-specific implied emission factors shows a large difference between industrialised countries and developing countries for acidifying gaseous air pollutant emissions (SO2 and NOx) from the energy and industry sectors. This is not observed for the particulate matter emissions (PM10, PM2.5), which show large differences between countries in the residential sector instead. The per capita emissions of all world countries, classified from low to high income, reveal an increase in level and in variation for gaseous acidifying pollutants, but not for aerosols. For aerosols, an opposite trend is apparent with higher per capita emissions of particulate matter for low income countries
French political science at a turning point
This paper outlines the origins and institutionalization process of French political science since 1945. It sketches the present state of the discipline, and it analyses recent trends that appear almost as a form of ‘de-institutionalization’. Overall, the discipline is quite well entrenched and is independent in terms of recruitment with its own teaching and research branches. However, political scientists suffer from a relative lack of visibility in the public space in comparison with their colleagues from more prominent disciplines. In many fields French political science remains invisible at the international level, though this may change considerably in the years to come. The main element of uncertainty comes from the ongoing reforms, the redefinition of the partnership between universities, the Instituts d'Etudes Politiques and the CNRS, and the way the autonomy of universities will be implemented
Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis
Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.Portuguese Fundacao para Ciencia e Tecnologia (FCT) [PTDC/EXPL/MARBIO/0430/2013]; CCMAR FCT Plurianual financing [UID/Multi/04326/2013]; FCT [SFRH/BD/111226/2015, SFRH/BD/108842/2015, SFRH/BPD/89889/2012]; FCT-IF Starting Grant [IF/01274/2014]info:eu-repo/semantics/publishedVersio
Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review
IMPORTANCE: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. OBSERVATIONS: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. CONCLUSIONS AND RELEVANCE: This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice
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