Association between sleep disturbances and challenging behavior in children and adolescents with Angelman syndrome.

Angelman Syndrome (AS) is a neurodevelopmental disorder with severe symptoms and associated comorbidities. It is caused by the inactivity or lack of the UBE3a gene. Symptoms of the syndrome include intellectual disability and developmental delay. The current study investigated sleep disturbances (SD) in children and adolescents with AS, associations between SD and possible predictors of SD. Variables examined included age, gender, newborn and infancy history, challenging behavior, type of therapy received, genetic type of AS, and seizures. The sample included data from 109 participants with a mean age of 8.21, accessed via the Global Angelman Syndrome Registry. Chi-square tests were carried out to assess the associations between the variables and a logistical regression was carried out to assess the possible predictors of SD. Associations were found between SD and certain repetitive behaviors: slapping walls, focal hand movements, and agitation at new situations. From these associations, a regression formed a predictive model for sleep disturbances. The findings of this research demonstrated the importance of investigating the relationship between sleep disturbances and challenging behavior in children and adolescents with AS and the need for further research in this area.

Association Between Challenging Behaviour and Sleep Problems in Adults Enrolled in the Global Angelman Syndrome Registry.

Angelman Syndrome (AS) is a rare genetic disorder that impacts 1:20,000 people. Challenging behaviour, such as severe injurious behaviour, aggression and frequent unprovoked episodes of laughter are a significant problem among adults with AS that adversely impacts an individual's quality of life. This study, for the first time, aims understand the characteristic of challenging behaviour, its frequency, and the factors associated with it in adults with AS. Data from participants with AS (N = 37; aged 18-46 years) registered with the Global Angelman Registry, were divided into challenging behaviour and non-challenging behaviour groups based on the presence or absence of 50% of the behaviours recorded in the registry. Descriptive statistics, chi-squared and t-test analysis were conducted to assess the impact of variables on challenging behaviour. Multiple regressions were conducted to investigate the predictors of challenging behaviour. 56% of the sample presented with challenging behaviour. Disorders of arousal, self-injury, behaviour dysregulation, repetitive behaviour, and the lack of physical therapy accounted for 59% of the variance of challenging behaviour in this population. It was found that challenging behaviour was very common in this population. A significant association was found between challenging behaviour and both sleep arousal and the lack of physical therapy. Sleep arousal and the lack of physical therapy were the key factors associated with challenging behaviour in this study. Targeted interventions are needed to decrease challenging behaviour and future research should focus on sleep interventions and increased opportunities for physical therapy.

Does the registry speak your language? A case study of the Global Angelman Syndrome Registry.

Global disease registries are critical to capturing common patient related information on rare illnesses, allowing patients and their families to provide information about their condition in a safe, accessible, and engaging manner that enables researchers to undertake critical research aimed at improving outcomes. Typically, English is the default language of choice for these global digital health platforms. Unfortunately, language barriers can significantly inhibit participation from non-English speaking participants. In addition, there is potential for compromises in data quality and completeness. In contrast, multinational commercial entities provide access to their websites in the local language of the country they are operating in, and often provide multiple options reflecting ethnic diversity. This paper presents a case study of how the Global Angelman Syndrome Registry (GASR) has used a novel approach to enable multiple language translations for its website. Using a "semi-automated language translation" approach, the GASR, which was originally launched in English in September 2016, is now available in several other languages. In 2020, the GASR adopted a novel approach using crowd-sourcing and machine translation tools leading to the availability of the GASR in Spanish, Traditional Chinese, Italian, and Hindi. As a result, enrolments increased by 124% percent for Spain, 67% percent for Latin America, 46% percent for Asia, 24% for Italy, and 43% for India. We describe our approach here, which we believe presents an opportunity for cost-effective and timely translations responsive to changes to the registry and helps build and maintain engagement with global disease communities.

TEDD: a database of temporal gene expression patterns during multiple developmental periods in human and model organisms.

Characterization of the specific expression and chromatin profiles of genes enables understanding how they contribute to tissue/organ development and the mechanisms leading to diseases. Whilst the number of single-cell sequencing studies is increasing dramatically; however, data mining and reanalysis remains challenging. Herein, we systematically curated the up-to-date and most comprehensive datasets of sequencing data originating from 2760 bulk samples and over 5.1 million single-cells from multiple developmental periods from humans and multiple model organisms. With unified and systematic analysis, we profiled the gene expression and chromatin accessibility among 481 cell-types, 79 tissue-types and 92 timepoints, and pinpointed cells with the co-expression of target genes. We also enabled the detection of gene(s) with a temporal and cell-type specific expression profile that is similar to or distinct from that of a target gene. Additionally, we illustrated the potential upstream and downstream gene-gene regulation interactions, particularly under the same biological process(es) or KEGG pathway(s). Thus, TEDD (Temporal Expression during Development Database), a value-added database with a user-friendly interface, not only enables researchers to identify cell-type/tissue-type specific and temporal gene expression and chromatin profiles but also facilitates the association of genes with undefined biological functions in development and diseases. The database URL is https://TEDD.obg.cuhk.edu.hk/.

Genome architecture and diverged selection shaping pattern of genomic differentiation in wild barley.

Divergent selection of populations in contrasting environments leads to functional genomic divergence. However, the genomic architecture underlying heterogeneous genomic differentiation remains poorly understood. Here, we de novo assembled two high-quality wild barley (Hordeum spontaneum K. Koch) genomes and examined genomic differentiation and gene expression patterns under abiotic stress in two populations. These two populations had a shared ancestry and originated in close geographic proximity but experienced different selective pressures due to their contrasting micro-environments. We identified structural variants that may have played significant roles in affecting genes potentially associated with well-differentiated phenotypes such as flowering time and drought response between two wild barley genomes. Among them, a 29-bp insertion into the promoter region formed a cis-regulatory element in the HvWRKY45 gene, which may contribute to enhanced tolerance to drought. A single SNP mutation in the promoter region may influence HvCO5 expression and be putatively linked to local flowering time adaptation. We also revealed significant genomic differentiation between the two populations with ongoing gene flow. Our results indicate that SNPs and small SVs link to genetic differentiation at the gene level through local adaptation and are maintained through divergent selection. In contrast, large chromosome inversions may have shaped the heterogeneous pattern of genomic differentiation along the chromosomes by suppressing chromosome recombination and gene flow. Our research offers novel insights into the genomic basis underlying local adaptation and provides valuable resources for the genetic improvement of cultivated barley.

MiNDAUS partnership: a roadmap for the cure and management of motor Neurone disease.

An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.

Immunomic Investigation of Holocyclotoxins to Produce the First Protective Anti-Venom Vaccine Against the Australian Paralysis Tick, Ixodes holocyclus.

Venom producing animals are ubiquitously disseminated among vertebrates and invertebrates such as fish, snakes, scorpions, spiders, and ticks. Of the ~890 tick species worldwide, 27 have been confirmed to cause paralysis in mammalian hosts. The Australian paralysis tick (Ixodes holocyclus) is the most potent paralyzing tick species known. It is an indigenous three host tick species that secretes potent neurotoxins known as holocyclotoxins (HTs). Holocyclotoxins cause a severe and harmful toxicosis leading to a rapid flaccid paralysis which can result in death of susceptible hosts such as dogs. Antivenins are generally polyclonal antibody treatments developed in sheep, horses or camels to administer following bites from venomous creatures. Currently, the methods to prevent or treat tick paralysis relies upon chemical acaricide preventative treatments or prompt removal of all ticks attached to the host followed by the administration of a commercial tick-antiserum (TAS) respectively. However, these methods have several drawbacks such as poor efficacies, non-standardized dosages, adverse effects and are expensive to administer. Recently the I. holocyclus tick transcriptome from salivary glands and viscera reported a large family of 19 holocyclotoxins at 38-99% peptide sequence identities. A pilot trial demonstrated that correct folding of holocyclotoxins is needed to induce protection from paralysis. The immunogenicity of the holocyclotoxins were measured using commercial tick antiserum selecting HT2, HT4, HT8 and HT11 for inclusion into the novel cocktail vaccine. A further 4 HTs (HT1, HT12, HT14 and HT17) were added to the cocktail vaccine to ensure that the sequence variation among the HT protein family was encompassed in the formulation. A second trial comparing the cocktail of 8 HTs to a placebo group demonstrated complete protection from tick challenge. Here we report the first successful anti-venom vaccine protecting dogs from tick paralysis.

BarleyVarDB: a database of barley genomic variation.

Barley (Hordeum vulgare L.) is one of the first domesticated grain crops and represents the fourth most important cereal source for human and animal consumption. BarleyVarDB is a database of barley genomic variation. It can be publicly accessible through the website at http://146.118.64.11/BarleyVar. This database mainly provides three sets of information. First, there are 57 754 224 single nuclear polymorphisms (SNPs) and 3 600 663 insertions or deletions (InDels) included in BarleyVarDB, which were identified from high-coverage whole genome sequencing of 21 barley germplasm, including 8 wild barley accessions from 3 barley evolutionary original centers and 13 barley landraces from different continents. Second, it uses the latest barley genome reference and its annotation information publicly accessible, which has been achieved by the International Barley Genome Sequencing Consortium (IBSC). Third, 522 212 whole genome-wide microsatellites/simple sequence repeats (SSRs) were also included in this database, which were identified in the reference barley pseudo-molecular genome sequence. Additionally, several useful web-based applications are provided including JBrowse, BLAST and Primer3. Users can design PCR primers to asses polymorphic variants deposited in this database and use a user-friendly interface for accessing the barley reference genome. We envisage that the BarleyVarDB will benefit the barley genetic research community by providing access to all publicly available barley genomic variation information and barley reference genome as well as providing them with an ultra-high density of SNP and InDel markers for molecular breeding and identification of functional genes with important agronomic traits in barley. Database URL: http://146.118.64.11/BarleyVar.

A platform in the use of medicines to treat chronic hepatitis C (PLATINUM C): protocol for a prospective treatment registry of real-world outcomes for hepatitis C.

BACKGROUND: Safe, highly curative, short course, direct acting antiviral (DAA) therapies are now available to treat chronic hepatitis C. DAA therapy is freely available to all adults chronically infected with the hepatitis C virus (HCV) in Australia. If left untreated, hepatitis C may lead to progressive hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Australia is committed to eliminating hepatitis as a public health threat by 2030 set by the World Health Organization. However, since the introduction of funded DAA treatment, uptake has been suboptimal. Australia needs improved strategies for testing, treatment uptake and treatment completion to address the persisting hepatitis C public health problem. PLATINUM C is a HCV treatment registry and research platform for assessing the comparative effectiveness of alternative interventions for achieving virological cure. METHODS: PLATINUM C will prospectively enrol people with active HCV infection confirmed by recent detection of HCV ribonucleic acid (RNA) in blood. Those enrolled will agree to allow standardised collection of demographic, lifestyle, treatment, virological outcome and other relevant clinical data to better inform the future management of HCV infection. The primary outcome is virological cure evidenced by sustained virological response (SVR), which is defined as a negative HCV PCR result 6 to 18 months after initial prescription of DAA therapy and no less than 12 weeks after the completion of treatment. Study participants will be invited to opt-in to medication adherence monitoring and quality of life assessments using validated self-reported instruments (EQ-5D-5L). DISCUSSION: PLATINUM C is a treatment registry and platform for nesting pragmatic trials. Data collected will inform the design, development and implementation of pragmatic trials. The digital infrastructure, study procedures and governing systems established by the registry will allow PLATINUM C to support a wider research platform in the management of hepatitis C in primary care. TRIAL REGISTRATION: The trial is registered with the Australia and New Zealand Clinical Trials Register ( ACTRN12619000023156 ). Date of registration: 10/01/2019.

Design, development and deployment of a web-based patient registry for rare genetic lipid disorders.

Rare genetic lipid disorders comprise all the monogenic disorders of lipoprotein metabolism with the exception of heterozygous familial hypercholesterolaemia (FH). The creation and maintenance of patient registries is critical for disease monitoring, improving clinical best practice, facilitating research and enabling the development of novel therapeutics, but very few disease-specific rare genetic lipid disorder registries currently exist. Our aim was to design, develop and deploy a web-based patient registry for rare genetic lipid disorders. The Rare Genetic Lipid Disorders Registry is based on the FH Australasia Network (FHAN) Registry, which has been operating since 2015. The Rare Genetic Lipid Disorders Registry was deployed utilising the open-source Rare Disease Registry Framework (RDRF), which enables the efficient customisation and sustainable deployment of web-based registries. The Registry has been designed to capture longitudinal data on 13 rare genetic lipid disorders, with the ability to add more if required in the future. Recruitment of volunteers into the Registry is currently through the Royal Perth Hospital Lipid Disorders Clinic in Western Australia. Although in essence a clinic-based patient registry, the web-based design allows for expansion and distribution across Australia and beyond. Data collated by the Registry may ultimately improve the diagnosis, management and treatment of these conditions.

Characterization of genome-wide variations induced by gamma-ray radiation in barley using RNA-Seq.

BACKGROUND: Artificial mutagenesis not only provides a new approach to increase the diversity of desirable traits for breeding new varieties but are also beneficial for characterizing the genetic basis of functional genes. In recent decades, many mutation genes have been identified which are responsible for phenotype changes in mutants in various species including Arabidopsis and rice. However, the mutation feature in induced mutants and the underlying mechanisms of various types of artificial mutagenesis remain unclear. RESULTS: In this study, we adopted a transcriptome sequencing strategy to characterize mutations in coding regions in a barley dwarf mutant induced by gamma-ray radiation. We detected 1193 genetic mutations in gene transcription regions introduced by gamma-ray radiation. Interestingly, up to 97% of the gamma irradiation mutations were concentrated in certain regions in chromosome 5H and chromosome 7H. Of the 26,745 expressed genes, 140 were affected by gamma-ray radiation; their biological functions included cellular and metabolic processes. CONCLUSION: Our results indicate that mutations induced by gamma-ray radiation are not evenly distributed across the whole genome but located in several concentrated regions. Our study provides an overview of the feature of genetic mutations and the genes affected by gamma-ray radiation, which should contribute to a deeper understanding of the mechanisms of radiation mutation and their application in gene function analysis.

RD-RAP: beyond rare disease patient registries, devising a comprehensive data and analytic framework.

Within the 21 APEC economies alone, there are an estimated 200 million individuals living with a rare disease. As such, health data on these individuals, and hence patient registries, are vital. However, registries can come in many different forms and operating models in different jurisdictions. They possess a varying degree of functionality and are used for a variety of purposes. For instance registries can facilitate service planning as well as underpin public health and clinical research by providing de-identified data to researchers. Furthermore, registries may be used to create and disseminate new knowledge to inform clinical best practice and care, to identify and enrol participants for clinical trials, and to enable seamless integration of patient data for diagnostic testing and cascade screening. Registries that add capability such as capturing patient reported outcomes enable patients, and their carers, to become active partners in their care, rapidly furthering research and ensuring up-to-date practice-based evidence. Typically, a patient registry centres around the notion of health data 'capture', usually for only one or a small subset of the functions outlined above, thereby creating fragmented datasets that, despite the best efforts and intentions, make it difficult to exchange the right data for the right purpose to the right stakeholder under appropriate governance arrangements. Trying to incorporate maximum functionality into a registry is an obvious strategy, but monolithic software solutions are not desirable. As an alternative, we propose that it is important to incorporate analytics as core to a patient registry, rather than just utilising registries as a 'data capture' solution. We contend that embracing an analytics-centric focus makes it reasonable to imagine a future where it will be possible to evaluate the individual outcomes of health interventions in real time. The purposeful and, importantly, the repurposable application of health data will allow stakeholders to extract, create and reuse knowledge to improve health outcomes, assist clinical decision making, and improve health service design and delivery. To realise this vision, we introduce and describe the concept of a Rare Disease Registry and Analytics Platform (RD-RAP); one that we hope will make a meaningful difference to the lives of those living with a rare disease.

Trial Refresh: A Case for an Adaptive Platform Trial for Pulmonary Exacerbations of Cystic Fibrosis.

Cystic fibrosis is a genetic disease typically characterized by progressive lung damage and premature mortality. Pulmonary exacerbations, or flare-ups of the lung disease, often require hospitalization for intensive treatment. Approximately 25% of patients with cystic fibrosis do not recover their baseline lung function after pulmonary exacerbations. There is a relative paucity of evidence to inform treatment strategies for exacerbations. Compounding this lack of evidence, there are a large number of treatment options already as well as becoming available. This results in significant variability between medication regimens prescribed by different physicians, treatment centers and regions with potentially adverse impact to patients. The conventional strategy is to undertake essential randomized clinical trials to inform treatment decisions and improve outcomes for patients with exacerbations. However, over the past several decades, clinical trials have generally failed to provide information critical to improved treatment and management of exacerbations. Bayesian adaptive platform trials hold the promise of addressing clinical uncertainties and informing treatment. Using modeling and response adaptive randomization, they allow for the evaluation of multiple treatments across different management domains, and progressive improvement in patient outcomes throughout the course of the trial. Bayesian adaptive platform trials require substantial amounts of preparation. Basic preparation includes extensive stakeholder involvement including elicitation of consumer preferences and clinician understanding of the research topic, defining the research questions, determining the best outcome measures, delineating study sub-groups, in depth statistical modeling, designing end-to-end digital solutions seamlessly supporting clinicians, researchers and patients, constructing randomisation algorithms and importantly, defining pre-determined intra-study end-points. This review will discuss the motivation and necessary steps required to embark on a Bayesian adaptive platform trial to optimize medication regimens for the treatment of pulmonary exacerbations of cystic fibrosis.

Differentially expressed genes in response to amitraz treatment suggests a proposed model of resistance to amitraz in R. decoloratus ticks.

The widespread geographical distribution of Rhipicephalus decoloratus in southern Africa and its ability to transmit the pathogens causing redwater, gallsickness and spirochaetosis in cattle makes this hematophagous ectoparasite of economic importance. In South Africa, the most commonly used chemical acaricides to control tick populations are pyrethroids and amitraz. The current amitraz resistance mechanism described in R. microplus, from South Africa and Australia, involves mutations in the octopamine receptor, but it is unlikely that this will be the only contributing factor to mediate resistance. Therefore, in this study we aimed to gain insight into the more complex mechanism(s) underlying amitraz resistance in R. decoloratus using RNA-sequencing. Differentially expressed genes (DEGs) were identified when comparing amitraz susceptible and resistant ticks in the presence of amitraz while fed on bovine hosts. The most significant DEGs were further analysed using several annotation tools. The predicted annotations from these genes, as well as KEGG pathways potentially point towards a relationship between the α-adrenergic-like octopamine receptor and ionotropic glutamate receptors in establishing amitraz resistance. All genes with KEGG pathway annotations were further validated using RT-qPCR across all life stages of the tick. In susceptible ticks, the proposed model is that in the presence of amitraz, there is inhibition of Ca2+ entry into cells and subsequent membrane hyperpolarization which prevents the release of neurotransmitters. In resistant ticks, we hypothesize that this is overcome by ionotropic glutamate receptors (NMDA and AMPA) to enhance synaptic transmission and plasticity in the presence of neurosteroids. Activation of NMDA receptors initiates long term potentiation (LTP) which may allow the ticks to respond more rapidly and with less stimulus when exposed to amitraz in future. Overactivation of the NMDA receptor and excitotoxicity is attenuated by the estrone, NAD+ and ATP hydrolysing enzymes. This proposed pathway paves the way to future studies on understanding amitraz resistance and should be validated using in vivo activity assays (through the use of inhibitors or antagonists) in combination with metabolome analyses.

The role of patient registries for rare genetic lipid disorders.

PURPOSE OF REVIEW: We review the role, utility and current status of patient registries for rare genetic lipid disorders. RECENT FINDINGS: The creation and maintenance of rare genetic lipid disorder patient registries is critical for disease monitoring, improving clinical best practice, facilitating research and enabling the development of novel therapeutics. An open-source disease registry platform, termed the Rare Disease Registry Framework, has been developed, optimized and deployed for homozygous familial hypercholesterolemia. A global disease-specific registry for lipoprotein lipase deficiency (LPLD), GENetherapy In the mAnagement of Lipoprotein Lipase deficiency, has been established with the aim of enrolling 20-40% of LPLD patients worldwide and will study the natural history of LPLD as well as therapeutic response to the gene therapy alipogene tiparvovec. Similarly, a registry for lysosomal acid lipase deficiency patients in Europe and the United States is studying the clinical outcomes of the enzyme-replacement therapy sebelipase alfa. SUMMARY: There are currently few disease-specific rare lipid disorder patient registries. The very nature of rare genetic lipid disorders would suggest that larger national or international registries are necessary to capture clinical data on a sufficient number of patients to provide insight into the prevalence and natural history of these conditions. Furthermore, these registries can help to identify and address deficiencies in current diagnostic and management practices, and facilitate clinical trials of new therapies.

De novo assembly of honey bee RNA viral genomes by tapping into the innate insect antiviral response pathway.

Bee pollination is critical for improving productivity of one third of all plants or plant products consumed by humans. The health of honey bees is in decline in many countries worldwide, and RNA viruses together with other biological, environmental and anthropogenic factors have been identified as the main causes. The rapid genetic variation of viruses represents a challenge for diagnosis. Thus, application of deep sequencing methods for detection and analysis of viruses has increased over the last years. In this study, we leverage from the innate Dicer-2 mediated antiviral response against viruses to reconstruct complete viral genomes using virus-derived small interfering RNAs (vsiRNAs). Symptomatic A. mellifera larvae collected from hives free of Colony Collapse Disorder (CCD) and the parasitic Varroa mite (Varroa destructor) were used to generate more than 107 million small RNA reads. We show that de novo assembly of insect viral sequences is less fragmented using only 22 nt long vsiRNAs rather than a combination of 21-22 nt small RNAs. Our results show that A. mellifera larvae activate the RNAi immune response in the presence of Sacbrood virus (SBV). We assembled three SBV genomes from three individual larvae from different hives in a single apiary, with 1-2% nucleotide sequence variability among them. We found 3-4% variability between SBV genomes generated in this study and earlier published Australian variants suggesting the presence of different SBV quasispecies within the country.

Design of a framework for the deployment of collaborative independent rare disease-centric registries: Gaucher disease registry model.

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these 'independent' registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease.

Transcriptome and toxin family analysis of the paralysis tick, Ixodes holocyclus.

The Australian paralysis tick (Ixodes holocyclus) secretes neuropathic toxins into saliva that induce host paralysis. Salivary glands and viscera were dissected from fully engorged female I. holocyclus ticks collected from dogs and cats with paralysis symptoms. cDNA from both tissue samples were sequenced using Illumina HiSeq 100 bp pair end read technologies. Unique and non-redundant holocyclotoxin sequences were designated as HT2-HT19, as none were identical to the previously described HT1. Specific binding to rat synaptosomes was determined for synthetic HTs, and their neurotoxic capacity was determined by neonatal mouse assay. They induced a powerful paralysis in neonatal mice, particularly HT4 which produced rapid and strong respiratory distress in all animals tested. This is the first known genomic database developed for the Australian paralysis tick. The database contributed to the identification and subsequent characterization of the holocyclotoxin family that will inform the development of novel anti-paralysis control methods.

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database.

BACKGROUND: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. OBJECTIVE: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. METHODS: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. RESULTS: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. CONCLUSIONS: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.