The Canadian Neuromuscular Disease Registry: Connecting Patients to National and International Research Opportunities

Introduction Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments. Methods In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry. Results As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population. Discussion The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canada’s visibility as a competitive location for the conduct of clinical trials for NM therapies

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B2 (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F2-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F2-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F2-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older

Open access inequalities in birth before arrival at hospital in South West England: A multimethods study of neonatal hypothermia and emergency medical services call-handler advice

Objectives To examine inequalities in birth before arrival (BBA) at hospitals in South West England, understand which groups are most likely to experience BBA and how this relates to hypothermia and outcomes (phase A). To investigate opportunities to improve temperature management advice given by emergency medical services (EMS) call-handlers during emergency calls regarding BBA in the UK (phase B). Design A two-phase multimethod study. Phase A analysed anonymised data from hospital neonatal records between January 2018 and January 2021. Phase B analysed anonymised EMS call transcripts, followed by focus groups with National Health Service (NHS) staff and patients. Setting Six Hospital Trusts in South West England and two EMS providers (ambulance services) in South West and North East England. Participants 18 multidisciplinary NHS staff and 22 members of the public who had experienced BBA in the UK. Results 35% (64/184) of babies conveyed to hospital were hypothermic on arrival. When compared with national data on all births in the South West, we found higher percentages of women with documented safeguarding concerns at booking, previous live births and 'late bookers' (booking their pregnancy >13 weeks gestation). These women may, therefore, be more likely to experience BBA. Preterm babies, babies to first-time mothers and babies born to mothers with disability or safeguarding concerns at booking were more likely to be hypothermic following BBA. Five main themes emerged from qualitative data on call-handler advice: (1) importance placed on neonatal temperature; (2) advice on where the baby should be placed following birth; (3) advice on how to keep the baby warm; (4) timing of temperature management advice and (5) clarity and priority of instructions. Conclusions Findings identified factors associated with BBA and neonatal hypothermia following BBA. Improvements to EMS call-handler advice could reduce the number of babies arriving at hospital hypothermic

Recombination-mediated remodelling of host-pathogen interactions during Staphylococcus aureus niche adaptation

Large-scale recombination events have led to the emergence of epidemic clones of several major bacterial pathogens. However, the functional impact of the recombination on clonal success is not understood. Here, we identified a novel widespread hybrid clone (ST71) of livestock-associated Staphylococcus aureus that evolved from an ancestor belonging to the major bovine lineage CC97, through multiple large-scale recombination events with other S. aureus lineages occupying the same ruminant niche. The recombination events, affecting a 329 kb region of the chromosome spanning the origin of replication, resulted in allele replacement and loss or gain of an array of genes influencing host–pathogen interactions. Of note, molecular functional analyses revealed that the ST71 hybrid clone has acquired multiple novel pathogenic traits associated with acquired and innate immune evasion and bovine extracellular matrix adherence. These findings provide a paradigm for the impact of large-scale recombination events on the rapid evolution of bacterial pathogens within defined ecological niches

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

Copernicus Ocean State Report, issue 6

The 6th issue of the Copernicus OSR incorporates a large range of topics for the blue, white and green ocean for all European regional seas, and the global ocean over 1993–2020 with a special focus on 2020

Manganese-Iron Phosphate Nodules at the Groken Site, Gale Crater, Mars

The MSL Curiosity rover investigated dark, Mn-P-enriched nodules in shallow lacustrine/fluvial sediments at the Groken site in Glen Torridon, Gale Crater, Mars. Applying all relevant information from the rover, the nodules are interpreted as pseudomorphs after original crystals of vivianite, (Fe2+,Mn2+)3(PO4)2·8H2O, that cemented the sediment soon after deposition. The nodules appear to have flat faces and linear boundaries and stand above the surrounding siltstone. ChemCam LIBS (laser-induced breakdown spectrometry) shows that the nodules have MnO abundances approximately twenty times those of the surrounding siltstone matrix, contain little CaO, and have SiO2 and Al2O3 abundances similar to those of the siltstone. A deconvolution of APXS analyses of nodule-bearing targets, interpreted here as representing the nodules’ non-silicate components, shows high concentrations of MnO, P2O5, and FeO and a molar ratio P/Mn = 2. Visible to near-infrared reflectance of the nodules (by ChemCam passive and Mastcam multispectral) is dark and relatively flat, consistent with a mixture of host siltstone, hematite, and a dark spectrally bland material (like pyrolusite, MnO2). A drill sample at the site is shown to contain minimal nodule material, implying that analyses by the CheMin and SAM instruments do not constrain the nodules’ mineralogy or composition. The fact that the nodules contain P and Mn in a small molar integer ratio, P/Mn = 2, suggests that the nodules contained a stoichiometric Mn-phosphate mineral, in which Fe did (i.e., could) not substitute for Mn. The most likely such minerals are laueite and strunzite, (Fe2+,Mn2+)3(PO4)2·8H2O and –6H2O, respectively, which occur on Earth as alteration products of other Mn-bearing phosphates including vivianite. Vivianite is a common primary and diagenetic precipitate from low-oxygen, P-enriched waters. Calculated phase equilibria show Mn-bearing vivianite could be replaced by laueite or strunzite and then by hematite plus pyrolusite as the system became more oxidizing and acidic. These data suggest that the nodules originated as vivianite, forming as euhedral crystals in the sediment, enclosing sediment grains as they grew. After formation, the nodules were oxidized—first to laueite/strunzite yielding the diagnostic P/Mn ratio, and then to hematite plus an undefined Mn oxy-hydroxide (like pyrolusite). The limited occurrence of these Mn-Fe-P nodules, both in space and time (i.e., stratigraphic position), suggests a local control on their origin. By terrestrial analogies, it is possible that the nodules precipitated near a spring or seep of Mn-rich water, generated during alteration of olivine in the underlying sediments