Decreasing case fatality rate following invasive pneumococcal disease, North East England, 2006-2016.

Declining mortality following invasive pneumococcal disease (IPD) has been observed concurrent with a reduced incidence due to effective pneumococcal conjugate vaccines. However, with IPD now increasing due to serotype replacement, we undertook a statistical analysis to estimate the trend in all-cause 30-day case fatality rate (CFR) in the North East of England (NEE) following IPD. Clinical, microbiological and demographic data were obtained for all laboratory-confirmed IPD cases (April 2006-March 2016) and the adjusted association between CFR and epidemiological year estimated using logistic regression. Of the 2510 episodes of IPD included in the analysis, 486 died within 30 days of IPD (CFR 19%). Increasing age, male sex, a diagnosis of septicaemia, being in ⩾1 clinical risk groups, alcohol abuse and individual serotypes were independently associated with increased CFR. A significant decline in CFR over time was observed following adjustment for these significant predictors (adjusted odds ratio 0.93, 95% confidence interval 0.89-0.98; P = 0.003). A small but significant decline in 30-day all-cause CFR following IPD has been observed in the NEE. Nonetheless, certain population groups remain at increased risk of dying following IPD. Despite the introduction of effective vaccines, further strategies to reduce the ongoing burden of mortality from IPD are needed.

Establishing and developing a Teenage and Young Adult dermatology clinic with embedded specialist psychological support.

Skin conditions are common in adolescence and impart considerable psychological burden. The Department of Health has identified the specialized needs of adolescents transitioning from paediatric to adult services as a priority, yet there are few dedicated transitional clinics in the UK providing appropriate psychosocial support. We have established a monthly Teenage and Young Adult (TYA) dermatology clinic dedicated to managing teenagers and young adults with skin disease alongside open-access psychological support. Demographic data and Teenagers' Quality of Life Index (T-QoL) measures were recorded for all patients in 2016. To evaluate patient experience, two online surveys were conducted. Statistically significant improvements in the T-QoL were recorded for patients with the most common skin condition (eczema) attending for repeat assessment by the psychologist. Patients reported high satisfaction rates in both patient experience surveys. These results demonstrate that specialized adolescent care both is well received and can improve outcomes for these patients.

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders.

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person's ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14-q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.

Social cognitive theory mediators of physical activity in a lifestyle program for cancer survivors and carers: findings from the ENRICH randomized controlled trial.

BACKGROUND: Despite increasing numbers of cancer survivors and evidence that diet and physical activity improves the health of cancer survivors, most do not meet guidelines. Some social cognitive theory (SCT)-based interventions have increased physical activity behavior, however few have used objective physical activity measures. The Exercise and Nutrition Routine Improving Cancer Health (ENRICH) randomized controlled trial reported a significant intervention effect for the primary outcome of pedometer-assessed step counts at post-test (8-weeks) and follow-up (20-weeks). The aim of this study was to test whether the SCT constructs operationalized in the ENRICH intervention were mediators of physical activity behavior change. METHODS: Randomized controlled trial with 174 cancer survivors and carers assessed at baseline, post-test (8-weeks), and follow-up (20-weeks). Participants were randomized to the ENRICH six session face-to-face healthy lifestyle program, or to a wait-list control. Hypothesized SCT mediators of physical activity behavior change (self-efficacy, behavioral goal, outcome expectations, impediments, and social expectations) were assessed using valid and reliable scales. Mediation was assessed using the Preacher and Hayes SPSS INDIRECT macro. RESULTS: At eight weeks, there was a significant intervention effect on behavioral goal (A = 9.12, p = 0.031) and outcome expectations (A = 0.25, p = 0.042). At 20 weeks, the intervention had a significant effect on self-efficacy (A = 0.31, p = 0.049) and behavioral goal (A = 13.15, p = 0.011). Only changes in social support were significantly associated with changes in step counts at eight weeks (B = 633.81, p = 0.023). Behavioral goal was the only SCT construct that had a significant mediating effect on step counts, and explained 22 % of the intervention effect at 20 weeks (AB = 397.9, 95 % CI 81.5-1025.5). CONCLUSIONS: SCT constructs had limited impact on objectively-assessed step counts in a multiple health behavior change intervention for cancer survivors and their carers. Behavioral goal measured post-intervention was a significant mediator of pedometer-assessed step counts at 3-months after intervention completion, and explained 22 % of the intervention effect. Future research should examine the separate impact of goals and planning, as well as examining mediators of behavior maintenance in physical activity interventions targeting cancer survivors. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials registry ANZCTRN1260901086257 .

Serotype-specific differences in short- and longer-term mortality following invasive pneumococcal disease.

Invasive pneumococcal disease (IPD), caused by infection with Streptococcus pneumoniae, has a substantial global burden. There are over 90 known serotypes of S. pneumoniae with a considerable body of evidence supporting serotype-specific mortality rates immediately following IPD. This is the first study to consider the association between serotype and longer-term mortality following IPD. Using enhanced surveillance data from the North East of England we assessed both the short-term (30-day) and longer-term (⩽7 years) independent adjusted associations between individual serotypes and mortality following IPD diagnosis using logistic regression and extended Cox proportional hazards models. Of the 1316 cases included in the analysis, 243 [18·5%, 95% confidence interval (CI) 16·4-20·7] died within 30 days of diagnosis. Four serotypes (3, 6A, 9N, 19 F) were significantly associated with overall increased 30-day mortality. Effects were observable only for older adults (⩾60 years). After extension of the window to 12 months and 36 months, one serotype was associated with significantly increased mortality at 12 months (19 F), but no individual serotypes were associated with increased mortality at 36 months. Two serotypes had statistically significant hazard ratios (HR) for longer-term mortality: serotype 1 for reduced mortality (HR 0·51, 95% CI 0·30-0·86) and serotype 9N for increased mortality (HR 2·30, 95% CI 1·29-4·37). The association with serotype 9N was no longer observed after limiting survival analysis to an observation period starting 30 days after diagnosis. This study supports the evidence for associations between serotype and short-term (30-day) mortality following IPD and provides the first evidence for the existence of statistically significant associations between individual serotypes and longer-term variation in mortality following IPD.

Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study.

BACKGROUND: There is limited data on the risk factors and phenotypical characteristics associated with spirometrically confirmed COPD in never-smokers in the general population. AIMS: To compare the characteristics associated with COPD by gender and by severity of airway obstruction in never-smokers and in ever-smokers. METHOD: We analysed the data from 5176 adults aged 40 years and older who participated in the initial cross-sectional phase of the population-based, prospective, multisite Canadian Cohort of Obstructive Lung Disease study. Never-smokers were defined as those with a lifetime exposure of <1/20 pack year. Logistic regressions were constructed to evaluate associations for 'mild' and 'moderate-severe' COPD defined by FEV1/FVC <5th centile (lower limits of normal). Analyses were performed using SAS V.9.1 (SAS Institute, Cary, North Carolina, USA). RESULTS: The prevalence of COPD (FEV1/FVC

Impact of a nutrition and physical activity intervention (ENRICH: Exercise and Nutrition Routine Improving Cancer Health) on health behaviors of cancer survivors and carers: a pragmatic randomized controlled trial.

BACKGROUND: Physical activity and consuming a healthy diet have clear benefits to the physical and psychosocial health of cancer survivors, with guidelines recognising the importance of these behaviors for cancer survivors. Interventions to promote physical activity and improve dietary behaviors among cancer survivors and carers are needed. The aim of this study was to determine the effects of a group-based, face-to-face multiple health behavior change intervention on behavioral outcomes among cancer survivors of mixed diagnoses and carers. METHODS: The Exercise and Nutrition Routine Improving Cancer Health (ENRICH) intervention was evaluated using a two-group pragmatic randomized controlled trial. Cancer survivors and carers (n = 174) were randomly allocated to the face-to-face, group-based intervention (six, theory-based two-hour sessions delivered over 8 weeks targeting healthy eating and physical activity [PA]) or wait-list control (after completion of 20-week data collection). Assessment of the primary outcome (pedometer-assessed mean daily step counts) and secondary outcomes (diet and alcohol intake [Food Frequency Questionnaire], self-reported PA, weight, body mass index, and waist circumference) were assessed at baseline, 8-and 20-weeks. RESULTS: There was a significant difference between the change over time in the intervention group and the control group. At 20 weeks, the intervention group had increased by 478 steps, and the control group had decreased by 1282 steps; this represented an adjusted mean difference of 1761 steps (184 to 3337; P = 0.0028). Significant intervention effects for secondary outcomes, included a half serving increase in vegetable intake (difference 39 g/day; 95 % CI: 12 to 67; P = 0.02), weight loss (kg) (difference -1.5 kg; 95 % CI, -2.6 to -0.3; P = 0.014) and change in body mass index (kg/m(2)) (difference -0.55 kg/m(2); 95 % CI, -0.97 to -0.13; P = 0.012). No significant intervention effects were found for self-reported PA, total sitting time, waist circumference, fruit, energy, fibre, alcohol, meat, or fat consumption. CONCLUSIONS: The ENRICH intervention was effective for improving PA, weight, body mass index, and vegetable consumption even with the inclusion of multiple cancer types and carers. As an example of successful research translation, the Cancer Council NSW has subsequently adopted ENRICH as a state-wide program. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Register identifier: ANZCTRN1260901086257.

Extended solid solutions and coherent transformations in nanoscale olivine cathodes.

Nanoparticle LiFePO4, the basis for an entire class of high power Li-ion batteries, has recently been shown to exist in binary lithiated/delithiated states at intermediate states of charge. The Mn-bearing version, LiMn(y)Fe(1-y)PO4, exhibits even higher rate capability as a lithium battery cathode than LiFePO4 of comparable particle size. To gain insight into the cause(s) of this desirable performance, the electrochemically driven phase transformation during battery charge and discharge of nanoscale LiMn0.4Fe0.6PO4 of three different average particle sizes, 52, 106, and 152 nm, is investigated by operando synchrotron radiation powder X-ray diffraction. In stark contrast to the binary lithiation states of pure LiFePO4 revealed in recent investigations, the formations of metastable solid solutions covering a remarkable wide compositional range, including while in two-phase coexistence, are observed. Detailed analysis correlates this behavior with small elastic misfits between phases compared to either pure LiFePO4 or LiMnPO4. On the basis of time- and state-of-charge dependence of the olivine structure parameters, we propose a coherent transformation mechanism. These findings illustrate a second, completely different phase transformation mode for pure well-ordered nanoscale olivines compared to the well-studied case of LiFePO4.

Exacerbation-like respiratory symptoms in individuals without chronic obstructive pulmonary disease: results from a population-based study.

RATIONALE: Exacerbations of COPD are defined clinically by worsening of chronic respiratory symptoms. Chronic respiratory symptoms are common in the general population. There are no data on the frequency of exacerbation-like events in individuals without spirometric evidence of COPD. AIMS: To determine the occurrence of 'exacerbation-like' events in individuals without airflow limitation, their associated risk factors, healthcare utilisation and social impacts. METHOD: We analysed the cross-sectional data from 5176 people aged 40 years and older who participated in a multisite, population-based study on lung health. The study cohort was stratified into spirometrically defined COPD (post-bronchodilator FEV1/FVC < 0.7) and non-COPD (post bronchodilator FEV1/FVC ≥ 0.7 and without self-reported doctor diagnosis of airway diseases) subgroups and then into those with and without respiratory 'exacerbation-like' events in the past year. RESULTS: Individuals without COPD had half the frequency of 'exacerbation-like' events compared with those with COPD. In the non-COPD group, the independent associations with 'exacerbations' included female gender, presence of wheezing, the use of respiratory medications and self-perceived poor health. In the non-COPD group, those with exacerbations were more likely than those without exacerbations to have poorer health-related quality of life (12-item Short-Form Health Survey), miss social activities (58.5% vs 18.8%), miss work for income (41.5% vs 17.3%) and miss housework (55.6% vs 16.5%), p<0.01 to <0.0001. CONCLUSIONS: Events similar to exacerbations of COPD can occur in individuals without COPD or asthma and are associated with significant health and socioeconomic outcomes. They increase the respiratory burden in the community and may contribute to the false-positive diagnosis of asthma or COPD.

Automation and validation of micronucleus detection in the 3D EpiDerm™ human reconstructed skin assay and correlation with 2D dose responses.

Recent restrictions on the testing of cosmetic ingredients in animals have resulted in the need to test the genotoxic potential of chemicals exclusively in vitro prior to licensing. However, as current in vitro tests produce some misleading positive results, sole reliance on such tests could prevent some chemicals with safe or beneficial exposure levels from being marketed. The 3D human reconstructed skin micronucleus (RSMN) assay is a promising new in vitro approach designed to assess genotoxicity of dermally applied compounds. The assay utilises a highly differentiated in vitro model of the human epidermis. For the first time, we have applied automated micronucleus detection to this assay using MetaSystems Metafer Slide Scanning Platform (Metafer), demonstrating concordance with manual scoring. The RSMN assay's fixation protocol was found to be compatible with the Metafer, providing a considerably shorter alternative to the recommended Metafer protocol. Lowest observed genotoxic effect levels (LOGELs) were observed for mitomycin-C at 4.8 µg/ml and methyl methanesulfonate (MMS) at 1750 µg/ml when applied topically to the skin surface. In-medium dosing with MMS produced a LOGEL of 20 µg/ml, which was very similar to the topical LOGEL when considering the total mass of MMS added. Comparisons between 3D medium and 2D LOGELs resulted in a 7-fold difference in total mass of MMS applied to each system, suggesting a protective function of the 3D microarchitecture. Interestingly, hydrogen peroxide (H2O2), a positive clastogen in 2D systems, tested negative in this assay. A non-genotoxic carcinogen, methyl carbamate, produced negative results, as expected. We also demonstrated expression of the DNA repair protein N-methylpurine-DNA glycosylase in EpiDerm™. Our preliminary validation here demonstrates that the RSMN assay may be a valuable follow-up to the current in vitro test battery, and together with its automation, could contribute to minimising unnecessary in vivo tests by reducing in vitro misleading positives.

Serotype dynamics of invasive pneumococcal disease post-PCV7 and pre-PCV13 introduction in North East England.

The 7-valent pneumococcal conjugate vaccine (PCV7) has been included in the routine childhood immunization programme in the UK since September 2006. A population-based study of serotypes causing invasive pneumococcal disease (IPD) post-PCV7 in North East England was conducted using data from a regional enhanced IPD surveillance system. Overall, there was a 20% reduction [95% confidence interval (CI) 5-32] from 12·1 cases/100 000 population in 2006/2007 to 9·7 in 2009/2010. There was a fall in IPD caused by PCV7 serotypes in all age groups, with reductions of 90% (95% CI 61-99) in children aged <5 years, 50% (95% CI 4-75) in persons aged 5-64 years and 66% (95% CI 40-82) in adults aged ⩾65 years. There was a non-significant increase in IPD caused by non-PCV7 serotypes in children aged <5 years of 88% (95% CI -10 to 312) and adults aged ⩾65 years of 12% (95% CI -19 to 50), which was largely caused by serotypes 7F, 19A and 22F. Replacement disease appears to have reduced the benefits of PCV7 in North East England.

Invasive pneumococcal disease and socioeconomic deprivation: a population study from the North East of England.

BACKGROUND: Some communicable diseases disproportionately affect poor and vulnerable groups. Invasive pneumococcal disease (IPD) is an important cause of morbidity and mortality; however, the relationship between IPD and deprivation has not been well described. METHODS: Population based study assessing the relationship between incidence of IPD and deprivation in the North East of England using data from an enhanced IPD surveillance system and the 2010 Indices of Multiple Deprivation and the Rural and Urban Area Classification. RESULTS: The incidence of IPD increased linearly with increasing deprivation from 7.0 per 100 000 population to 13.6 per 100 000 population. This association was demonstrated for the 16-64 and ≥65 year age groups, but not the <16 year age group. IPD incidence was strongly associated with all individual domains of deprivation except for the 'barriers to housing and services' domain. IPD incidence was higher in urban than rural areas. CONCLUSIONS: The risk of IPD is strongly associated with deprivation in adults, but not children. The mechanisms producing the associations observed remain unclear and require further investigation. Findings from this study reinforce the need to address social inequalities to reduce the burden of disease. Targeting vaccination at adults living in deprived areas could reduce the burden of IPD.

Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia, primarily characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. Mutations in the genes encoding cartilage oligomeric matrix protein (COMP) and type IX collagen (COL9A2 and COL9A3) have previously been shown to cause different forms of MED (refs. 4-13). These dominant forms of MED (EDM1-3) are caused by mutations in the genes encoding structural proteins of the cartilage extracellular matrix (ECM); these proteins interact with high affinity in vitro. A recessive form of MED (EDM4) has also been reported; it is caused by a mutation in the diastrophic dysplasia sulfate transporter gene (SLC26A). A genomewide screen of family with autosomal-dominant MED not linked to the EDM1-3 genes provides significant genetic evidence for a MED locus on the short arm of chromosome 2 (2p24-p23), and a search for candidate genes identified MATN3 (ref. 18), encoding matrilin-3, within the critical region. Matrilin-3 is an oligomeric protein that is present in the cartilage ECM. We have identified two different missense mutations in the exon encoding the von Willebrand factor A (vWFA) domain of matrilin-3 in two unrelated families with MED (EDM5). These are the first mutations to be identified in any of the genes encoding the matrilin family of proteins and confirm a role for matrilin-3 in the development and homeostasis of cartilage and bone.

Contribution of local regeneration of glucocorticoids to tissue steroid pools.

11ß-Hydroxysteroid dehydrogenase 1 (11ßHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11ßHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11ßHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11ßHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- mice, showing the importance for whole-body 11ßHSD1 reductase activity. Disruption of liver 11ßHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11ßHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11ßHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

The clinical impact of single inhaler therapy in asthma.

BACKGROUND: Low-dose budesonide/formoterol combination used in the SMART fashion with symptom-reactive supplemental dosing has been reported to reduce asthma exacerbations as compared to the use of budesonide alone or to lower doses of budesonide/formoterol without supplemental dosing. OBJECTIVE: We undertook to review the non-exacerbation outcomes of SMART therapy and to assess the patient education implications of this treatment strategy. MATERIALS & METHODS: Systematic review. RESULTS: Patients treated with this strategy appear to be under-treated in that the majority fail to achieve guideline-defined control standards. The SMART strategy has not been tested against equivalent or higher doses of budesonide/formoterol given in symptom-prevention fashion. Existing educational strategies that focus on recognition of poor disease control may not be applicable with SMART therapy and the use of action plans has not been clarified with this symptom-reactive strategy. There is some evidence from that the current clinical use of SMART therapy may be contaminated frequently by the concurrent prescription of short-acting bronchodilators. There is no information on long-term outcomes with a symptom-reactive ICS/LABA strategy but the use of the strategy for one year has been associated with rising sputum and airway biopsy eosinophil counts. CONCLUSION: Despite fewer severe exacerbations with SMART therapy as compared to ICS monotherapy or lower dose ICS/LABA therapy, the strategy produces poor day-to-day control of symptoms and is associated with increasing inflammation. CLINICAL RELEVANCE: The symptom-reactive strategy described as SMART therapy is associated with poor symptom control of asthma.

Reactive gas environment induced structural modification of noble-transition metal alloy nanoparticles.

Noble-transition metal (noble=Pt,Au; transition=Co,Ni,Cu) alloy particles with sizes of about 5 nm have been studied by in situ high-energy x-ray diffraction while subjected to oxidizing (O(2)) and reducing (H(2)) gas atmospheres at elevated temperatures. The different gas atmospheres do not affect substantially the random alloy, face-centered-cubic structure type of the particles but do affect the way the metal atoms pack together. In an O(2) atmosphere, atoms get extra separated from each other, whereas, in an H(2) atmosphere, they come closer together. The effect is substantial, amounting to 0.1 Å difference in the first neighbor atomic distances, and concurs with a dramatic change of the particle catalytic properties. It is argued that such reactive gas induced "expansion shrinking" is a common phenomenon that may be employed for the engineering of "smart" nanoparticles responding advantageously to envisaged gas environments.

Evidence of cis-acting regulatory variation in PTPN22 in patients with rheumatoid arthritis.

OBJECTIVES: To assess whether there are cis-regulatory polymorphisms that regulate protein tyrosine phosphatase, non-receptor type 22 (PTPN22) expression in rheumatoid arthritis (RA). METHODS: RNA was extracted from positively selected CD56+, CD8+, and CD4+ mononuclear cells and the 'residual' cells from 12 RA patients heterozygous for the PTPN22 C1858T single nucleotide polymorphism (SNP) (rs2476601). Relative allelic expression was measured by single base extension (SBE) assay. RESULTS: There was relative differential allelic expression (DAE ≥ 20%) in eight patients (p < 10(-5)); seven patients demonstrated DAE in more than one cell type; four patients had statistically significant differences between these cell populations (p(corrected) < 0.05). CONCLUSIONS: We have demonstrated significant differences in expression of PTPN22 alleles in RA patients, indicating the probable existence of cis-acting regulatory elements.

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.

OBJECTIVES: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. METHODS: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. RESULTS: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. CONCLUSIONS: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Retrotransposition mechanisms.

Recent developments in the area of the transposition mechanisms used by retrotransposons and related retroviral pathways are discussed. In particular, advances in the areas of retrotransposon gene expression, virus-like particle assembly, reverse transcription, and integration are reviewed.

The Canadian Neuromuscular Disease Registry 2010-2019: A Decade of Facilitating Clinical Research Througha Nationwide, Pan-NeuromuscularDisease Registry.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.