Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Factors Associated with Discontinuation of Active Surveillance among Men with Low-Risk Prostate Cancer: A Population-Based Study.

PURPOSE: The purpose of this study was to describe the uptake, discontinuation and variation of active surveillance (AS) by provider and patient level characteristics. MATERIALS AND METHODS: This observational, population-based study used linked administrative databases and pathology reports to identify all men diagnosed with Gleason score ≤6 prostate cancer (PC) between January 1, 2008 and December 31, 2014 in Ontario, Canada. The Cochran-Armitage test was used for AS trend over time. Treatment-free survival was estimated using cumulative incidence function. Factors associated with discontinuation of AS were evaluated using Cox proportional hazard models. RESULTS: Active surveillance was the initial management strategy for 8,541 cases (51%). Use of AS significantly increased from 38% in 2008 to 69% in 2014 (p=0.001). Men on AS were significantly older (64 years, SD 8.0) than those on initial treatment (62 years, SD 7.7; p=0.001). After a median followup of 48 months, 4,337 (51%) patients had discontinued AS. Treatment-free survival for AS patients at 1, 3, and 5 years were 85%, 58% and 52%, respectively. Median time to definitive treatment after initial AS was 16 months (IQR 11-25 months). Factors associated with AS discontinuation were younger age at diagnosis, year of diagnosis, higher comorbidities, treatment at academic center, treatment by physician and institution in the highest volume tertile, and adverse cancer-specific characteristics (higher prostate specific antigen [PSA], higher number of positive cores and higher percentage of core involvement at diagnosis). CONCLUSIONS: Although the uptake of AS significantly increased over time, there has been a relatively high rate of discontinuation over 5 years. Factors associated with transition to definitive treatment were younger age, care provided by higher volume physicians and institutions, higher PSA and greater PC volume at diagnosis. These results may help guide policy making, developing quality indicators, and developing targeted continued education for physician and patients embarking on AS to establish realistic expectations.

Real-World Practice Patterns and Predictors of Continuous versus Intermittent Androgen Deprivation Therapy Use for Prostate Cancer in Older Men.

PURPOSE: Phase-III randomized control trial evidence suggests intermittent androgen deprivation therapy (IADT) is not significantly inferior to continuous androgen deprivation therapy (ADT) for patients with prostate cancer (PC). However, clinical practice and guidelines differ in their recommendations. We evaluate real-world utilization and practice patterns of IADT. MATERIALS AND METHODS: Ontario men ≥65 years of age with PC who initiated ADT for ≥3 months were identified (1997-2017). Lapses in ADT ≥6 months (initial gap) and ≥3 months (subsequent gaps) were used to classify IADT. Neoadjuvant/adjuvant therapy was excluded. Disease stage adjustment was completed for patients with likely metastatic disease based on de novo presentation with ADT. Patient and physician predictors of IADT were analyzed using multivariable logistic regression. RESULTS: We identified 8,544 patients with 1,715 having previously received local therapy. Among all patients, 16.4% received IADT. This ranged from 11.4%-24.8% across health-planning regions and increased to 26.6% in those with previous local therapy. Mean followup was 8.3 years. Patients with prior local therapy (OR 1.85, 95% CI 1.59-2.17, p <0.001) and those in the highest income quintile (OR 1.32, 95% CI 1.08-1.60, p=0.005) had increased odds of receiving IADT. Radiation oncologists were more likely to use IADT than urologists (OR 1.99, 95% CI 1.59-2.50, p <0.001), as were physicians with more experience (≥10 years in practice: OR 1.44, 95% CI 1.11-1.88, p=0.007). In specialty-stratified analyses, case volume was significantly associated with IADT for radiation oncologists (highest quartile: OR 1.73, 95% CI 1.14-2.62, p=0.009). CONCLUSIONS: IADT remains underutilized for patients with PC who ≥65 years of age with only 1 in 4 to 1 in 6 eligible patients receiving this form of care. Clinical, sociodemographic and physician characteristics play an important role in treatment selection.

Higher levels of social and material deprivation are associated with higher rates of influenza-like illness-related emergency department visits: Edmonton, Alberta, 2004-2014.

OBJECTIVES: Neighbourhood-level deprivation is associated with hospitalization related to respiratory infections; however, hospitalizations exclude many who seek care with less severe respiratory illnesses. Another major seasonal contributor to respiratory illness-associated healthcare burdens are influenza-like illness (ILI)-related emergency department (ED) visits. We investigated associations between area-level social and material deprivation and ILI-related ED use. STUDY DESIGN: This is a retrospective ecological study. METHODS: We linked ILI-related ED visit data (2004-2014) for Edmonton, Alberta to a Canadian area-level material and social deprivation index, categorizing deprivation into quintiles. Using a multivariable Poisson model with log population as the offset, we modelled the relationship between visit rates and material and social deprivation adjusting for week and season, age, sex and the interaction between age and sex. RESULTS: We included 67,585 ILI-related ED visits, representing 1075.5 (95% confidence interval (CI) = 1067.4-1083.6) visits per 100,000 person-years. ILI-related visit rates increased as each of material and social deprivation increased; increases were slightly greater for material deprivation. Comparing the most deprived quintile to the least deprived quintile: for material deprivation, ILI-related ED visit rates were two times higher (rate ratio (RR) = 2.00, 95% CI = 1.96-2.05); and, for social deprivation, one-and-a-half times higher (RR = 1.47, 95% CI = 1.44-1.51). CONCLUSIONS: Higher area-level material and social deprivation were associated with higher ILI-related ED visit rates. These findings can be used to identify areas that may need additional public health and healthcare resources and to improve targeting of prevention strategies. Understanding differentials in healthcare use such as this may be especially relevant to ensuring equity of outcomes for pandemic preparedness planning.

Predicting influenza-like illness-related emergency department visits by modelling spatio-temporal syndromic surveillance data.

Predicting the magnitude of the annual seasonal peak in influenza-like illness (ILI)-related emergency department (ED) visit volumes can inform the decision to open influenza care clinics (ICCs), which can mitigate pressure at the ED. Using ILI-related ED visit data from the Alberta Real Time Syndromic Surveillance Net for Edmonton, Alberta, Canada, we developed (training data, 1 August 2004-31 July 2008) and tested (testing data, 1 August 2008-19 February 2014) spatio-temporal statistical prediction models of daily ILI-related ED visits to estimate high visit volumes 3 days in advance. Our Main Model, based on a generalised linear mixed model with random intercept, incorporated prediction residuals over 14 days and captured increases in observed volume ahead of peaks. During seasonal influenza periods, our Main Model predicted volumes within ±30% of observed volumes for 67%-82% of high-volume days and within 0.3%-21% of observed seasonal peak volumes. Model predictions were not as successful during the 2009 H1N1 pandemic. Our model can provide early warning of increases in ILI-related ED visit volumes during seasonal influenza periods of differing intensities. These predictions may be used to support public health decisions, such as if and when to open ICCs, during seasonal influenza epidemics.

ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children.

Respiratory depression (RD) is a serious side effect of morphine and detrimental to effective analgesia. We reported that variants of the ATP binding cassette gene ABCC3 (facilitates hepatic morphine metabolite efflux) affect morphine metabolite clearance. In this study of 316 children undergoing tonsillectomy, we found significant association between ABCC3 variants and RD leading to prolonged postoperative care unit stay (prolonged RD). Allele A at rs4148412 and allele G at rs729923 caused a 2.36 (95% CI=1.28-4.37, P=0.0061) and 3.7 (95% CI 1.47-9.09, P=0.0050) times increase in odds of prolonged RD, respectively. These clinical associations were supported by increased formation clearance of morphine glucuronides in children with rs4148412 AA and rs4973665 CC genotypes in this cohort, as well as an independent spine surgical cohort of 67 adolescents. This is the first study to report association of ABCC3 variants with opioid-related RD, and morphine metabolite formation (in two independent surgical cohorts).

Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.

Eosinophilic esophagitis (EoE) is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Other pathologic features have not been emphasized. We developed a histology scoring system for esophageal biopsies that evaluates eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces (DIS), surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities were scored using a 4-point scale (0 normal; 3 maximum change). Reliability was demonstrated by strong to moderate agreement among three pathologists who scored biopsies independently (P ≤ 0.008). Several features were often abnormal in 201 biopsies (101 distal, 100 proximal) from 104 subjects (34 untreated, 167 treated). Median grade and stage scores were significantly higher in untreated compared with treated subjects (P ≤ 0.0062). Grade scores for features independent of eosinophil counts were significantly higher in biopsies from untreated compared with treated subjects (basal zone hyperplasia P ≤ 0.024 and DIS P ≤ 0.005), and were strongly correlated (R-square >0.67). Principal components analysis identified three principal components that explained 78.2% of the variation in the features. In logistic regression models, two principal components more closely associated with treatment status than log distal peak eosinophil count (PEC) (R-square 17, area under the curve (AUC) 77.8 vs. R-square 9, AUC 69.8). In summary, the EoE histology scoring system provides a method to objectively assess histologic changes in the esophagus beyond eosinophil number. Importantly, it discriminates treated from untreated patients, uses features commonly found in such biopsies, and is utilizable by pathologists after minimal training. These data provide rationales and a method to evaluate esophageal biopsies for features in addition to PEC.

Google Flu Trends in Canada: a comparison of digital disease surveillance data with physician consultations and respiratory virus surveillance data, 2010-2014.

The value of Google Flu Trends (GFT) remains unclear after it overestimated the proportion of physician visits related to influenza-like illness (ILI) in the United States in 2012-2013. However, GFT estimates (%GFT) have not been examined nationally in Canada nor compared with positivity for respiratory viruses other than influenza. For 2010-2014, we compared %GFT for Canada to Public Health Agency of Canada ILI consultation rates (%PHAC) and to positivity for influenza A and B, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and rhinoviruses. %GFT correlated well with %PHAC (ρ = 0·77-0·90) and influenza A positivity (ρ = 0·64-0·96) and overestimated the 2012-2013 %PHAC peak by 0·99 percentage points. %GFT peaks corresponded temporally with peaks in positivity for influenza A and rhinoviruses (all seasons) and RSV and hMPV when their peaks preceded influenza peaks. In Canada, %GFT represented traditional surveillance data and corresponded temporally with patterns in circulating respiratory viruses.

Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents.

The µ1 opioid receptor (OPRM1) genetic variant A118G results in decreased µ-receptor binding potential in the brain and increases morphine requirement. We hypothesized that OPRM1 A118G polymorphism will affect morphine-induced respiratory depression (MIRD) risk in children receiving morphine. A prospective genotype-blinded study was conducted in 88 healthy adolescents (11-18 years; 67% female, 85% Caucasian) who underwent spine fusion for scoliosis. They were followed for 48 h postoperatively for MIRD, pain scores, morphine consumption and use of analgesic adjuvants. Patients were genotyped for OPRM1 A118G variant-76% were wild type (AA) and 24% heterozygous/homozygous for variant (AG/GG). Multivariable logistic regression showed that the risk of MIRD in patients with AA genotype was significantly higher (odds ratio 5.6, 95% CI: 1.4-37.2, P=0.030). Presence of G allele was associated with higher pain scores (effect size 0.73, P=0.045). This novel association is an important step toward predicting MIRD susceptibility and personalizing morphine use.

Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics.

Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood-brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1-10.8, P=0.0002).

Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects.

Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year because of opioid-induced respiratory depression (RD) in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype-blinded observational study in which 259 healthy children between 6 and 15 years of age who received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold increased risk for refractory PONV (adjusted P<0.0018), and nominal associations (P<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. The FAAH SNP, rs324420, is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

N-acetyltransferase 1 polymorphism increases cotinine levels in Caucasian children exposed to secondhand smoke: the CCAAPS birth cohort.

Cotinine is a proxy for secondhand smoke (SHS) exposure. Genetic variation along nicotine and cotinine metabolic pathways may alter the internal cotinine dose, leading to misinterpretations of exposure-health outcome associations. Caucasian children with available SHS exposure and hair cotinine data were genotyped for metabolism-related genes. SHS-exposed children had 2.4-fold higher hair cotinine (0.14±0.22 ng mg(-1)) than unexposed children (0.06±0.05 ng mg(-1), P<0.001). SHS-exposed children carrying the NAT1 minor allele had twofold higher hair cotinine (0.18 ng mg(-1) for heterozygotes and 0.17 ng mg(-1) for homozygotes) compared with major allele homozygotes (0.09 ng mg(-1), P=0.0009), even after adjustment for SHS dose. These findings support that NAT1 has a role in the metabolic pathway of nicotine/cotinine and/or their metabolites. The increased cotinine levels observed for those carrying the minor allele may lead to SHS exposure misclassification in studies utilizing cotinine as a biomarker. Additional studies are required to identify functional single-nucleotide polymorphism(s) (SNP(s)) in NAT1 and elucidate the biological consequences of the mutation(s).

Genetic approach identifies distinct asthma pathways in overweight vs normal weight children.

The pathogenesis of asthma in the context of excess body weight may be distinct from asthma that develops in normal weight children. The study's objective was to explore the biology of asthma in the context of obesity and normal weight status using genetic methodologies. Associations between asthma and SNPs in 49 genes were assessed, as well as, interactions between SNPs and overweight status in child participants of the Greater Cincinnati Pediatric Clinic Repository. Asthma was significantly associated with weight (OR = 1.38; P = 0.037). The number of genes and the magnitude of their associations with asthma were notably greater when considering overweight children alone vs normal weight and overweight children together. When considering weight, distinct sets of asthma-associated genes were observed, many times with opposing effects. We demonstrated that the underlying heterogeneity of asthma is likely due in part to distinct pathogenetic pathways that depend on preceding/comorbid overweight and/or allergy. It is therefore important to consider both obesity and asthma when conducting studies of asthma.

Transformational teaching and adolescent physical activity: multilevel and mediational effects.

BACKGROUND: Regular physical activity is associated with a range of physical and psychological health benefits. In North America the majority of adolescents are insufficiently active. PURPOSE: The purpose of this study was to examine the prospective relationship between adolescents' perceptions of transformational leadership displayed by their school physical education teachers and their own physical activity behaviors, both with respect to within-class physical activity (WCPA) and also leisure time physical activity (LTPA). METHOD: The study used a prospective observational design. Using multilevel structural equation modeling (MSEM), we examined the extent to which adolescents' affective attitudes mediated the effects of teachers' behaviors on adolescents' physical activity responses. Two thousand nine hundred and forty-eight adolescents (M age = 14.33, SD = 1.00, N female = 1,641, 55.7 %) from 133 Grade 8-10 classes in British Columbia (Canada) provided ratings of their physical education teachers' behaviors midway through the school year. Two months later, students completed measures of affective attitudes, WCPA, and LTPA. RESULTS: The results indicated that adolescents' perceptions of transformational teaching explained significant variance in both WCPA and LTPA, and these effects were fully mediated by adolescents' affective attitudes (total indirect effect: b = 0.581, p < 0.001). CONCLUSION: The findings suggest that transformational leadership behaviors displayed by physical education teachers may be an important source of adolescent enjoyment of physical education as well as health-enhancing physical activity involvement within school and outside of school.

Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR), Spanish Society of Emergency and Emergency Medicine (SEMES) and Spanish Society of Otolaryngology, Head and Neck Surgery (SEORL-CCC) Guideline for difficult airway management. Part I.

The Airway Management section of the Spanish Society of Anesthesiology, Resuscitation, and Pain Therapy (SEDAR), the Spanish Society of Emergency Medicine (SEMES), and the Spanish Society of Otorhinolaryngology and Head and Neck Surgery (SEORL-CCC) present the Guide for the comprehensive management of difficult airway in adult patients. Its principles are focused on the human factors, cognitive processes for decision-making in critical situations, and optimization in the progression of strategies application to preserve adequate alveolar oxygenation in order to enhance safety and the quality of care. The document provides evidence-based recommendations, theoretical-educational tools, and implementation tools, mainly cognitive aids, applicable to airway management in the fields of anesthesiology, critical care, emergencies, and prehospital medicine. For this purpose, an extensive literature search was conducted following PRISMA-R guidelines and was analyzed using the GRADE methodology. Recommendations were formulated according to the GRADE methodology. Recommendations for sections with low-quality evidence were based on expert opinion through consensus reached via a Delphi questionnaire.

Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR), Spanish Society of Emergency and Emergency Medicine (SEMES) and Spanish Society of Otolaryngology, Head and Neck Surgery (SEORL-CCC) Guideline for difficult airway management. Part II.

The Airway Management section of the Spanish Society of Anesthesiology, Resuscitation, and Pain Therapy (SEDAR), the Spanish Society of Emergency Medicine (SEMES), and the Spanish Society of Otorhinolaryngology and Head and Neck Surgery (SEORL-CCC) present the Guide for the comprehensive management of difficult airway in adult patients. Its principles are focused on the human factors, cognitive processes for decision-making in critical situations, and optimization in the progression of strategies application to preserve adequate alveolar oxygenation in order to enhance safety and the quality of care. The document provides evidence-based recommendations, theoretical-educational tools, and implementation tools, mainly cognitive aids, applicable to airway management in the fields of anesthesiology, critical care, emergencies, and prehospital medicine. For this purpose, an extensive literature search was conducted following PRISMA-R guidelines and was analyzed using the GRADE methodology. Recommendations were formulated according to the GRADE methodology. Recommendations for sections with low-quality evidence were based on expert opinion through consensus reached via a Delphi questionnaire.

Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS): a protocol for a randomised controlled trial.

BACKGROUND: Patients with recent stroke or TIA are at high risk for new vascular events. Several evidence based strategies in secondary prevention of stroke are available but frequently underused. Support programs with multifactorial risk factor modifications after stroke or TIA have not been investigated in large-scale prospective controlled trials so far. INSPiRE-TMS is a prospective, multi-center, randomized open intervention trial for intensified secondary prevention after minor stroke and TIA. METHODS/DESIGN: Patients with acute TIA or minor stroke admitted to the participating stroke centers are screened and recruited during in-hospital stay. Patients are randomised in a 1:1 ratio to intervention (support program) and control (usual care) arms. Inclusion of 2.082 patients is planned. The support program includes cardiovascular risk factor measurement and feedback, monitoring of medication adherence, coaching in lifestyle modifications, and active involvement of relatives. Standardized motivational interviewing is used to assess and enhance patients' motivation. Primary objective is a reduction of new major vascular events defined as nonfatal stroke and myocardial infarction or vascular death. Recruitment time is planned for 3.5 years, follow up time is at least 2 years for every patient resulting in a total study time of 5 years (first patient in to last patient out). DISCUSSION: Given the high risk for vascular re-events in acute stroke and the available effective strategies in secondary prevention, the INSPIRE-TMS support program has the potential to lead to a relevant reduction of recurrent events and a prolongation of the event-free survival time. The trial will provide the basis for the decision whether an intensified secondary prevention program after stroke should be implemented into regular care. A cost-effectiveness evaluation will be performed. TRIAL REGISTRATION: clinicaltrials.gov: 01586702.

A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.

An exceptional muscle development commonly referred to as 'double-muscled' (Fig. 1) has been seen in several cattle breeds and has attracted considerable attention from beef producers. Double-muscled animals are characterized by an increase in muscle mass of about 20%, due to general skeletal-muscle hyperplasia-that is, an increase in the number of muscle fibers rather than in their individual diameter. Although the hereditary nature of the double-muscled condition was recognized early on, the precise mode of inheritance has remained controversial; monogenic (domainant and recessive), oligogenic and polygenic models have been proposed. In the Belgian Blue cattle breed (BBCB), segregation analysis performed both in experimental crosses and in the outbred population suggested an autosomal recessive inheritance. This was confirmed when the muscular hypertrophy (mh) locus was mapped 3.1 cM from microsatellite TGLA44 on the centromeric end of bovine chromosome 2 (ref. 5). We used a positional candidate approach to demonstrate that a mutation in bovine MSTN, which encodes myostatin, a member of the TGF beta superfamily, is responsible for the double-muscled phenotype. We report an 11-bp deletion in the coding sequence for the bioactive carboxy-terminal domain of the protein causing the muscular hypertrophy observed in Belgian Blue cattle.

South Africa's male homicide epidemic hiding in plain sight: exploring sex differences and patterns in homicide risk in a retrospective descriptive study of postmortem investigations.

Background: South Africa has homicide rates six times the global average, predominantly among men, but little is known about male victims. As part of the country's first ever study of male homicide we compared 2017 male and female victim profiles for selected covariates, against global averages and previous estimates for 2009. Methods: We conducted a retrospective descriptive study of routine data collected through postmortem investigations, calculating age-standardised mortality rates for manner of death by age, sex and province and male-to-female incidence rate ratios with 95% confidence intervals. We then used generalised linear models and linear regression models to assess the association between sex and victim characteristics including age and mechanism of injury (guns, stabs and blunt force) within and between years. Findings: 87% of 19,477 homicides in 2017 were males, equating to seven male deaths for every female, with sharp force and firearm discharge the most common external causes. Rates were higher among males than females at all ages, and up to eight times higher among males aged 15-44 years. Provincial rates varied overall and by sex, with the highest comparative risk for men vs. women in the Western Cape Province (11.4 males for every 1 female). Male homicides peaked during December and were highest on weekends, underscoring the prominent role of alcohol as a risk factor. Significantly more males tested positive for alcohol than females. Interpretation: The massive, disproportionate and enduring homicide risk borne by adult South African men highlights the negligible prevention response. Only through challenging the normative perception of male invulnerability can we begin to address the enormous burden of violence impacting men. There is an urgent need to address the insidious effect of such societal norms alongside implementing structural interventions to overcome the root causes of poverty and inequality and better control alcohol and firearms. Funding: South African Medical Research Council and Ford Foundation.

Further evidence of misclassification of the injury deaths in South Africa: When will the barriers to accurate injury death statistics be removed?

BACKGROUND: Contrary to the World Health Organization's internationally recommended medical certificate of cause of death, the South African (SA) death notification form (DNF) does not allow for the reporting of the manner of death to permit accurate coding of external causes of injury deaths. OBJECTIVES: To describe the injury cause-of-death profile from forensic pathology records collected for the National Cause-of-Death Validation (NCoDV) Project and compare it with profiles from other sources of injury mortality data. In particular, the recording of firearm use in homicides is compared between sources. METHODS: The NCoDV Project was a cross-sectional study of deaths that occurred during a fixed period in 2017 and 2018, from a nationally representative sample of 27 health subdistricts in SA. Trained fieldworkers scanned forensic records for all deaths investigated at the forensic mortuaries serving the sampled subdistricts during the study period. Forensic practitioners reviewed the records and completed a medical certificate of cause of death for each decedent. Causes of death were coded to the International Statistical Classification of Diseases, 10th revision (ICD-10), using Iris automated coding software. Cause-specific mortality fractions for injury deaths were compared with Injury Mortality Survey 2017 (IMS 2017) and Statistics South Africa 2017 (Stats SA 2017) datasets. The cause profile for all firearm-related deaths was compared between the three datasets. RESULTS: A total of 5 315 records were available for analysis. Males accounted for 77.6% of cases, and most decedents were aged between 25 and 44 years. Homicide was the leading cause of death (34.7%), followed by transport injuries (32.6%) and suicide (14.7%). This injury cause profile was similar to IMS 2017 but differed markedly from the official statistics, which showed markedly lower proportions of these three causes (15.0%, 11.6% and 0.7%, respectively), and a much higher proportion of other unintentional causes. Investigation of firearm-related deaths revealed that most were homicides in NCoDV 2017/18 (88.5%) and IMS 2017 (93.1%), while in the Stats SA 2017 data, 98.7% of firearm deaths were classified as accidental. Approximately 7% of firearm-related deaths were suicides in NCoDV 2017/18 and IMS 2017, with only 0.3% in Stats SA 2017. CONCLUSION: The official cause-of-death data for injuries in SA in 2017 differed substantially from findings from the NCoDV 2017/18 study and IMS 2017. Accurate data sources would ensure that public health interventions are designed to reduce the high injury burden. Inclusion of the manner of death on the DNF, as is recommended internationally, is critically important to enable more accurate, reliable and valid reporting of the injury profile.