Histone H3 E50K mutation confers oncogenic activity and supports an EMT phenotype.

Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype in human cells. Expression of H3E50K is sufficient to transform human cells as evidenced by a dramatic increase in cell migration and invasion, and a statistically significant increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K perturbs proximal H3 post-translational modifications globally and dysregulates gene expression, activating the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional histone H3 mutations have the potential to be oncogenic drivers and function through distinct mechanisms that dysregulate gene expression.

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

The association of postnatal urinary tract dilation risk score with clinical outcomes.

BACKGROUND: There are limited data on the predictive value of the consensus urinary tract dilation (UTD) score with respect to subsequent clinical diagnoses. We sought to define the relationship between postnatal UTD risk score and clinical outcomes during childhood. METHODS: Complete ultrasound image sets from a random selection of infants aged 0-90 days undergoing initial ultrasound at a single institution for prenatal hydronephrosis between 2012 and 2014 were assigned a UTD score by 1 pediatric urologist and 1 pediatric radiologist. Urinary tract dilation risk score was analyzed for association with a composite outcome comprising urinary tract infection, vesicoureteral reflux (VUR), ureteropelvic junction obstruction, non-refluxing megaureter (NRM), ureterocele, bladder outlet obstruction (BOO), and chronic kidney disease. Surgical intervention and resolution of UTD were evaluated separately. Descriptive and survival analyses were performed. RESULTS: Urinary tract dilation scores for 494 subjects were P0 in 23.5%, P1 in 26.5%, P2 in 23.5%, and P3 in 26.5%. Seventy-four percent were male. Median age at initial imaging was 28 days; median follow-up was 19.8 months. The composite outcome occurred in 138 of 494 patients (27.9%) and varied significantly (p < 0.001) by UTD score: 11.2% for P0, 10.7% for P1, 29.3% for P2, and 58.8% for P3. On survival analysis (Summary Figure), higher UTD grade was significantly associated with the composite outcome (hazard ratio for P3 vs. P0 was 7.4 [95% CI: 3.44-15.92, p < 0.001]). Urinary tract infection and VUR diagnosis varied by UTD score (p = 0.03 and p < 0.001, respectively). Ureteropelvic junction obstruction was diagnosed (based on MAG3 results) in 6.3% of patients, 84% of whom were P3. Non-refluxing megaureter was diagnosed in 7.7%. Ureterocele and BOO were uncommon (1.4%, and 0.6%, respectively). Surgical intervention was also associated with UTD risk, with 46% of P3 undergoing surgery vs. 1% of P0, 1% of P1, and 6% of P2 (p < 0.001). Resolution of UTD occurred in 41% (median 10.1 months) and varied significantly by UTD risk (p < 0.001). DISCUSSION: Urinary tract dilation risk score is associated with clinical events, although ascertainment bias may influence some of the differences in outcomes, particularly for VUR, because VCUG utilization varied by the UTD group. The lack of any significant difference in outcomes between patients with UTD P0 versus P1 suggests that the P1 category could be eliminated as it does not meaningfully distinguish between outcome risk. CONCLUSIONS: Higher UTD risk scores are strongly associated with genitourinary diagnoses during the first two years of life.

A contemporary single-institution retrospective cohort study comparing perioperative outcomes between robotic and open partial nephrectomy for poorly functioning renal moieties in children with duplex collecting systems.

INTRODUCTION: Studies evaluating robotic-assisted laparoscopic partial nephrectomy (RALPN) are limited to case series, amounting to a lack of studies directly comparing perioperative outcomes for RALPN to open partial nephrectomy (OPN). OBJECTIVE: To compare perioperative outcomes between RALPN and OPN. METHODS: A single-institution, retrospective cohort study was performed to compare perioperative outcomes (operative time (OT), length of stay (LOS), complications, readmissions, postoperative interventions, loss in size of the residual moiety, and the presence of postoperative 'contained fluid collections') for RALPN and OPN between February 2007 and July 2014. Descriptive statistics were calculated and unadjusted analyses performed, including Chi-squared/Fisher's exact for categorical variables and Wilcoxon rank sum for continuous variables. RESULTS: During the study period, 43 partial nephrectomies were performed for benign disease: 27 (63%) RALPN and 16 (37%) OPN. The RALPN cohort was significantly older than the OPN cohort (3.5 vs. 0.8 years; P = 0.003). The cohorts were otherwise similar regarding race, American Society of Anesthesiologist score (ASA), affected moiety, laterality, associated anomalies, moiety function, and surgical indication. Robotic-assisted laparoscopic partial nephrectomy was associated with a significantly shorter LOS (1 vs. 3 days; P = 0.002). Operative time and complication rates were comparable. The OPN group had a longer median follow-up (2.7 years vs. 1.1; P = 0.03). No differences were observed between the cohorts for readmissions, postoperative interventions, loss in size of residual moiety, or development of 'contained fluid collections'. These outcomes are reported in the Summary Table. 'Contained fluid collections' occurred more frequently after lower pole resections (73% vs. 30%; P = 0.009). DISCUSSION: This study is one of the few to directly compare RALPN to OPN, and demonstrated that RALPN has comparable (if not better) outcomes than OPN. In particular, RALPN provides the advantage of a shorter LOS. Avoiding the flank incision used in OPN may also offer reduced pain; however, this was not studied here and the literature provides weak evidence for this effect. This unadjusted analysis may have been confounded by its short median follow-up and significantly younger OPN cohort. CONCLUSION: In this contemporary comparative analysis, RALPN predicted a similar median OT and safety profile to OPN while offering the advantage of a shorter LOS. Regardless of surgical cohort, there were no adverse effects on the residual renal moieties and postoperative 'contained fluid collections' occurred with notable frequency and were independently associated with lower pole pathology.

A transdiagnostic study of education, employment, and training outcomes in young people with mental illness.

BACKGROUND: Optimizing functional recovery in young individuals with severe mental illness constitutes a major healthcare priority. The current study sought to quantify the cognitive and clinical factors underpinning academic and vocational engagement in a transdiagnostic and prospective youth mental health cohort. The primary outcome measure was 'not in education, employment or training' ('NEET') status. METHOD: A clinical sample of psychiatric out-patients aged 15-25 years (n = 163) was assessed at two time points, on average, 24 months apart. Functional status, and clinical and neuropsychological data were collected. Bayesian structural equation modelling was used to confirm the factor structure of predictors and cross-lagged effects at follow-up. RESULTS: Individually, NEET status, cognitive dysfunction and negative symptoms at baseline were predictive of NEET status at follow-up (p < 0.05). Baseline cognitive functioning was the only predictor of follow-up NEET status in the multivariate Bayesian model, while controlling for baseline NEET status. For every 1 s.d. deficit in cognition, the probability of being disengaged at follow-up increased by 40% (95% credible interval 19-58%). Baseline NEET status predicted poorer negative symptoms at follow-up (ß = 0.24, 95% credible interval 0.04-0.43). CONCLUSIONS: Disengagement with education, employment or training (i.e. being NEET) was reported in about one in four members of this cohort. The initial level of cognitive functioning was the strongest determinant of future NEET status, whereas being academically or vocationally engaged had an impact on future negative symptomatology. If replicated, these findings support the need to develop early interventions that target cognitive phenotypes transdiagnostically.

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence.

Epigenetic consequences of exposure to psychostimulants are substantial but the relationship of these changes to compulsive drug taking and abstinence is not clear. Here, we used a paradigm that helped to segregate rats that reduce or stop their methamphetamine (METH) intake (nonaddicted) from those that continue to take the drug compulsively (addicted) in the presence of footshocks. We used that model to investigate potential alterations in global DNA hydroxymethylation in the nucleus accumbens (NAc) because neuroplastic changes in the NAc may participate in the development and maintenance of drug-taking behaviors. We found that METH-addicted rats did indeed show differential DNA hydroxymethylation in comparison with both control and nonaddicted rats. Nonaddicted rats also showed differences from control rats. Differential DNA hydroxymethylation observed in addicted rats occurred mostly at intergenic sites located on long and short interspersed elements. Interestingly, differentially hydroxymethylated regions in genes encoding voltage (Kv1.1, Kv1.2, Kvb1 and Kv2.2)- and calcium (Kcnma1, Kcnn1 and Kcnn2)-gated potassium channels observed in the NAc of nonaddicted rats were accompanied by increased mRNA levels of these potassium channels when compared with mRNA expression in METH-addicted rats. These observations indicate that changes in differentially hydroxymethylated regions and increased expression of specific potassium channels in the NAc may promote abstinence from drug-taking behaviors. Thus, activation of specific subclasses of voltage- and/or calcium-gated potassium channels may provide an important approach to the beneficial treatment for METH addiction.

Search for common targets of lithium and valproic acid identifies novel epigenetic effects of lithium on the rat leptin receptor gene.

Epigenetics may have an important role in mood stabilizer action. Valproic acid (VPA) is a histone deacetylase inhibitor, and lithium (Li) may have downstream epigenetic actions. To identify genes commonly affected by both mood stabilizers and to assess potential epigenetic mechanisms that may be involved in their mechanism of action, we administered Li (N = 12), VPA (N = 12), and normal chow (N = 12) to Brown Norway rats for 30 days. Genomic DNA and mRNA were extracted from the hippocampus. We used the mRNA to perform gene expression analysis on Affymetrix microarray chips, and for genes commonly regulated by both Li and VPA, we validated expression levels using quantitative real-time PCR. To identify potential mechanisms underlying expression changes, genomic DNA was bisulfite treated for pyrosequencing of key CpG island 'shores' and promoter regions, and chromatin was prepared from both hippocampal tissue and a hippocampal-derived cell line to assess modifications of histones. For most genes, we found little evidence of DNA methylation changes in response to the medications. However, we detected histone H3 methylation and acetylation in the leptin receptor gene, Lepr, following treatment with both drugs. VPA-mediated effects on histones are well established, whereas the Li effects constitute a novel mechanism of transcriptional derepression for this drug. These data support several shared transcriptional targets of Li and VPA, and provide evidence suggesting leptin signaling as an epigenetic target of two mood stabilizers. Additional work could help clarify whether leptin signaling in the brain has a role in the therapeutic action of Li and VPA in bipolar disorder.

Neuropsychological and functional outcomes in recent-onset major depression, bipolar disorder and schizophrenia-spectrum disorders: a longitudinal cohort study.

Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M=21.5 years old, s.d.=4.8) and returned for follow-up (M=20.6 months later, s.d.=7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n=71), bipolar disorder (BD; n=61), schizophrenia-spectrum disorders (n=35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P>0.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (P<0.01). Improved sustained attention was independently associated with greater likelihood of follow-up employment (P<0.01). Diagnosis of BD uniquely predicted both follow-up employment and independent living. Neuropsychological course appears to be independently predictive of subjective and objective functional outcomes. Importantly, cognitive phenotypes may reflect distinct pathophysiologies shared across major psychiatric conditions, and be ideal targets for personalized early intervention.

Influence of pathogenic bacteria species present in the postpartum bovine uterus on proteome profiles.

In the first 2-3 weeks after parturition >90% of dairy cows will have some form of uterine infection. Uterine contamination with pathogens, such as Trueperella (formerly Arcanobacterium) pyogenes increases the risk of developing more severe endometritis, which can reduce conception rates. In this study, we compared the uterine proteome of cows infected with Trueperella pyogenes with that of uninfected cows, using 2D gel electrophoresis, and identified annexins A1 and A2 (ANXA1 and ANXA2), apolipoprotein A-1, calprotectin (S100A9), cathelicidin, enolase 1 (ENO1), peptidoglycan recognition protein 1 (PGLYRP1), phosphoglycerate mutase 1 (PGAM1), serine dehydratase (SDS) and serine protease inhibitors (SERPIN) B1, B3 and B4 proteins as differing in abundance in endometritis. Subsequently, levels of ten of these proteins were monitored in uterine samples collected from a herd of lactating, dairy cows at 15 and 42 days post-partum (DPP). The levels were compared with the cytology scores of the samples and the bacterial species isolated from the uterus. Cathelicidin, PGLYRP1, SERPINB1 and S100A9 levels at 15DPP showed strong positive correlations (r=0.78, 0.80, 0.79, and 0.68 respectively; P<0.001) with % of polymorphonuclear neutrophils (PMN). When compared with other bacterial pathogens identified, Streptococcus agalactiae and Truperella pyogenes induced increased expression of the indicator proteins, suggesting that these organisms may adversely affect the subsequent ability of the cow to conceive. Interestingly, there was no difference in the proportion of cows pregnant at 6 and 17 weeks after start of mating between the cows with high or low %PMN.

Epidemiology and risk factors for severe respiratory syncytial virus infections requiring pediatric intensive care admission in Hong Kong children.

PURPOSE: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infection in young children. However, there are limited data on severe RSV infection requiring pediatric intensive care unit (PICU) admission. This retrospective study described features of RSV-associated PICU admissions in Hong Kong and investigated factors for mortality and duration of PICU stay. METHODS: Children with laboratory-confirmed RSV infection and admitted to the PICUs of all eight government hospitals in Hong Kong between January 2009 and June 2011 were identified from computerized auditing systems and PICU databases. RSV in respiratory samples was detected by direct immunofluorescence and/or viral culture. The relationships between mortality and PICU duration and demographic and clinical factors were analyzed. RESULTS: A total of 118 (2.4 %) PICU admissions were identified among 4,912 RSV-positive pediatric cases in all hospitals. Sixty-five (55.6 %) patients were infants. PICU admissions were higher between October and March. Eight (6.8 %) patients died, but only two were infants. RSV-associated mortality was related to prior sick contact, presence of older siblings, neurodevelopmental conditions, chromosomal and genetic diseases, and bacterial co-infections, but none was significant following logistic regression analyses (odds ratio 9.36, 95 % confidence interval 0.91-96.03 for prior sick contact, p = 0.060). Chronic lung disease was the only risk factor for the duration of PICU admission (ß = 0.218, p = 0.017). CONCLUSIONS: The majority of RSV-infected children do not require PICU support. There is winter seasonality for RSV-associated PICU admission in Hong Kong. Prior sick contact is the only risk factor for RSV-associated mortality, whereas the presence of chronic lung disease is associated with longer PICU stay. The current risk-based approach of RSV prophylaxis may not be effective in reducing severe RSV infections.

Tuberculosis is associated with increased lung cancer mortality.

SETTING: Elderly persons living in the community in Hong Kong. OBJECTIVE: To examine the association between tuberculosis (TB) and lung cancer. DESIGN: Elderly clients enrolled in a health programme from 2000 to 2003 were retrospectively cross-matched with the territory-wide TB notification registry for TB before enrolment. The cohort was followed up prospectively through linkage with the territory-wide death registry for cause of death until 31 December 2011. All subjects with suspected malignancy or recent weight loss (≥5%) at enrolment and deaths within the first 2 years of follow-up were excluded. RESULTS: Of the 61,239 subjects included, 516 had TB before enrolment. After 490,258 person-years of follow-up, respectively 1344, 910 and 2003 deaths were caused by lung cancer, other tobacco-related malignancies and non-tobacco-related malignancies. TB before enrolment was associated with death due to lung cancer (Mantel-Haenszel weighted relative risk 2.61, 95%CI 1.82-3.74, P < 0.001) but not other malignancies after stratification by sex. TB remained an independent predictor of lung cancer death (adjusted hazard ratio 2.01, 95%CI 1.40-2.90; P < 0.001), after adjustment for multiple potential confounders. CONCLUSIONS: TB was independently associated with subsequent mortality due to lung cancer. This finding calls for intensification of tobacco control and better targeting of lung cancer screening in high TB burden areas.

Cognitive remediation improves memory and psychosocial functioning in first-episode psychiatric out-patients.

BACKGROUND: Cognitive remediation (CR) is an effective treatment for several psychiatric disorders. To date, there have been no published studies examining solely first-episode psychiatric cohorts, despite the merits demonstrated by early intervention CR studies. The current study aimed to assess the effectiveness of CR in patients with a first-episode of either major depression or psychosis. Method Fifty-five patients (mean age = 22.8 years, s.d. = 4.3) were randomly assigned to either CR (n = 28) or treatment as usual (TAU; n = 27). CR involved once-weekly 2-h sessions for a total of 10 weeks. Patients were comprehensively assessed before and after treatment. Thirty-six patients completed the study, and analyses were conducted using an intent-to-treat (ITT) approach with all available data. RESULTS: In comparison to TAU, CR was associated with improved immediate learning and memory controlling for diagnosis and baseline differences. Similarly, CR patients demonstrated greater improvements than TAU patients in psychosocial functioning irrespective of diagnosis. Delayed learning and memory improvements mediated the effect of treatment on psychosocial functioning at a marginal level. CONCLUSIONS: CR improves memory and psychosocial outcome in first-episode psychiatric out-patients for both depression and psychosis. Memory potentially mediated the functional gains observed. Future studies need to build on the current findings in larger samples using blinded allocation and should incorporate longitudinal follow-up and assessment of potential moderators (e.g. social cognition, self-efficacy) to examine sustainability and the precise mechanisms of CR effects respectively.

Review: Placental perturbations induce the developmental abnormalities often observed in bovine somatic cell nuclear transfer.

Since the first success in cloning sheep, the production of viable animals by somatic cell nuclear transfer (SCNT) has developed significantly. Cattle are by far the most successfully cloned species but, despite this, the technique is still associated with a high incidence of pregnancy failure and accompanying placental and fetal pathologies. Pre- and early post-implantation losses can affect up to 70% of the pregnancies. In the surviving pregnancies, placentomegaly and fetal overgrowth are commonly observed, but the incidence varies widely, depending on the genotype of the nuclear donor cell and differences in SCNT procedures. In all cases, the placenta is central to the onset of the pathologies. Although cellular organisation of the SCNT placenta appears normal, placental vascularisation is modified and fetal-to-maternal tissue ratios are slightly increased in the SCNT placentomes. In terms of functionality, steroidogenesis is perturbed and abnormal estrogen production and metabolism probably play an important part in the increased gestation length and lack of preparation for parturition observed in SCNT recipients. Maternal plasma concentrations of pregnancy-associated glycoproteins are increased, mostly due to a reduction in turnover rate rather than increased placental production. Placental glucose transport and fructose synthesis appear to be modified and hyperfructosemia has been observed in neonatal SCNT calves. Gene expression analyses of the bovine SCNT placenta show that multiple pathways and functions are affected. Abnormal epigenetic re-programming appears to be a key component of the observed pathologies, as shown by studies on the expression of imprinted genes in SCNT placenta.

AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy.

The phosphatidylinositol 3-kinase (PI3K)/AKT and RAS oncogenic signalling modules are frequently mutated in sporadic human cancer. Although each of these pathways has been shown to play critical roles in driving tumour growth and proliferation, their activation in normal human cells can also promote cell senescence. Although the mechanisms mediating RAS-induced senescence have been well characterised, those controlling PI3K/AKT-induced senescence are poorly understood. Here we show that PI3K/AKT pathway activation in response to phosphatase and tensin homolog (PTEN) knockdown, mutant PI3K, catalytic, α polypeptide (PIK3CA) or activated AKT expression, promotes accumulation of p53 and p21, increases cell size and induces senescence-associated ß-galactosidase activity. We demonstrate that AKT-induced senescence is p53-dependent and is characterised by mTORC1-dependent regulation of p53 translation and stabilisation of p53 protein following nucleolar localisation and inactivation of MDM2. The underlying mechanisms of RAS and AKT-induced senescence appear to be distinct, demonstrating that different mediators of senescence may be deregulated during transformation by specific oncogenes. Unlike RAS, AKT promotes rapid proliferative arrest in the absence of a hyperproliferative phase or DNA damage, indicating that inactivation of the senescence response is critical at the early stages of PI3K/AKT-driven tumourigenesis. Furthermore, our data imply that chronic activation of AKT signalling provides selective pressure for the loss of p53 function, consistent with observations that PTEN or PIK3CA mutations are significantly associated with p53 mutation in a number of human tumour types. Importantly, the demonstration that mTORC1 is an essential mediator of AKT-induced senescence raises the possibility that targeting mTORC1 in tumours with activated PI3K/AKT signalling may exert unexpected detrimental effects due to inactivation of a senescence brake on potential cancer-initiating cells.

Intrathoracic dislocation of the inferior pole of the scapula following thoracotomy.

Intrathoracic dislocation of the scapula is extremely rare. We present the case of a 64 year old man who underwent a lung transplant for emphysema via a standard posterior thoracotomy approach. Four weeks later, following a bronchoscopy, he experienced severe pain and restriction of movement in his shoulder. CT scans revealed intrathoracic dislocation of the inferior angle of the scapula. Two manipulations under anaesthesia were unsuccessful and formal exploration required with closure of the intercostal defect. We describe our surgical technique.

Bisphosphonates induce senescence in normal human oral keratinocytes.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) commonly occurs in individuals receiving bisphosphonates (BPs) with clinical manifestations of the exposed necrotic bone. Although defective wound healing of soft tissue is frequently, if not always, observed in BRONJ, the effects of BPs on oral soft tissue or cells remain unknown. To investigate the effects of BPs on cells of oral mucosal tissue, we studied the effect of pamidronate (PAM), one of the BPs most commonly administered to cancer patients, on the phenotypes of normal human oral keratinocytes (NHOK) and fibroblasts (NHOF). When exposed to PAM at 10 µM, NHOK, not NHOF, underwent senescence: NHOK overexpressed senescence-associated ß-galactosidase (SA-ß-Gal), p16INK4A, IL-6, and IL-8. When exposed to a higher level (50 µM) of PAM, NHOK maintained senescent phenotypes, but NHOF underwent apoptosis. PAM-induced senescence in NHOK is mediated, in part, via geranylgeranylation of the mevalonate pathway. Our in vitro 3D oral mucosal tissue construction studies further demonstrated that PAM induced senescence and impaired re-epithelialization of oral mucosa. Analysis of these data indicates that premature senescence of oral mucosal cells and subsequent defective soft-tissue wound healing might be partly responsible for the development of BRONJ in individuals receiving PAM or other BPs.

Factors associated with incorrect bicycle helmet use.

BACKGROUND: Incorrect bicycle helmet use increases head injury risk. OBJECTIVE: To evaluate the patterns of incorrect helmet use based on unobtrusive field observations. METHODS: Two observational surveys conducted in Alberta in 2000 and 2006 captured information on cyclist characteristics, including correct helmet use. Prevalence of correct helmet use was compared across multiple factors: age, gender, riding companionship, and environmental factors such as riding location, neighbourhood median family income, and region. Poisson regression analysis was used to relate predictor variables to the prevalence of incorrect helmet use, adjusting for clustering by site of observation. RESULTS: Among helmeted cyclists (n=5862), 15.3% were wearing their helmet incorrectly or were using a non-bicycle helmet. Children (53%) and adults (51%) tended to wear their helmet too far back, while adolescents tended not have their straps fastened (48%). Incorrect helmet use declined approximately 50% over the study period for children and adolescents, but 76% (95% CI 68% to 82%) in adults. Children were 1.8 times more likely to use their helmets incorrectly in 2000 compared with adults, but this effect increased to 3.9 (95% CI 2.9 to 5.4) in 2006. Adolescents were more likely to use their helmets incorrectly in 2006 compared with adults (prevalence ratio 2.76; 95% CI 1.9 to 4.02). Children and adolescents cycling alone, compared with adults cycling alone, cycling at non-school sites and cycling in Edmonton, was associated with incorrect helmet use. CONCLUSIONS: Important factors not previously identified were associated with incorrect bicycle helmet use. This information can be used to target interventions to increase correct use.

A systematic review of correct bicycle helmet use: how varying definitions and study quality influence the results.

BACKGROUND: Bicycle helmets effectively reduce the risk of bicycle-related head injuries and trauma; however, they must fit properly to be effective. Little is known about the prevalence of correctly worn helmets and factors associated with proper helmet use. OBJECTIVE: To examine proper bicycle helmet use through a systematic review. METHODS: Comprehensive searches of electronic medical databases were performed, and completed by grey literature and reference list checks to identify eligible studies. Studies eligible for inclusion had to involve cyclists and report on the prevalence of correct or incorrect helmet use. Two reviewers independently selected studies and data were extracted regarding the prevalence and factors influencing proper helmet wearing of cyclists. RESULTS: An inclusive search strategy led to 2285 prescreened citations; 11 of the studies were finally included in the review. Overall, correct helmet use varied from 46% to 100%, depending on the criteria used by researchers to define proper helmet use; stricter criteria reduced the proportion of properly worn helmets. Adulthood, female sex and educational interventions were associated with correct helmet use in some studies. Self-reported poor helmet fit (OR = 1.96; 95% CI 1.10 to 3.75), posterior positioning of helmet (OR = 1.52; 95% CI 1.02 to 2.26) and helmet loss in crash (OR = 3.25; 95% CI 1.82 to 5.75) increased the risk of head injury. In addition, educational programmes on helmet use in schools increased correct helmet use among schoolchildren. CONCLUSIONS: This systematic review outlines the current state of the literature including the variability in research methodology and definitions used to study proper helmet-wearing behaviour among cyclists.