Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Enhanced retinoid response by a combination of the vitamin A ester retinyl propionate with niacinamide and a flavonoid containing Ceratonia siliqua extract in retinoid responsive in vitro models.

OBJECTIVES: Retinoids have been used for decades as efficacious topical agents to treat photoaged skin. The purpose of our present research is to evaluate whether the activity of the vitamin A ester retinyl propionate (RP) can be enhanced by niacinamide (Nam) and a flavonoid containing Ceratonia siliqua (CS) fruit extract in retinoid responsive in vitro models. METHODS: Retinyl propionate was tested alone and in combination with Nam and CS in an RARα reporter cell line for promoter activation and compared to trans-retinoic acid (tRA) activation. These treatments were also tested in keratinocytes for gene expression profiling by qPCR using a panel of 40 retinoid responsive genes. RESULTS: tRA or RP elicited RARα reporter activation in a dose-dependent manner. The combination of 0.5 µM or 2 µM RP with 10 mM Nam had a 56% and 95% signal increase compared to RP, respectively. The addition of 1% CS to 0.5 µM or 2 µM RP with 10 mM Nam elicited a further increase of 114% and 156%, respectively, over RP and Nam combinations. All retinoids elicited an increase in expression of 40 retinoid sensitive genes over control levels. Of the 40 genes, 27 were enhanced by either 0.1 µM RP or 0.5 µM RP with 10 mM Nam and 1% CS. Nam or CS had very modest activity in both models. CONCLUSION: The combination of RP with Nam and CS showed a higher retinoid response than RP in two separate retinoid responsive in vitro models. We hypothesize Nam and CS enhances RP activity by modulating metabolism to tRA via increasing NAD+ pools and inhibiting reduction of retinal (RAL) back to retinol, respectively. The findings provide evidence that this combination may have enhanced efficacy for treating the appearance of photoaged skin.

OBJECTIFS: Les rétinoïdes sont utilisés depuis des décennies comme agents topiques efficaces pour traiter la peau photo-âgée. Le but de notre recherche actuelle est d'évaluer si l'activité du propionate rétinyl ester de vitamine A (RP) peut être augmentée par le niacinamide (Nam) et un flavonoïde contenant un extrait de fruit de Ceratonia Siliqua (CS) dans les modèles in vitro sensibles aux rétinoïdes. MÉTHODES: RP a été testé seul et en combinaison avec Nam et CS dans une ligne de cellule rapporteur de RARα pour l'activation du promoteur et par rapport à l'activation de l'acide transrétinoïque(tRA). Ces traitements ont également été testés dans les kératinocytes pour le profilage d'expression génique par qPCR à l'aide d'un panel de 40 gènes rétinoïdes sensibles. RÉSULTATS: tRA ou RP ont provoqué l'activation du promoteur RARα d'une manière dépendante de la dose. La combinaison de 0,5 µM ou 2 µM de RP avec 10 mM de Nam a permis une augmentation respectivement de 56% et 95% du signal par rapport à RP. L'ajout de 1 % de CS à 0,5 µM ou 2 µM de RP avec 10 mM de Nam a permis une nouvelle augmentation de 114 % et 156 %, respectivement, qu'avec la combinaison RP et Nam. Tous les rétinoïdes ont provoqué une augmentation de l'expression de 40 gènes sensibles aux rétinoïdes sur les niveaux de contrôle. Sur les 40 gènes, 27 ont été améliorés soit par 0,1 µM de RP ou 0.5 µM de RP avec 10 mM de Nam et 1% de CS. Nam ou CS avaient une activité très modeste dans les deux modèles. CONCLUSION: La combinaison de RP avec Nam et CS a montré une réponse rétinoïde plus élevée que RP dans deux modèles in vitro séparés sensibles aux rétinoïdes. Nous émettons l'hypothèse que Nam et CS améliorent l'activité RP en modulant le métabolisme de tRA par l'augmentation des groupement NAD+ et en inhibant la réduction du rétinal (RAL) en rétinol, respectivement. Les résultats fournissent la preuve que cette combinaison peut améliorer l'efficacité du traitement de l'aspect de la peau photo-âgée.

Impact of compliance to chemoradiation on long-term outcomes in squamous cell carcinoma of the anus: results of a post hoc analysis from the randomised phase III ACT II trial.

BACKGROUND: Concurrent chemoradiation is standard-of-care for patients with squamous cell carcinoma of the anus. Poor compliance to chemotherapy, radiotherapy treatment interruptions and unplanned breaks may impact adversely on long-term outcomes. METHODS: The ACT II trial recruited 940 patients with localised squamous cell carcinoma of the anus, and assigned patients to mitomycin (week 1) or cisplatin (weeks 1 and 5), with fluorouracil (weeks 1 and 5) and radiotherapy (50.4 Gy in 28 fractions over 38 days). This post hoc analysis examined the association between baseline factors (age, gender, site, T stage and N stage), and compliance to treatment (radiotherapy and chemotherapy), and their effects on locoregional failure-free survival, progression-free survival (PFS) and overall survival (OS). Compliance was categorised into groups. Radiotherapy: six groups according to total dose and overall treatment time (OTT). Chemotherapy: three groups (A = per-protocol; B = dose reduction or delay; C = omitted). RESULTS: A total of 931/940 patients were assessable for radiotherapy and 936 for chemotherapy compliance. Baseline glomerular filtration rate <60 ml/min and cisplatin were significantly associated with poor week 5 compliance to chemotherapy (P = 0.003 and 0.02, respectively). Omission of week 5 chemotherapy was associated with significantly worse locoregional failure-free survival [hazard ratio (HR) 2.53 (1.33-4.82) P = 0.005]. Dose reductions/delays or omission of week 5 chemotherapy were associated with significantly worse PFS {HR: 1.56 [95% confidence interval (CI): 1.18-2.06], P = 0.002 and HR: 2.39 (95% CI: 1.44-3.98), P = 0.001, respectively} and OS [HR: 1.92 (95% CI: 1.41-2.63), P < 0.001 and HR: 2.88 (95% CI: 1.63-5.08), P < 0.001, respectively]. Receiving the target radiotherapy dose in >42 days is associated with worse PFS and OS [HR: 1.72 (95% CI: 1.17-2.54), P =0.006]. CONCLUSION: Poor compliance to chemotherapy and radiotherapy were associated with worse locoregional failure-free survival, PFS and OS. Treatment interruptions should be minimised, and OTT and total dose maintained. CLINICAL TRIAL NUMBER: ISRCTN 26715889.

Optimized low pH formulation of niacinamide enhances induction of autophagy marker ATG5 gene expression and protein levels in human epidermal keratinocytes.

BACKGROUND: Macromolecules in skin cells are damaged when exposed to environmental stressors, leading to disrupted cellular function and homeostasis. While epidermal turnover can eliminate some of this damage, autophagy can rapidly remove these defective components. Niacinamide (Nam) is known to induce autophagy and optimizing formulations to maximize this response could provide improved homeostasis in stressed skin. OBJECTIVE: To determine (i) whether Nam can induce autophagy related 5 (ATG5), an autophagy marker, in human keratinocytes and (ii) whether optimized low pH Nam formulations can enhance the response in 3D skin models. METHODS: Human keratinocytes treated with Nam were evaluated for autophagosome accumulation and induction of ATG5 by gene expression, immunoblotting and immune-fluorescence microscopy. 3D skin equivalents were topically treated with Nam formulations at pH 5.8 and 3.8. Gene expression profiling and immunoblot analysis of ATG5 were performed. RESULTS: Nam treatment of keratinocytes led to an accumulation of autophagosomes with a maximal signal at 48 h. Gene expression of ATG5 was induced by Nam, and immunoblots stained for ATG5 showed a significant increase after 6 h of treatment. Gene expression profiling of 3D epidermal skin equivalents treated with Nam at pH 3.8 showed stronger induction of autophagy-related genes, including ATG5, compared with pH 5.8 formulas. Enrichment for gene ontology terms on autophagy showed an increased linkage with Nam formulas at pH 3.8. CONCLUSIONS: We found that Nam induces autophagosome accumulation and ATG5 levels in keratinocytes. We also discovered that a Nam formulation at pH 3.8 can further increase levels of ATG5 in 3D skin models when compared to Nam at pH 5.8. These data support that Nam can induce autophagy in keratinocytes and formulations at pH 3.8 can enhance the impact. We hypothesize that optimized formulations at pH 3.8 can improve skin ageing appearance via autophagy induction.

Evaluation of sex differences in patients with ST-elevated myocardial infarction: an observational cohort study in Amsterdam and surrounding region.

INTRODUCTION: Women with ST-elevation myocardial infarction (STEMI) present with different symptoms compared to men. This can result in delays in diagnosis and in the timely treatment of women. The aim of this study is to examine these differences, including the short- and long-term mortality in women and men. METHODS: This quality registry study included all patients with STEMI who received primary percutaneous coronary intervention in 2015 or 2016 in Amsterdam and the surrounding region. RESULTS: Three PCI centres and the Emergency Medical Service in Amsterdam participated. In total, 558 men (71%) and 229 women (29%) were included. Women were on average 7 years older than men (68 vs 61 years, p < 0.001), and suffered more often from hypertension (46% vs 34%, p = 0.002) and monovascular disease (69% vs 57%, p = 0.002). A higher percentage of men were current smokers (41% vs 49%, p = 0.043). Patient delay, system delay and overall ischaemic times were similar in both women and men (medians: 51, 94 and 157 min, respectively). Initiation of treatment was achieved within 90 min after STEMI diagnosis in 85% of patients (87% in women, 85% in men). Thirty-day and 1­year mortality adjusted hazard ratio for women versus men was 1.60 (95% CI 0.9-3.0) and 1.24 (95% CI 0.8-2.0), respectively. DISCUSSION: Recognition of cardiac complaints remains challenging for patients. In the Amsterdam region, time delays and mortality were not significantly different between men and women presenting with STEMI. These results are in contrast to findings in similar registries. This suggests that implementation of current knowledge and national campaigns are effective in increasing awareness of the signs and symptoms suggestive of myocardial infarction.

Expansion of off-site percutaneous coronary intervention centres significantly reduces ambulance driving time to primary PCI in the Netherlands.

INTRODUCTION: In patients with ST-elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI)-mediated reperfusion is preferred over pharmacoinvasive reperfusion with fibrinolysis if transfer to a PCI centre can be ensured in ≤120 min. We evaluated the ambulance driving time to primary PCI centres in the Netherlands and assessed to what extent ambulance driving times were impacted by the expansion of off-site PCI centres. METHODS AND RESULTS: We calculated the driving routes from every Dutch postal code to the nearest PCI centre with (on-site) or without (off-site) surgical back-up. We used data from ambulance records to estimate the ambulance driving time on each route. There were 16 on-site and 14 off-site PCI centres. The median (interquartile range) time to on-site PCI centres was 18.8 min (12.2-26.3) compared with 14.9 min (8.9-20.9) to any PCI centre (p < 0.001). In postal code areas that were impacted by the initiation of off-site PCI, the median driving time decreased from 25.4 (18.2-33.1) to 14.7 min (8.9-20.9) (p < 0.001). Ambulance driving times of >120 min were only seen in non-mainland areas. CONCLUSION: Based on a computational model, timely ambulance transfer to a PCI centre within 120 min is available to almost all STEMI patients in the Netherlands. Expansion of off-site PCI has significantly reduced the driving time to PCI centres.

Autism spectrum disorder in children with Type 1 diabetes.

AIM: Links between autism spectrum disorder (ASD) and autoimmune diseases, including Type 1 diabetes have been proposed. This study assessed the frequency of ASD in children with Type 1 diabetes in the T1D Exchange (T1DX) registry and the impact of ASD on characteristics of children with Type 1 diabetes. METHODS: Analysis included 10 032 participants aged < 18 years (median Type 1 diabetes duration 6.5 years, 48% female, 77% non-Hispanic White). Diagnosis of ASD was defined as autism, Asperger's or pervasive developmental disorder. RESULTS: A diagnosis of ASD was recorded for 159 (1.58%) participants. Those with ASD were predominantly male (88% vs. 51% of those without ASD, P < 0.001) and slightly older (median 14 vs. 13 years, P = 0.022). Occurrence of diabetic ketoacidosis at Type 1 diabetes diagnosis was similar (35% vs. 41%, P = 0.161). Pump use was lower in those with ASD (51% vs. 63%, P = 0.005) but continuous glucose monitor use was similar (24% vs. 27%, P = 0.351). Median HbA1c was slightly lower in those with ASD [68 vs. 69 mmol/mol (8.4% vs. 8.5%), P = 0.006]. This difference was more pronounced after adjusting for confounders. CONCLUSIONS: The frequency of ASD in the T1DX registry was similar to that in the general population. These data show that despite deficits in communication, occurrence of diabetic ketoacidosis was similar in youth with and without ASD. Pump use was less frequent in those with ASD, possibly due to sensory issues, although CGM use did not differ. The lower HbA1c may be due to a more regimented routine with ASD. Because comorbidities such as ASD complicate care of patients with Type 1 diabetes, further research is needed to support these children.

Introduction of an Alcohol-Related Electronic Screening and Brief Intervention (eSBI) Program to Reduce Hazardous Alcohol Consumption in Namibia's Antiretroviral Treatment (ART) Program.

Alcohol is the most widely abused substance in Namibia and is associated with poor adherence and retention in care among people on antiretroviral therapy (ART). Electronic screening and brief interventions (eSBI) are effective in reducing alcohol consumption in various contexts. We used a mixed methods approach to develop, implement, and evaluate the introduction of an eSBI in two ART clinics in Namibia. Of the 787 participants, 45% reported some alcohol use in the past 12 months and 25% reported hazardous drinking levels. Hazardous drinkers were more likely to be male, separated/widowed/divorced, have a monthly household income > $1000 NAD, and report less than excellent ART adherence. Based on qualitative feedback from participants and providers, ART patients using the eSBI for the first time found it to be a positive and beneficial experience. However, we identified several programmatic considerations that could improve the experience and yield in future implementation studies.

Chronic Gestational Inflammation: Transfer of Maternal Adaptation over Two Generations of Progeny.

Changes in the in utero environment result in generational transfer of maladapted physiology in the context of conditions such as stress, obesity, and anxiety. Given the significant contribution of noncommunicable diseases-which are characterised by chronic inflammation-to population mortality, the potential for chronic maternal inflammation mediating foetal programming is a growing concern. The extent of generational transfer in terms of immune functionality and leukocyte glucocorticoid sensitivity was investigated over two generations of offspring (F1 and F2) in a model of chronic LPS-induced maternal inflammation in C57/BL/6 mice. Maternal inflammation resulted in glucocorticoid hypersensitivity (increased glucocorticoid receptor expression levels) in the majority of leukocyte subpopulations in both F1 and F2 offspring. Furthermore, splenocytes stimulated with LPS in vitro exhibited exacerbated inflammatory cytokine responses, which were even more prominent in F2 than F1; this effect could be ascribed to NLRP3 inflammasome hyperactivity in F1 but not F2. Current data illustrates that parental chronic inflammation may mediate the inflammatory profile in offspring, potentially propagating a maladapted proinflammatory phenotype in subsequent generations.

The cardiopulmonary exercise test grey zone; optimising fitness stratification by application of critical difference.

BACKGROUND: Cardiorespiratory fitness can inform patient care, although to what extent natural variation in CRF influences clinical practice remains to be established. We calculated natural variation for cardiopulmonary exercise test (CPET) metrics, which may have implications for fitness stratification. METHODS: In a two-armed experiment, critical difference comprising analytical imprecision and biological variation was calculated for cardiorespiratory fitness and thus defined the magnitude of change required to claim a clinically meaningful change. This metric was retrospectively applied to 213 patients scheduled for colorectal surgery. These patients underwent CPET and the potential for misclassification of fitness was calculated. We created a model with boundaries inclusive of natural variation [critical difference applied to oxygen uptake at anaerobic threshold (V˙O2-AT): 11 ml O2 kg-1 min-1, peak oxygen uptake (V˙O2 peak): 16 ml O2 kg-1 min-1, and ventilatory equivalent for carbon dioxide at AT (V̇E/V̇CO2-AT): 36]. RESULTS: The critical difference for V˙O2-AT, V˙O2 peak, and V˙E/V˙CO2-AT was 19%, 13%, and 10%, respectively, resulting in false negative and false positive rates of up to 28% and 32% for unfit patients. Our model identified boundaries for unfit and fit patients: AT <9.2 and ≥13.6 ml O2 kg-1 min-1, V˙O2 peak <14.2 and ≥18.3 ml kg-1 min-1, V˙E/V˙CO2-AT ≥40.1 and <32.7, between which an area of indeterminate-fitness was established. With natural variation considered, up to 60% of patients presented with indeterminate-fitness. CONCLUSIONS: These findings support a reappraisal of current clinical interpretation of cardiorespiratory fitness highlighting the potential for incorrect fitness stratification when natural variation is not accounted for.

Session 4: What should we do for poor responders after chemoradiotherapy: bad biology or should the fight go on?

Just over 50% of patients with advanced rectal cancer have a poor response to chemoradiotherapy with resultant poor outcomes. Professor Glimelius reviews the evidence base for defining such patients and the potential role, if any, of further treatment.

Differential Impact of Index Stroke on Dementia Risk in African-Americans Compared to Whites.

OBJECTIVE: To compare whites and African-Americans in terms of dementia risk following index stroke. METHODS: The data consisted of billing and International Classification of Diseases, Ninth Revision diagnosis codes from the South Carolina Revenue and Fiscal Affairs office on all hospital discharges within the state between 2000 and 2012. The sample consisted of 68,758 individuals with a diagnosis of ischemic stroke prior to 2010 (49,262 white [71.65%] and 19,496 African-Americans [28.35%]). We identified individuals in the dataset who were subsequently diagnosed with any of 5 categories of dementia and evaluated time to dementia diagnosis in Cox Proportional Hazards models. We plotted cumulative hazard curves to illustrate the effect of race on dementia risk after controlling for age, sex, and occurrence of intervening stroke. RESULTS: Age at index stroke was significantly different between the 2 groups, with African-Americans being younger on average (70.0 [SD 12.5] in whites versus 64.5 [SD 14.1] in African-Americans, P < .0001). Adjusted hazard ratios revealed that African-American race increased risk for all 5 categories of dementia following incident stroke, ranging from 1.37 for AD to 1.95 for vascular dementia. Age, female sex, and intervening stroke likewise increased risk for dementia. CONCLUSIONS: African-Americans are at higher risk for dementia than whites within 5 years of ischemic stroke, regardless of dementia subtype. Incident strokes may have a greater likelihood of precipitating dementia in African-Americans due to higher prevalence of nonstroke cerebrovascular disease or other metabolic or vascular factors that contribute to cognitive impairment.

Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials.

Background: To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types. Patients and methods: 2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status. Results: 231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months. Conclusions: BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression.

How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials.

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting.

Head injury trends and helmet use in skiers and snowboarders in Western Canada, 2008-2009 to 2012-2013: an ecological study.

This research explored associations between helmet use and head injuries in snowsports by investigating reported snowsport injuries in Western Canada from 2008-2009 to 2012-2013. The key finding was that increased helmet use (from 69% to 80%) was not associated with a reduction in reported head injuries. Over the study period, the average rate of reported head injuries was 0.2/1000 skier visits, with a statistically significant variation (P < 0.001). The line of best fit showed an non-significant upward trend (P = 0.13). Lacerations were the only subcategory of head injuries that decreased significantly with helmet use. A higher proportion of people who reported a head injury were wearing a helmet than for injuries other than to the head. Skiers were more likely to report a head injury when wearing a helmet than snowboarders (P < 0.001 cf. P = 0.22). There were significant differences in characteristics of helmet and non-helmet wearers. Helmet wearers were more likely to be: young adults (P < 0.001); beginner/novices (P = 0.004); and snowboarders (P < 0.001), but helmet wearing was not associated with gender (P = 0.191). Further research is needed to explore the possible reasons for the failure of helmets to reduce head injuries, for example, increased reporting of head injuries and increased risk-taking combined with over-rating of the helmets' protection.

Influence of landscape features on the microgeographic genetic structure of a resident songbird.

Landscape features influence individual dispersal and as a result can affect both gene flow and genetic variation within and between populations. The landscape of British Columbia, Canada, is already highly heterogeneous because of natural ecological and geological transitions, but disturbance from human-mediated processes has further fragmented continuous habitat, particularly in the central plateau region. In this study, we evaluated the effects of landscape heterogeneity on the genetic structure of a common resident songbird, the black-capped chickadee (Poecile atricapillus). Previous work revealed significant population structuring in British Columbia that could not be explained by physical barriers, so our aim was to assess the pattern of genetic structure at a microgeographic scale and determine the effect of different landscape features on genetic differentiation. A total of 399 individuals from 15 populations were genotyped for fourteen microsatellite loci revealing significant population structuring in this species. Individual- and population-based analyses revealed as many as nine genetic clusters with isolation in the north, the central plateau and the south. Moreover, a mixed modelling approach that accounted for non-independence of pairwise distance values revealed a significant effect of land cover and elevation resistance on genetic differentiation. These results suggest that barriers in the landscape influence dispersal which has led to the unexpectedly high levels of population isolation. Our study demonstrates the importance of incorporating landscape features when interpreting patterns of population differentiation. Despite taking a microgeographic approach, our results have opened up additional questions concerning the processes influencing dispersal and gene flow at the local scale.

Chamber bioaerosol study: human emissions of size-resolved fluorescent biological aerosol particles.

Humans are a prominent source of airborne biological particles in occupied indoor spaces, but few studies have quantified human bioaerosol emissions. The chamber investigation reported here employs a fluorescence-based technique to evaluate bioaerosols with high temporal and particle size resolution. In a 75-m(3) chamber, occupant emission rates of coarse (2.5-10 µm) fluorescent biological aerosol particles (FBAPs) under seated, simulated office-work conditions averaged 0.9 ± 0.3 million particles per person-h. Walking was associated with a 5-6× increase in the emission rate. During both walking and sitting, 60-70% or more of emissions originated from the floor. The increase in emissions during walking (vs. while sitting) was mainly attributable to release of particles from the floor; the associated increased vigor of upper body movements also contributed. Clothing, or its frictional interaction with human skin, was demonstrated to be a source of coarse particles, and especially of the highly fluorescent fraction. Emission rates of FBAPs previously reported for lecture classes were well bounded by the experimental results obtained in this chamber study. In both settings, the size distribution of occupant FBAP emissions had a dominant mode in the 3-5 µm diameter range.

RNAi as a tool for target discovery in early pharmaceutical research.

The pharmaceutical industry is currently faced with increasing pressure due to patent expirations for block busters, healthcare reforms with strained budgets and growing demands for approval by administrative organizations like the FDA and the EMA. High attrition rates especially in the later expensive stages of the drug development process ask for thoroughly validated drug targets at the beginning of such projects. The great potential of RNA interference strategies toward reaching this goal is outlined in this article.