Recent trends in breast, cervical, and colorectal cancer screening test utilization in Canada, using self-reported data from 2008 and 2012.

In Canada, self-reported data from the Canadian Community Health Survey 2008 and 2012 provide an opportunity to examine overall utilization of breast, cervical, and colorectal cancer screening tests for both programmatic and opportunistic screening. Among women 50-74 years of age, utilization of screening mammography was stable (62.0% in 2008 and 63.0% in 2012). Pap test utilization for women 25-69 years of age remained high and stable across Canada in 2008 and 2012 (78.9% in 2012). The percentage of individuals 50-74 years of age who reporting having at least 1 fecal test within the preceding 2 years increased in 2012 (to 23.0% from 16.9% in 2008), but remains low. Stable rates of screening mammography utilization (about 30%) were reported in 2008 and 2012 among women 40-49 years of age, a group for which population-based screening is not recommended. Although declining over time, cervical cancer screening rates were high for women less than 25 years of age (for whom screening is not recommended). Interestingly, an increased percentage of women 70-74 years of age reported having a Pap test. In 2012, a smaller percentage of women 50-69 years of age reported having no screening test (5.9% vs. 8.5% in 2008), and more women reported having the three types of cancer screening tests (19.0% vs. 13.2%). Efforts to encourage use of screening within the recommended average-risk age groups are needed, and education for stakeholders about the possible harms of screening outside those age groups has to continue.

Injury rate and injury pattern among elite World Cup snowboarders: a 6-year cohort study.

BACKGROUND: There is limited knowledge on the injury rate and injury pattern in the different disciplines among elite snowboarders. OBJECTIVE: The aim of this study was to describe and compare the injury rate and injury pattern among the different International Ski Federation (Fédération Internationale de Ski, FIS) World Cup (WC) snowboard disciplines. METHODS: We conducted retrospective interviews with FIS WC snowboard athletes at the end of each season in the period 2007-2012, to register all acute injuries sustained during training or competition during the competitive season requiring attention by medical personnel. To calculate the exposure, we obtained information from result lists from the FIS competition database for all WC competitions for each of the interviewed athletes. RESULTS: We registered a total of 574 injuries among 1432 athletes, accounting for an overall injury rate of 40.1 injuries/100 athlete/season. A total of 171 injuries occurred during the FIS WC competitions, corresponding to 6.4 injuries/1000 runs. During competition, injury risk was highest in snowboard cross with 11.9/1000 runs, followed by 6.3 in halfpipe, 3.6 in big air and 2.8 in parallel giant slalom/parallel slalom (PGS/PSL). Snowboard cross also had the highest risk of severe injuries (>28 days absence). No differences in injury risk were detected between male and female snowboarders. The most commonly injured body part was the knee (17.8%), followed by the shoulder/clavicle (13.4%) and head/face (13.2%). The risk of knee injury (the most common injury type) and head injury was significantly higher in snowboard cross and halfpipe compared to PGS/PSL. CONCLUSIONS: The risk of injuries was higher in snowboard cross than in halfpipe, big air and PGS/PSL. The most commonly injured body part was the knee. Prevention of snowboard injuries among elite snowboarders should focus on knee injuries, severe injuries and snowboard cross athletes.

Healthcare workers' attitude towards influenza vaccination after the 2009 pandemic.

BACKGROUND: Previous studies have demonstrated the variability of healthcare workers' (HCWs) willingness to consider seasonal influenza vaccination, possibly to the detriment of their patients. AIMS: To ascertain HCW uptake of H1N1 and seasonal influenza vaccination and the reasons why one or both might have been declined following the pandemic of 2009. METHODS: An online, anonymous survey of HCWs across five, acute National Health Service trusts was undertaken in 2010. RESULTS: A total of 765 responses were obtained, of which the two main groups of participants were doctors of all grades (42%) and qualified nurses (40%). The willingness to be vaccinated increased with age. Senior doctors were the occupational group most likely to have had both vaccinations, but where they did decline they mainly did so because they perceived influenza to be a minor illness. Females were more likely to decline vaccination due to a fear of side effects, whereas males, particularly younger ones, viewed influenza as a minor illness. Junior doctors cited lack of availability of immunization sessions as one of the main reasons why they may not have had vaccination. CONCLUSIONS: Future influenza vaccination campaigns should consider using different approaches depending on the gender and occupational mix of the target population, rather than adopting a 'one-size' fits all approach.

Colorectal cancer screening in Canada: results from the first round of screening for five provincial programs.

BACKGROUND: Early implementation of programmatic colorectal cancer (crc) screening for average-risk individuals 50-74 years of age in Canada has used fecal occult blood tests [fts (guaiac or immunochemical)] and colonoscopy for follow-up of abnormal fts. This paper presents results of an evaluation of this crc screening. METHODS: Five Canadian provincial programs provided aggregated data for individuals with a first-round ft processed between January 1, 2009, and December 31, 2011. RESULTS: The 104,750 people who successfully completed a first round of screening represented 16.1% of those who had access to the programs between January 1, 2009, and December 31, 2011 (mean age: 61.2 years; men: 61.4 years; women: 61.1 years). Of those participants, 4661 had an abnormal ft (4.4%). Uptake of colonoscopy within 180 days after an abnormal ft was 80.5%, ranging from 67.8% to 89.5% by program. The positive predictive value (ppv) for adenoma was 35.9% for guaiac ft and 50.6% for immunochemical ft. Adenoma and crc detection rates were, respectively, 16.9 and 1.8 per 1000 screened. Of invasive crcs detected, 64.6% were stage i or ii. CONCLUSIONS: Considering the variation in characteristics and stage of implementation of each provincial program, the collaboration of the provinces leading to this report on the early performance of crc screening in Canada is a major milestone. Targets are met or nearly met for significant indicators such as ppv for adenoma and cancer detection rate. Participation is expected to increase as programs are fully implemented in the provinces. Additional effort may be needed to improve timely access to follow-up colonoscopy.

Synapses of horizontal cells in rabbit and cat retinas.

Horizontal cells in the retinas of cats and rabbits are morphologically similar; in both species, two types can be distinguished in Golgistained material. Horizontal cells and their processes are readily recognized in electron micrographs, and many of the horizontal cell processes appear to make synaptic contacts with dendrites and somata of bipolar cells, and probably with other horizontal cells. The synapses of the horizontal cell appear similar to chemical synaptic contacts described throughout the nervous system. With the finding of synaptic contacts, it seems clear that retinal horizontal cells should be classified as neurons.

Cobalt accumulation in horses following repeated administration of cobalt chloride.

OBJECTIVE: To monitor cobalt concentrations in urine, red blood cells and plasma after chronic parenteral administration of cobalt chloride evaluate these results against the current International Federation of Horseracing Authorities thresholds for detecting cobalt misuse. DESIGN: Eight mares were randomly assigned to four treatment groups, with two mares in each group: Group 1 - control group, Group 2 - 25 milligrams cobalt intravenously as CoCl2 weekly, Group 3 - 50 milligrams cobalt intravenously as CoCl2 weekly, and Group 4 - 25 milligrams cobalt intravenously mid-week and at the end of the week. Urine and blood samples were collected before each weekly administration so that trough levels were assessed. In the group receiving two doses per week, urine and blood were collected prior to the dose given at the end of each week. Samples were initially collected at time zero then weekly for 10 weeks. Three further collections of urine and blood were made at days 81, 106 and 127. METHODS: Urine creatinine measurements to assess horse hydration status were performed by the Jaffe reaction method. Cobalt determinations in plasma, blood and urine were by inductively coupled plasma-mass spectrometry. Haematocrit concentrations, used to calculate red cell cobalt levels, were performed using a microhematocrit centrifuge. Statistical analyses were conducted in Genstat (v17, VSNi). RESULTS: Marked cobalt accumulation was evident with increasing cobalt concentrations for all sample matrices in specimens collected immediately prior to cobalt administration. Correlation between the sample matrices improved when urine cobalt concentration was adjusted for creatinine level. Red cell cobalt levels remained elevated for at least 12 weeks after cessation of administration, consistent with the lifespan of the red cell. There was no significant change in haematocrit concentrations for the duration of the study. CONCLUSION: The current urine cobalt threshold was only effective at detecting acute cobalt exposure while the plasma cobalt threshold was able to consistently identify chronic high-level cobalt exposure and potential cobalt misuse. The threshold values legislated for urine cobalt do not correlate with those set for plasma. The acute nature of urinary cobalt excretion provides a relatively small window through which cobalt administration is detected. Plasma and red cell cobalt concentrations can provide a clearer picture of potential cobalt misuse.

Prospecting for an HIV vaccine.

Human immunodeficiency virus (HIV) sets several challenges for the development of a preventative HIV vaccine. Predictable, protective natural immunity against HIV does not occur and so unlike most other diseases for which vaccines exist, there are few guideposts from natural infection. Nonetheless, six vaccine efficacy trials have occurred. One in particular, the Thai trial called RV144, showed partial protective efficacy and potential ways ahead to a better vaccine approach. This coupled with other lessons from studies of acute infections as well as an increasingly complex knowledge of HIV-related vaccine immunology bring hope that a vaccine solution might be reached for this pervasive and deadly pandemic.

Practical Aspects of Multiscale Classical and Quantum Simulations of Enzyme Reactions.

This chapter aims to present some basic multiscale approaches available for enzyme simulations, and to point out practical details and pitfalls that are not often discussed in the literature, but can greatly influence the outcome of any in silico enzyme study. We cover principle methodological steps of multiscale studies of general enzyme reactions. This includes choice of starting structures, boundary conditions, potential energy surfaces, reaction coordinates, simulation methods, as well as the choice of method for the treatment of nuclear quantum effects. Together, these and additional steps are crucial for the success of enzyme-modeling projects and should be considered prior to embarking on multiscale modeling.

Modulation of the Surface-Layer Protein of Clostridium difficile through Cwp84 Inhibition.

Cysteine protease Cwp84 is responsible for surface-layer processing in Clostridium difficile and was also shown to cleave several human extracellular matrix components in vitro. To enable the facile identification and characterization of Cwp84 inhibitors, we developed a fluorogenic 10-mer peptide based on the enzyme's natural substrate SlpA that is amenable for use in FRET-based high-throughput screening. The design of substrate-mimetic inhibitors led to epoxysuccinate 8c, which displayed an inactivation efficiency (kinact/KI) of (4.7 ± 0.3) × 10(4) M(-1) min(-1). Further evaluation of 8c demonstrated its ability to inhibit fibronectin cleavage and, more importantly, subvert surface-layer biogenesis in C. difficile.

Are you PEPped and PrEPped for travel? Risk mitigation of HIV infection for travelers.

The HIV pandemic persists globally and travelers are at risk for infection by the Human Immunodeficiency Virus (HIV). While HIV-focused guidelines delineate risk stratification and mitigation strategies for people in their home communities, travel issues are not addressed. In this review, direct and indirect evidence on HIV risk among travelers is explored. The burgeoning practice of employing pre-exposure prophylaxis (PrEP) with anti-retroviral therapy in the non-travel setting is introduced, as well as the more established use of post-exposure prophylaxis (PEP). Challenges in applying these lessons to travelers are discussed, and a new guidelines process is scoped and recommended.

Life-long dietary restriction attenuates age-related increases in hippocampal glial fibrillary acidic protein mRNA.

The expression of astrocyte-specific glial fibrillary acidic protein increases after experimental lesions and is elevated throughout the brain in aged rodents and primates. Clusterin (ApoJ) expression increases in astrocytes and microglia after lesions, but changes during aging have not been reported. Dietary restriction (DR) delays the onset and progression of many age-related physiological deficits in rodents. This study showed that the age-related increase in glial fibrillary acidic protein mRNA in the hippocampus was attenuated in 24-month-old male Fischer 344 rats subjected to a 50% DR beginning at 6 weeks of age. ApoJ mRNA expression in astrocytes was unchanged by DR. These results demonstrate that DR can delay neurodegeneration in aged rats as assessed by a marker of reactive astrogliosis.

Bottlebrush dendritic endings and large dendritic fields: motion-detecting neurons in the mammalian tectum.

The widefield vertical neurons of the lower stratum griseum superficiale (SGS3) and upper stratum opticum (SO) of the superior colliculus provide an extrageniculate route for visual information to reach the pulvinar. Previous physiological studies indicate that SGS3/SO neurons have large receptive fields and respond to small moving stimuli. We sought to better characterize the dendritic morphology of SGS3/SO neurons with intracellular filling in slice preparations of the ground squirrel superior colliculus. We found that dendrites of widefield vertical cells end in monostratified arrays of spiny terminal specializations called "bottlebrush" dendritic endings. Two major subtypes of neurons are described. Type I neurons have somata restricted to the SGS3 and bottlebrush endings in the most superficial sublayer of the SGS. Type II neurons are found at the base of the SGS and in the upper SO, and have bottlebrush endings arrayed within the middle sublayers of the SGS. Bottlebrush endings may sample and integrate laminated afferents to the superior colliculus, and cellular subtypes may underlie multiple information streams within the tectopulvinar pathway. A similar dendritic morphology and projection pattern can be found in cells of the avian optic tectum that project upon the nucleus rotundus, a thalamic nucleus homologous to the mammalian caudal/inferior pulvinar. Because motion processing is a dominant feature of the avian tectorotundal pathway, the current results suggest that both dendritic morphology and motion processing are conserved features of widefield vertical cells in the tectopulvinar pathway of vertebrates.

Molecular recognition of modified adenine nucleotides by the P2Y(1)-receptor. 2. A computational approach.

The molecular recognition of C2- or C8-substituted ATP derivatives by the P2Y(1)-receptor (P2Y(1)-R) is analyzed using ab initio quantum mechanical calculations. Parameters that may determine ligand specificity toward P2Y(1)-R were examined on reduced models and correlated with the biochemical data for the parent compounds. These include tautomerism and protonation energy in the gas and aqueous phases, as well as molecular electrostatic potential (MEP) and dipole moment vector. The calculated electronic parameters cannot explain the inactivity of the C8-substituted ATP derivatives, nor the difference in activity among the C2-substituted ATP analogues. These results indicate that neither tautomerism nor changes in the electronic distribution of the adenine ring play a major role in determining binding specificity of adenine nucleotides to the receptor. It is suggested that the higher potency of the C2-substituted ATP derivatives, compared to ATP, might be due to interaction between the C2 side chain heteroatom and the receptor. Furthermore, the interaction of the C2 alkyl side chain with a hydrophobic pocket at the receptor binding site is suggested. In addition, NMR data in the companion paper indicate that the inactivity of the C8-substituted ATP analogues may be due to steric and conformational, rather than electronic, effects.

Characterization of "mini-nucleotides" as P2X receptor agonists in rat cardiomyocyte cultures. An integrated synthetic, biochemical, and theoretical study.

The design and synthesis of "mini-nucleotides", based on a xanthine-alkyl phosphate scaffold, are described. The physiological effects of the new compounds were evaluated in rat cardiac cell culture regarding Ca(2+) elevation and contractility. The results indicate biochemical and physiological profiles similar to those of ATP, although at higher concentrations. The biological target molecules of these "mini-nucleotides" were identified by using selective P2-R and A(1)-R antagonists and P2-R subtype selective agonists. On the basis of these results and of experiments in Ca(2+) free medium, in which [Ca(2+)](i) elevation was not observed, we concluded that interaction of the analogues is likely with P2X receptor subtypes, which causes Ca(2+) influx. Theoretical calculations analyzing electronic effects within the series of xanthine-alkyl phosphates were performed on reduced models at quantum mechanical levels. Calculated dipole moment vectors, electrostatic potential maps, and volume parameters suggest an explanation for the activity or inactivity of the synthesized derivatives and predict a putative binding site environment for the active agonists. Xanthine-alkyl phosphate analogues proved to be selective agents for activation of P2X-R subtypes, whereas ATP activated all P2-R subtypes in cardiac cells. Therefore, these analogues may serve as prototypes of selective drugs aiming at cardiac disorders mediated through P2X receptors.

Molecular recognition of modified adenine nucleotides by the P2Y(1)-receptor. 1. A synthetic, biochemical, and NMR approach.

The remarkably high potencies of 2-thioether-adenine nucleotides regarding the activation of the P2Y(1)-receptor (P2Y(1)-R) in turkey erythrocyte membranes represent some of the largest substitution-promoted increases in potencies over that of a natural receptor ligand. This paper describes the investigation regarding the origin of the high potency of these P2Y(1)-R ligands over that of ATP. For this study, an integrated approach was employed combining the synthesis of new ATP analogues, their biochemical evaluation, and their SAR analysis involving NMR experiments and theoretical calculations. These experiments and calculations were performed to elucidate the conformation and to evaluate the electronic nature of the investigated P2Y(1)-R ligands. ATP analogues synthesized included derivatives where C2 or C8 positions were substituted with electron-donating groups such as ethers, thioethers, or amines. The compounds were tested for their potency to induce P2Y(1)-R-mediated activation of phospholipase C in turkey erythrocytes and Ca(2+) response in rat astrocytes. 8-Substituted ATP and AMP derivatives had little or no effect on phospholipase C or on calcium levels, whereas the corresponding 2-substituted ATP analogues potently increased the levels of inositol phosphates and ¿Ca(2+)(i). AMP analogues were ineffective except for 2-butylthio-AMP which induced a small Ca(2+) response. P2Y(1)-R activity of these compounds was demonstrated by testing these ligands also on NG108-15 neuroblastoma x glioma hybrid cells. NMR data together with theoretical calculations imply that steric, rather than electronic, effects play a major role in ligand binding to the P2Y(1)-R. Hydrophobic interactions and H-bonds of the C2 substituent appear to be important determinants of a P2Y(1)-R ligand affinity.

Effect of ABT-627 (A-147627), a potent selective ET(A) receptor antagonist, on the cardiopulmonary profile of newborn lambs with surgically-induced diaphragmatic hernia.

1. Postnatal mortality in isolated congenital diaphragmatic hernia (CDH) is mainly related to the associated pulmonary hypertension (PH) and to right-to-left shunting. 2. Endothelins (ETs) are potent vasoconstrictors and pro-mitogenic peptides. Strong evidences support their participation in CDH and in the etiology of PH via the activation of ET(A) receptors (ET(A)-Rs). 3. Evaluation of the effect of ABT-627, a selective non-peptidic ET(A)-R antagonist, given from -15 to 210 min post-delivery (1 mg kg(-1) bolus +0.01 mg kg(-1) h(-1) infusion, i.v.), was conducted in the lamb model of CDH. 4. Severity of CDH was assessed in comparison to untreated controls (n=5). Untreated CDH lambs (n=7) had a higher mean pulmonary arterial pressure (MPAP; P<0.0001), lower mean blood pressure (MBP; P=0.0004), higher MPAP / MBP ratio (P<0.0001), lower arterial pH (P<0.0001), higher paCO(2) (P<0.0001), lower paO(2) (P<0.0001) and lower post-ductal pulsatile SaO(2) (P<0.0001) than untreated controls. 5. Treated controls (n=7) showed a higher MPAP, lower MBP, higher MPAP/MBP ratio, lower arterial pH, higher paCO(2), lower paO(2), lower post-ductal pulsatile SaO(2) and lower plasmatic ir-ET ratios compared to untreated controls (P<0.0001). 6. Treated CDH lambs (n=8) showed a higher MBP (P<0.0001), lower MPAP / MBP ratio (P<0.0001), higher arterial pH (P<0.0001), lower paCO(2) (P<0.0001), higher paO(2) (P=0.0228), higher post-ductal pulsatile SaO(2) (P=0.0016) and lower plasmatic ir-ET ratios (P=0.0247) when compared to untreated CDH lambs. 7. These observations revealed that, although acute perinatal treatment with a selective non-peptidic ET(A)-R antagonist had some adverse effects in controls, it attenuated the progressive cardiopulmonary deterioration that occurred after birth in CDH lambs.

Resorbable lamellar particles of polylactide as adjuvants for influenza virus vaccines.

Lamellar particles and microspheres were produced by precipitation from solutions of resorbable, biocompatible, semi-crystalline poly(L-lactide)[PLA] and amorphous poly(DL lactide co-glycolide)[PLG] copolymer, respectively, to investigate their adjuvanticity towards adsorbed influenza virus. Both types of substrate were capable of adsorbing large quantities of virus (> 15% w/w) and retaining virus (> 60% of the initial load) over an 8 week time scale in-vitro. Potent immune responses were obtained in mice after the intra-muscular injection of adsorbed vaccine systems. The response to virus adsorbed on PLA lamellar particles was almost five times that obtained using PLG microspheres and fourteen times that using aqueous vaccine. The lamellar forms of PLA may function as an immunomodulator enhancing phagocytic activity due to their irregular shape and may be useful in improving the immune response to a variety of protein and viral antigens.

Age-related features of the resting pattern-reversal visual evoked response using the dipole localization method and cortical imaging technique.

Two mathematical techniques, the dipole localization method (DLM) and the cortical imaging technique (CIT), are used to analyze the resting visual response to pattern-reversal stimulation. These methods identify certain age-related features of this evoked response that are not found by using standard topographic maps. These features include the symmetry of the N1 and P1 responses. The amplitudes of the N1 and P2 responses and the latency of N2 are also significantly different between old and young groups of test subjects, findings consistent with differences seen in conventional topographical analyses. Theoretical dipole sources and simulated cortical surface maps are also constructed for the "average" normal older subject and one patient with documented progressive frontal lobe degenerative disease. Standard topographical imaging studies of this patient were unremarkable, except for the P300 auditory response. DLM and CIT analyses of the VER components were exceptional and consistent with the clinical diagnosis. These mathematical methods appear to enhance the discriminating power of traditional electrophysiological measures.