Search

Introduction: The Framingham risk model estimates a person's 10-year cardiovascular disease (CVD) risk. This study used this model to calculate the changes in sex- and age-specific CVD risks in the Hong Kong Population Health Survey (PHS) 2014/15 compared with two previous surveys conducted during 2003 and 2005, namely, PHS 2003/2004 and Heart Health Survey (HHS) 2004/2005., Methods: This study included individuals aged 30 to 74 years from PHS 2014/15 (n=1662; n=4 445 868 after population weighting) and PHS 2003/2004 and HHS 2004/2005 (n=818; n=3 495 074 after population weighting) with complete data for calculating the risk of CVD predicted by the Framingham model. Sex-specific CVD risks were calculated based on age, total cholesterol and high-density lipoprotein cholesterol levels, mean systolic blood pressure, smoking habit, diabetic status, and hypertension treatment. Mean sex- and age-specific CVD risks were calculated; differences in CVD risk between the two surveys were compared by independent t tests., Results: The difference in 10-year CVD risk from 2003-2005 to 2014-2015 was not statistically significant (10.2% vs 10.6%; P=0.29). After age standardisation according to World Health Organization world standard population data, a small decrease in CVD risk was observed, from 9.4% in 2003-2005 to 8.8% in 2014-2015. Analysis according to age-group showed that more participants aged 65 to 74 years were considered high risk in 2003 to 2005 (2003-2005: 66.8% vs 2014-2015: 53.1%; P=0.028). This difference may be due to the decrease in smokers among men (2003-2005: 30.5% vs 2014-2015: 24.0%; P<0.001)., Conclusion: From 2003-2005 to 2014-2015, there was a small decrease in age-standardised 10-year CVD risk. A holistic public health approach simultaneously targeting multiple risk factors is needed to achieve greater decreases in CVD risk., Competing Interests: As advisers of the journal, CKH Wong and EYT Yu were not involved in the peer review process. Other authors have disclosed no conflicts of interest.

Background: The Early CDT®-Lung antibody blood test plus serial computed tomography scans for test-positives (TPGs) reduces late-stage lung cancer presentation. This study assessed the psychological outcomes of this approach., Methods: Randomized controlled trial (n = 12 208) comparing psychological outcomes 1-12 months post-recruitment in a subsample (n = 1032) of TPG, test-negative (TNG) and control groups (CG)., Results: Compared to TNG, TPG had lower positive affect (difference between means (DBM), 3 months (3m: -1.49 (-2.65, - 0.33)), greater impact of worries (DBM 1m: 0.26 (0.05, 0.47); 3m: 0.28 (0.07, 0.50)), screening distress (DBM 1m: 3.59 (2.28, 4.90); 3m: 2.29 (0.97, 3.61); 6m: 1.94 (0.61, 3.27)), worry about tests (odds ratio (OR) 1m: 5.79 (2.66, 12.63) and more frequent lung cancer worry (OR 1m: 2.52 (1.31, 4.83); 3m: 2.43 (1.26, 4.68); 6m: 2.87 (1.48, 5.60)). Compared to CG, TPG had greater worry about tests (OR 1m: 3.40 (1.69, 6.84)). TNG had lower negative affect (log-transformed DBM 3m: -0.08 (-0.13, -0.02)), higher positive affect (DBM 1m: 1.52 (0.43, 2.61); 3m: 1.43 (0.33, 2.53); 6m: 1.27 (0.17, 2.37)), less impact of worries (DBM 3m: -0.27 (-0.48, -0.07)) and less-frequent lung cancer worry (OR 3m: 0.49 (0.26, 0.92))., Conclusions: Negative psychological effects in TPG and positive effects in TNG were short-lived and most differences were small., (© The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health.)

Health empowerment can be an effective way to reduce health inequities. This prospective cohort study evaluated the 5 year impact of a health empowerment program (HEP) on health outcomes among adults from low-income families. The Patient Enablement Instrument version 2 (PEI-2), Depression, Anxiety and Stress Scale 21 (DASS-21), and 12 item Short-Form Health Survey version 2 (SF-12v2) were administered at baseline and follow-up for both intervention and comparison groups. A total of 289 participants ( n = 162 for intervention group, n = 127 for comparison group) were included in the analysis. Most of the participants were female (72.32%), and aged from 26 to 66 years old (M = 41.63, SD = 6.91). Linear regressions weighted by inverse probability weighting using the propensity score showed that, after follow-up of 5 years, the intervention group demonstrated significantly greater increases in all items and total scores for the PEI-2 (all B > 0.59, p < 0.001), greater decreases in the DASS depression score (B = -1.98 p = 0.001), and greater increases in the Mental Component Summary score of the SF-12v2 (B = 2.99, p = 0.027) than the comparison group. The HEP may be an effective intervention enabling adults from low-income families to manage their health-related issues and improve their mental health, as evidenced by our study.

This paper describes electrospray sampling efficiency measurements obtained on a triple quadrupole mass spectrometer equipped with a large atmosphere to vacuum sampling aperture and modified ion optics designed to confine the ions traveling in the intense expanding gas beam and prevent scattering losses in the entrance optics of the mass analyzer. Sampling efficiency, defined as the ratio of the number of ions captured in the first vacuum stage of the entrance optics to the number of analyte molecules entering the ion source, is a measure of sensitivity that takes into account both ionization efficiency at atmospheric pressure, the efficiency of transporting the ions from atmosphere to vacuum, and the efficiency of confining them in the subsequent gas expansion before mass analysis. Sampling efficiency measurements were conducted under high-performance liquid chromatography sample introduction conditions using columns and flow rates spanning the nanoflow (300 nL/min), microflow (3-60 μL/min), and milliflow (100-500 μL/min) ranges. The results show a convergence in the sampling efficiencies across this range, narrowing the sensitivity gap between the nanoflow and higher flow rate ranges largely because nanoflow sampling efficiency has been shown to be close to 100% for more than a decade, leaving little room for improvement. Under situations where sample volumes are not limiting, lower concentration detection limits can now be achieved with the higher flow rate systems versus nanoflow as a direct consequence of the higher sample loading capacity of the columns and the reduction in the difference in their ion sampling efficiencies.

The COVID-19 pandemic has spread rapidly throughout the world. In the UK, the initial peak was in April 2020; in the county of Norfolk (UK) and surrounding areas, which has a stable, low-density population, over 3200 cases were reported between March and August 2020. As part of the activities of the national COVID-19 Genomics Consortium (COG-UK) we undertook whole genome sequencing of the SARS-CoV-2 genomes present in positive clinical samples from the Norfolk region. These samples were collected by four major hospitals, multiple minor hospitals, care facilities and community organizations within Norfolk and surrounding areas. We combined clinical metadata with the sequencing data from regional SARS-CoV-2 genomes to understand the origins, genetic variation, transmission and expansion (spread) of the virus within the region and provide context nationally. Data were fed back into the national effort for pandemic management, whilst simultaneously being used to assist local outbreak analyses. Overall, 1565 positive samples (172 per 100 000 population) from 1376 cases were evaluated; for 140 cases between two and six samples were available providing longitudinal data. This represented 42.6 % of all positive samples identified by hospital testing in the region and encompassed those with clinical need, and health and care workers and their families. In total, 1035 cases had genome sequences of sufficient quality to provide phylogenetic lineages. These genomes belonged to 26 distinct global lineages, indicating that there were multiple separate introductions into the region. Furthermore, 100 genetically distinct UK lineages were detected demonstrating local evolution, at a rate of ~2 SNPs per month, and multiple co-occurring lineages as the pandemic progressed. Our analysis: identified a discrete sublineage associated with six care facilities; found no evidence of reinfection in longitudinal samples; ruled out a nosocomial outbreak; identified 16 lineages in key workers which were not in patients, indicating infection control measures were effective; and found the D614G spike protein mutation which is linked to increased transmissibility dominates the samples and rapidly confirmed relatedness of cases in an outbreak at a food processing facility. The large-scale genome sequencing of SARS-CoV-2-positive samples has provided valuable additional data for public health epidemiology in the Norfolk region, and will continue to help identify and untangle hidden transmission chains as the pandemic evolves.

Bedside nurses are assuming the faculty role without the necessary skill set to meet their role's rigorous expectations. The researchers sought to explore the lived experiences of early-career nursing faculty and what it feels to be unprepared to teach. A qualitative research design using semi-structured interviews served as the primary data collection method. The purposive sample consisted of nine graduate-prepared early-career nursing faculty with less than five years' experience teaching who felt unprepared for the faculty role. Four themes emerged from the data: (1) balance between theory and practice; (2) socialization to the role; (3) real-world experience; and (4) ownership for ongoing learning. The findings bring transparency for nurse faculty to assess the educational and transitional process outcomes from early-career nursing faculties' perspectives., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Diabetes mellitus (DM) is a serious public health issue worldwide, and DM patients have higher risk of cardiovascular diseases (CVDs), which is the leading cause of DM-related deaths. China has the largest DM population, yet a robust model to predict CVDs in Chinese DM patients is still lacking. This systematic review is carried out to summarize existing models and identify potentially important predictors for CVDs in Chinese DM patients., Study Design: Systematic review., Methods: Medline and Embase were searched for data from April 1st, 2011 to May 31st, 2018. A study was eligible if it developed CVD (defined as total CVD or any major cardiovascular component) risk prediction models or explored potential predictors of CVD specifically for Chinese people with type 2 DM. Standardized forms were utilized to extract information, appraise applicability, risk of bias, and availabilities., Results: Five models and 29 studies focusing on potential predictors were identified. Models for a primary care setting, or to predict total CVD, are rare. A number of common predictors (e.g. age, sex, diabetes duration, smoking status, glycated hemoglobin (HbA1c), blood pressure, lipid profile, and treatment modalities) were observed in existing models, in which urine albumin:creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) are highly recommended for the Chinese population. Variability of blood pressure (BP) and HbA1c should be included in prediction model development as novel factors. Meanwhile, interactions between age, sex, and risk factors should also be considered., Conclusions: A 10-year prediction model for CVD risk in Chinese type 2 DM patients is lacking and urgently needed. There is insufficient evidence to support the inclusion of other novel predictors in CVDs risk prediction functions for routine clinical use., (Copyright © 2020 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Vulvodynia (idiopathic vulvar pain) affects up to 8% of women by age 40 years, has a poorly understood etiology, and has variable treatment efficacy. Several risk factors are associated with vulvodynia from a history of yeast infections to depression and allergies. Recent work suggests an altered immune inflammatory mechanism plays a role in vulvodynia pathophysiology. Because the vaginal microbiome plays an important role in local immune-inflammatory responses, we evaluated the vaginal microbiome among women with vulvodynia compared with controls as 1 component of the immune system., Objective: The objective of the study was to characterize the vaginal microbiome in women with clinically confirmed vulvodynia and age-matched controls and assess its overall association with vulvodynia and how it may serve to modify other factors that are associated with vulvodynia as well., Study Design: We conducted a case-control study of 234 Minneapolis/Saint Paul-area women with clinically confirmed vulvodynia and 234 age-matched controls clinically confirmed with no history of vulvar pain. All participants provided vulvovaginal swab samples for culture-based and non-culture (sequencing)-based microbiological assessments, background and medical history questionnaires on demographic characteristics, sexual and reproductive history, and history of psychosocial factors. Vaginal microbiome diversity was assessed using the Shannon alpha diversity Index. Data were analyzed using logistic regression., Results: Culture and molecular-based analyses of the vaginal microbiome showed few differences between cases and controls. However, among women with alpha diversity below the median (low), there was a strong association between increasing numbers of yeast infections and vulvodynia onset, relative to comparable time periods among controls (age-adjusted odds ratio, 8.1, 95% confidence interval, 2.9-22.7 in those with 5 or more yeast infections). Also among women with low-diversity microbiomes, we observed a strong association between moderate to severe childhood abuse, antecedent anxiety, depression, and high levels of rumination and vulvodynia with odds ratios from 1.83 to 2.81. These associations were not observed in women with high-diversity microbiomes., Conclusion: Although there were no overall differences in microbiome profiles between cases and controls, vaginal microbiome diversity influenced associations between environmental and psychosocial risk factors and vulvodynia. However, it is unclear whether vaginal diversity modifies the association between the risk factors and vulvodynia or is altered as a consequence of the associations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale: The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Moreover, UPS and autophagic-lysosomal pathway defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the 2 catabolic pathways will help advance cardiac pathophysiology and medicine., Objective: Systemic proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. Here we investigate how proteasome malfunction activates cardiac autophagic-lysosomal pathway., Methods and Results: Myocardial macroautophagy, TFEB (transcription factor EB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (an essential proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted by pharmacological and genetic calcineurin inhibition and by siRNA-mediated Molcn1 silencing. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null (p62-KO) mice. Bortezomib-induced left ventricular wall thickening and diastolic malfunction was exacerbated by p62 deficiency. In cultured cardiomyocytes from wild type mice but not p62-KO mice, PSMI induced increases in LC3-II flux and the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62-KO mice compared with wild type mice., Conclusions: (1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) p62 unexpectedly exerts a feed-forward effect on TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1 (mucolipin1)-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac autophagic-lysosomal pathway activation during proteasome malfunction.

Rationale, Aims, and Objectives: High response rates to research questionnaires can help to ensure results are more representative of the population studied and provide increased statistical power, on which the study may have been predicated. Improving speed and quality of response can reduce costs., Method: We conducted a randomized study within a trial (SWAT) to assess questionnaire response rates, reminders sent, and data completeness with unconditional compared with conditional monetary incentives. Eligible individuals were mailed a series of psychological questionnaires as a follow-up to a baseline host trial questionnaire. Half received a £5 gift voucher with questionnaires (unconditional), and half were promised the voucher after returning questionnaires (conditional)., Results: Of 1079 individuals, response rates to the first follow-up questionnaire were 94.2% and 91.7% in the unconditional and conditional monetary incentive groups, respectively (OR 1.78; 95% CI, 0.85-3.72). There were significantly greater odds of returning repeat questionnaires in the unconditional group at 6 months (OR 2.97; 95% CI, 1.01-8.71; .047) but not at 12 months (OR 1.12; 95% CI, 0.44-2.85). Incentive condition had no impact at any time point on the proportion of sent questionnaires that needed reminders. Odds of incomplete questionnaires were significantly greater at 3 months in the unconditional compared with the conditional incentive group (OR 2.45; 95% CI, 1.32-4.55; .004)., Conclusions: Unconditional monetary incentives can produce a transitory greater likelihood of mailed questionnaire response in a clinical trial participant group, consistent with the direction of effect in other settings. However, this could have been a chance finding. The use of multiple strategies to promote response may have created a ceiling effect. This strategy has potential to reduce administrative and postage costs, weighed against the cost of incentives used, but could risk compromising the completeness of data., (© 2019 John Wiley & Sons, Ltd.)

Introduction: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC., Methods: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated., Results: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths., Conclusions: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We find that patients <40 years old with a first invasive encapsulated bacterial infection have a high likelihood of death or readmission within 23 months. It is imperative to highlight them for immunological screening and initiate prophylactic interventions and treatment., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The sampling efficiency in electrospray ionization-mass spectrometry (ESI-MS) can be improved by decreasing the liquid flow rate to the nanoflow regime, where it is possible to draw a large fraction of the ESI plume into the mass spectrometer. This mode of operation is typically more difficult than ESI-MS at higher flow rates because it requires careful optimization of a number of parameters to achieve optimal sampling efficiency. In this work, we screened the relative impact on signal intensity and spray stability of factors that included sprayer position, spray electrode protrusion, sprayer tip shape, spray angle relative to the MS inlet, nebulizer gas flow rate, ESI potential, and means for generating the electric field to initiate electrospray. Based on the screening results, we explore the possibility of providing fixed optimal values for many of the key source parameters to eliminate much of the tuning that is required for conventional nanoflow sources. This approach has potential to greatly simplify nanoflow ESI-MS, while providing optimized sensitivity, stability, and robustness, with decreased variability between analyses.

Monoamine oxidases (MAOs) are located on the outer mitochondrial membrane and are drug targets for the treatment of neurological disorders. MAOs control the levels of neurotransmitters in the brain via oxidative deamination and contribute to reactive oxygen species (ROS) generation through their catalytic by-product H 2 O 2 . Increased ROS levels may modulate mitochondrial function and mitochondrial dysfunction is implicated in a vast array of disorders. However, the downstream effects of MAO-A mediated ROS production in a neuronal model has not been previously investigated. In this study, using MAO-A overexpressing neuroblastoma cells, we demonstrate that higher levels of MAO-A protein/activity results in increased basal ROS levels with associated increase in protein oxidation. Increased MAO-A levels result in increased Lysine-63 linked ubiquitination of mitochondrial proteins and promotes autophagy through Bcl-2 phosphorylation. Furthermore, ROS generated locally on the mitochondrial outer membrane by MAO-A promotes phosphorylation of dynamin-1-like protein, leading to mitochondrial fragmentation and clearance without complete loss of mitochondrial membrane potential. Cellular ATP levels are maintained following MAO-A overexpression and complex IV activity/protein levels increased, revealing a close relationship between MAO-A levels and mitochondrial function. Finally, the downstream effects of increased MAO-A levels are dependent on the availability of amine substrates and in the presence of exogenous substrate, cell viability is dramatically reduced. This study shows for the first time that MAO-A generated ROS is involved in quality control signalling, and increase in MAO-A protein levels leads to a protective cellular response in order to mediate removal of damaged macromolecules/organelles, but substrate availability may ultimately determine cell fate. The latter is particularly important in conditions such as Parkinson's disease, where a dopamine precursor is used to treat disease symptoms and highlights that the fate of MAO-A containing dopaminergic neurons may depend on both MAO-A levels and catecholamine substrate availability., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

This Campbell systematic review examines the predictors of youth gang membership in low- and middle-income countries. The review summarises findings from eight reports from five countries and the Caribbean region. The lack of available evidence limits the extent to which clear conclusions can be drawn about the factors associated with youth gang membership. The review is based on a very small number of studies, and has significant limitations in coverage. The limited evidence of the correlates of youth gang membership suggests factors that may drive gang membership and suggests areas where interventions may prove promising in the family, school, and community domains, as well as provide a starting point for future studies., Plain Language Summary: Evidence shows which factors predict gang membership in low- and middle-income countries, but more studies needed: Youth gang membership is associated with delinquency, violent crime and trafficking. A range of individual, peer, family, school and community factors can predict the likelihood of youths getting involved with gangs. Knowledge of these factors can be helpful for reducing gang membership. What is this review about?: Youth gang membership is associated with delinquency, violent crime and trafficking - and gang members are themselves frequently the victims of these offences. Yet youth gangs can also provide a form of social capital, a sense of belonging and purpose to disenfranchised youth.This review identifies the factors associated with young people joining gangs, and the differences between gang-involved and non-gang-involved youth. Understanding these associations is essential to reduce the levels of gang membership and the incidence of related violence. What studies are included?: Studies of youth gangs in in low- and middle-income countries were included, with participants aged 10-29 years. The studies had to assess an individual predictor or correlate of youth gang membership, where the predictor or correlate is a single characteristic, not a conglomeration of multiple constructs. Included studies had designs including data on both gang-involved and non-gang-involved youth, recruited with strategies that were eligible.Nine studies met the eligibility criteria and were included in the review. One of these studies did not report all the required data and so was not included in the analyses. The studies were conducted in Turkey, Trinidad and Tobago, the Caribbean, El Salvador, China and Brazil. Factors associated with gang membership [Table: see text] What are the main results in this review?: The eight studies analysed in the review address the associations between life events and circumstances, and the likelihood of being a youth gang member across five domains: individual, peers, family, school and community. Significant associations were found with factors in each domain. What do the findings of this review mean?: The lack of available evidence limits the extent to which clear conclusions can be drawn about the factors associated with youth gang membership. The review is based on a very small number of studies, and has significant limitations in coverage. The limited evidence of the correlates of youth gang membership suggests factors that may drive gang membership and suggests areas where interventions may prove promising in the family, school, and community domains, as well as provide a starting point for future studies. How up-to-date is this review?: The review authors searched for studies published up to September 2013. This Campbell systematic review was published in December 2018., Summary: Background: Youth gang membership is well documented throughout low- and middle-income countries, and youth gang members are increasingly associated with delinquency, violent crime and trafficking. They are also frequently the victims of these offences, often in disproportionate numbers compared to non-gang youth. Yet youth gangs can also provide a form of social capital, a sense of belonging and purpose to disenfranchised youth.Extensive research, primarily from high-income countries, has categorized five domains of risk and protective factors for youth gang involvement, drawn from the realm of developmental psychology. These domains are: Individual, Peer, Family, School, and Community. Youth gang membership is seen as the culmination of interrelated structural and process factors, which in combination with negative life events may increase the attractiveness of gang membership.This review aimed to identify the factors associated with young people joining gangs, and to identify and quantify the differences between gang-involved and non-gang-involved youth. Understanding these associations is essential to reduce the levels of gang membership and the incidence of related violence. Objectives: This review addresses two key objectives: (1) to synthesize the published and unpublished empirical evidence on the factors associated with membership of youth gangs in low- and middle-income countries;(2) to assess the relative strength of the different factors across the domains of individual, family, school, peer group and community. Search methods: The search was conducted in English, French, Chinese, Arabic, Russian, Spanish and Portuguese. We searched 55 locations including academic databases, journals, and grey literature locations, and located over 54,000 documents to screen. Selection criteria: We included studies meeting the following criteria: Reports on youth gangsAll participants aged 10-29 yearsLocated in low- or middle-income countryAssesses an individual predictor or correlate of youth gang membershipPredictor or correlate is a single characteristicPredictor or correlate is not a conglomeration of multiple constructsEligible recruitment strategy for respondentsStudy design included data on both gang involved and non-gang involved youth. Data collection and analysis: We conducted a broad abstract screening of over 54,000 titles and abstracts, followed by a close abstract screening of 1509 abstracts. We screened the full-text of 98 documents. Nine studies met the eligibility criteria and were included in the review. One of these studies did not report sufficient data to allow the calculation of a standardized effect size, and so was not included in the analyses. A total of 85 independent effect sizes were extracted from the eight studies with sufficient data to create a standardized effect size. We calculated Cohen's d from continuous data and the Log Odds Ratio from dichotomous data. All effects were categorized into the five predictor domains, and further classified into conceptually similar group and risk or protective factors. We synthesized the data using multiple random effects meta-analyses with inverse variance weighting. Results: The eight studies analysed in the review address the associations between life events and circumstances, and the likelihood of being a youth gang member. All studies were based on cross-sectional survey data, using different statistical methods to identify correlations between youth characteristics and the likelihood of being a member of a youth gang. No longitudinal, prospective or retrospective studies were located. The studies were conducted in Turkey, Trinidad and Tobago, the Caribbean, El Salvador, China and Brazil. We organized the analyses according to five domains of factors that may be associated with youth gang involvement and summarize the main findings below: Individual factors Delinquency, alcohol and soft drug use, male gender, risky sexual behaviours, employment, psychological risk factors (low self-control, impulsivity), and victimisation were each associated with significantly higher odds of youth gang membership.Psychological protective factors (empathy, future orientation, belief in moral order) were associated with lower odds.No association between youth gang membership and age, minority ethnicity, or protective behaviours surrounding sexual behaviour or alcohol and soft drug use. Peer factors There is a small amount of evidence that socialising with delinquent peers is associated with increased odds of youth gang membership, but there is no significant relationship demonstrated between socialising with pro-social peers and youth gang membership. Family factors Negative family environments are associated with more youth gang membership, while both a positive family environment and parental monitoring were associated with lower odds.One study showed that youth from middle-income families had greater odds of reporting youth gang membership than those from either high or low-income families.No significant relationship was seen between youth gang membership and parental education or parental attitudes to antisocial behaviour. School factors Low school attachment, exposure to violence at school, educational difficulties and opportunities for prosocial involvement all show significant association with more youth gang membership.No significant relationship was seen between youth gang membership and level of education, school type, or school performance. Community factors There were significantly higher odds of youth gang membership amongst those who reported that they were exposed to violence in their neighbourhood.No demonstrated association between youth gang membership and neighbourhood environment risk or protective factors, or geography. Gang membership is typically viewed as a culmination of interrelated structural and process factors. Understanding the factors associated with youth gang membership can help inform prevention strategies to reduce the levels of youth gang membership and the incidence of youth gang violence. Unfortunately the small number of studies contributing to any analysis limits the conclusions that can be drawn from this study. Moreover, many of the individual and peer associations identified in this review (such as delinquency, drug use, and sexual risk factors) may be as a result of gang membership rather than its cause. However, our results suggest certain family, school, and community level factors associated with gang membership that could be addressed through targeted preventive interventions, particularly family environment, parental monitoring, school attachment, educational difficulties, and exposure to violence in the home, at school, or in the community. Authors' conclusions: The lack of available evidence limits the extent to which we can draw any clear conclusions about the factors associated with youth gang membership. This current review is based on a very small number of studies, and has significant limitations in coverage; however it provides some limited evidence of the correlates of youth gang membership. Specifically, this review suggests factors that may drive gang membership and suggests areas where interventions may prove promising in the family, school, and community domains, as well as provide a starting point for future studies., (© 2018 Higginson et al.)

Background: This review aimed to better understand experiences of being invited to cancer screening and associated decision-making., Methods: Qualitative evidence explaining UK cancer screening attendance decisions was systematically identified. Data were extracted and meta-ethnography used to identify shared themes, synthesize findings and generate higher level interpretations., Results: Thirty-four studies met inclusion criteria. They related to uptake of breast, cervical, colorectal, prostate, ovarian and lung cancer screening. Three primary themes emerged from the synthesis. 'Relationships with the health service' shaped decisions, influenced by trust, compliance with power, resistance to control or surveillance and perceived failures to meet cultural, religious and language needs. 'Fear of cancer screening' was both a motivator and barrier in different ways and to varying degrees. Strategies to negotiate moderate fear levels were evident. 'Experiences of risk' included the creation of alternative personal risk discourses and the use of screening as a coping strategy, influenced by disease beliefs and feelings of health and wellness., Conclusions: The findings highlight the importance of the provider-patient relationship in screening uptake and enrich our understanding of how fear and risk are experienced and negotiated. This knowledge can help promote uptake and improve the effectiveness of cancer screening.

Background: VRE bacteraemia has a high mortality and continues to defy control. Antibiotic risk factors for VRE bacteraemia have not been adequately defined. We aimed to determine the risk factors for VRE bacteraemia focusing on duration of antibiotic exposure., Methods: A retrospective matched nested case-control study was conducted amongst hospitalized patients at Cambridge University Hospitals NHS Foundation Trust (CUH) from 1 January 2006 to 31 December 2012. Cases who developed a first episode of VRE bacteraemia were matched 1:1 to controls by length of stay, year, specialty and ward type. Independent risk factors for VRE bacteraemia were evaluated using conditional logistic regression., Results: Two hundred and thirty-five cases were compared with 220 controls. Duration of exposure to parenteral vancomycin, fluoroquinolones and meropenem was independently associated with VRE bacteraemia. Compared with patients with no exposure to vancomycin, those who received courses of 1-3 days, 4-7 days or >7 days had a stepwise increase in risk of VRE bacteraemia [conditional OR (cOR) 1.2 (95% CI 0.4-3.8), 3.8 (95% CI 1.2-11.7) and 6.6 (95% CI 1.9-22.8), respectively]. Other risk factors were: presence of a central venous catheter (CVC) [cOR 8.7 (95% CI 2.6-29.5)]; neutropenia [cOR 15.5 (95% CI 4.2-57.0)]; hypoalbuminaemia [cOR 8.5 (95% CI 2.4-29.5)]; malignancy [cOR 4.4 (95% CI 1.6-12.0)]; gastrointestinal disease [cOR 12.4 (95% CI 4.2-36.8)]; and hepatobiliary disease [cOR 7.9 (95% CI 2.1-29.9)]., Conclusions: Longer exposure to vancomycin, fluoroquinolones or meropenem was associated with VRE bacteraemia. Antimicrobial stewardship interventions targeting high-risk antibiotics are required to complement infection control procedures against VRE bacteraemia.

Metabolite profiling is an important tool that may better capture the multiple features of neurodegeneration. With the considerable parallels between mouse and human metabolism, the use of metabolomics in mouse models with neurodegenerative pathology provides mechanistic insight and ready translation into aspects of human disease. Using 400 MHz nuclear magnetic resonance spectroscopy we have carried out a temporal region-specific investigation of the metabolome of neuron-specific 26S proteasome knockout mice characterised by progressive neurodegeneration and Lewy-like inclusion formation in the forebrain. An early significant decrease in N-acetyl aspartate revealed evidence of neuronal dysfunction before cell death that may be associated with changes in brain neuroenergetics, underpinning the use of this metabolite to track neuronal health. Importantly, we show early and extensive activation of astrocytes and microglia in response to targeted neuronal dysfunction in this context, but only late changes in myo-inositol; the best established glial cell marker in magnetic resonance spectroscopy studies, supporting recent evidence that additional early neuroinflammatory markers are needed. Our results extend the limited understanding of metabolite changes associated with gliosis and provide evidence that changes in glutamate homeostasis and lactate may correlate with astrocyte activation and have biomarker potential for tracking neuroinflammation.

Background: Recent evidence shows that patient engagement is an important strategy in achieving a high performing healthcare system. While there is considerable evidence of implementation initiatives in direct care context, there is limited investigation of implementation initiatives in decision-making context as it relates to program planning, service delivery and developing policies. Research has also shown a gap in consistent application of system-level strategies that can effectively translate organizational policies around patient and family engagement into practice., Methods: The broad objective of this initiative was to develop a system-level implementation strategy to include patient and family advisors (PFAs) at decision-making points in primary healthcare (PHC) based on wellestablished evidence and literature. In this opportunity sponsored by the Canadian Foundation for Healthcare Improvement (CFHI) a co-design methodology, also well-established was applied in identifying and developing a suitable implementation strategy to engage PFAs as members of quality teams in PHC. Diabetes management centres (DMCs) was selected as the pilot site to develop the strategy. Key steps in the process included review of evidence, review of the current state in PHC through engagement of key stakeholders and a co-design approach., Results: The project team included a diverse representation of members from the PHC system including patient advisors, DMC team members, system leads, providers, Public Engagement team members and CFHI improvement coaches. Key outcomes of this 18-month long initiative included development of a working definition of patient and family engagement, development of a Patient and Family Engagement Resource Guide and evaluation of the resource guide., Conclusion: This novel initiative provided us an opportunity to develop a supportive system-wide implementation plan and a strategy to include PFAs in decision-making processes in PHC. The well-established co-design methodology further allowed us to include value-based (customer driven quality and experience of care) perspectives of several important stakeholders including patient advisors. The next step will be to implement the strategy within DMCs, spread the strategy PHC, both locally and provincially with a focus on sustainability., (© 2017 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

The frequent occurrence of disease outbreaks in humans caused by group A Streptococcus (GAS) is an on-going public health threat. Conventional bacterial typing methods lack the discriminatory power to confidently confirm or refute outbreaks in hospital and community settings. Microbial whole genome sequencing (WGS) provides a potential solution to this, but, there has been limited population-based surveillance with accompanying sequence data. We performed retrospective genomic surveillance of 93 clinical GAS isolates from individuals in a defined geographic region. Detailed clinical information was obtained for closely related clusters of isolates. Genomic sequence data was contextualised through comparison with international data. We identified 18 different emm genotypes within our bacterial population, and revealed both highly diverse and closely related isolates. This high level of diversity was maintained even in the context of international sequence data. We also identified two emm1 clusters, and one emm3 cluster, of closely-related isolates that differed only by 1 to 4 single nucleotide polymorphisms. Analysis of clinical information identified no healthcare associated contact between patients, indicating cryptic community transmission. Our findings suggest that genomic surveillance of GAS would increase detection of transmission and highlight opportunities for intervention.

Background: Lung cancer is the most common cause of cancer related death worldwide. The majority of cases are detected at a late stage when prognosis is poor. The EarlyCDT®-Lung Test detects autoantibodies to abnormal cell surface proteins in the earliest stages of the disease which may allow tumour detection at an earlier stage thus altering prognosis. The primary research question is: Does using the EarlyCDT®-Lung Test to identify those at high risk of lung cancer, followed by X-ray and computed tomography (CT) scanning, reduce the incidence of patients with late-stage lung cancer (III & IV) or unclassified presentation (U) at diagnosis, compared to standard practice?, Methods: A randomised controlled trial of 12 000 participants in areas of Scotland targeting general practices serving patients in the most deprived quintile of the Scottish Index of Multiple Deprivation. Adults aged 50-75 who are at high risk of lung cancer and healthy enough to undergo potentially curative therapy (Performance Status 0-2) are eligible to participate. The intervention is the EarlyCDT®-Lung Test, followed by X-ray and CT in those with a positive result. The comparator is standard clinical practice in the UK. The primary outcome is the difference, after 24 months, between the rates of patients with stage III, IV or unclassified lung cancer at diagnosis. The secondary outcomes include: all-cause mortality; disease specific mortality; a range of morbidity outcomes; cost-effectiveness and measures examining the psychological and behavioural consequences of screening. Participants with a positive test result but for whom the CT scan does not lead to a lung cancer diagnosis will be offered 6 monthly thoracic CTs for 24 months. An initial chest X-ray will be used to determine the speed and the need for contrast in the first screening CT. Participants who are found to have lung cancer will be followed-up to assess both time to diagnosis and stage of disease at diagnosis., Discussion: The study will determine the clinical and cost effectiveness of EarlyCDT®-Lung Test for early lung cancer detection and assess its suitability for a large-scale, accredited screening service. The study will also assess the potential psychological and behavioural harms arising from false positive or false negative results, as well as the potential benefits to patients of true negative EarlyCDT lung test results. A cost-effectiveness model of lung cancer screening based on the results of the EarlyCDT Lung Test study will be developed., Trial Registration: NCT01925625 . August 19, 2013.

The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated.

Background: Pseudomonas aeruginosa is a rare cause of meningitis and ventriculitis but is generally associated with significant morbidity and mortality., Aim: We sought to determine the epidemiology, risk factors and outcome of meningitis and ventriculitis due to P. aeruginosa at our institution in order to inform preventive strategies and treatment guidelines., Methods: Retrospective study of all patients with a positive cerebrospinal fluid (CSF) culture admitted to a tertiary care hospital over 18 years. Clinical details, demographic, microbiological and antibiotic data were obtained from laboratory and medical records., Results: Twenty-four episodes occurred in 21 patients over 18 years. Pyrexia (75%), fluctuating mental status (50%) and headache (41%) were the most frequent presenting symptoms. Nineteen of the 21 patients had previously undergone a neurosurgical procedure and seven had extra-ventricular devices in situ. Twelve (57%) patients had P. aeruginosa isolated from another site prior to their episode. Most (89%) CSF samples demonstrated a neutrophilia; the CSF protein, when measured, was raised in all cases. Gram-negative bacilli were visible on CSF microscopy in only three isolates. There were relatively low rates of resistance to most antimicrobials tested and combination treatment of intravenous with intrathecal antibiotics was often used. No patients died within 28 days., Conclusion: Pseudomonas aeruginosa meningitis and ventriculitis are predominantly nosocomial and related to prior neurosurgery. It can be difficult to diagnose as CSF Gram-film and meningism are insensitive markers. Appropriate empirical treatment, neurosurgical prophylaxis and surveillance can aid in managing this infection., (© The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent trends show an increase in the prevalence and costs associated with managing individuals with multimorbidities. Enabling better care for these individuals requires system-level changes such as the shift from a focus on a single disease or single service to multimorbidities and integrated systems of care. In this paper, a novel patient-centred redesign framework that was developed to support system-level process changes in four service areas has been discussed. The novelty of this framework is that it is embedded in patient perspectives and in the chronic care model as the theoretical foundation. The aims of this paper are to present an application of the framework in the context of four chronic disease prevention and management services, and to discuss early results from the pilot initiative along with an overview of the spread opportunities for this initiative.

The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. These pathways are interdependent, and dysfunction in either pathway causes accumulation of ubiquitin-positive aggregates, a hallmark of human pathological conditions. To elucidate in vivo compensatory action(s) against proteasomal dysfunction, we developed mice with reduced proteasome activity in their livers. The mutant mice exhibited severe liver damage, accompanied by formation of aggregates positive for ubiquitin and p62/Sqstm1, an adaptor protein for both selective autophagy and the anti-oxidative Keap1-Nrf2 pathway. These aggregates were selectively entrapped by autophagosomes, and pathological features of livers with impaired proteasome activity were exacerbated by simultaneous suppression of autophagy. In contrast, concomitant loss of p62/Sqstm1 had no apparent effect on the liver pathology though p62/Sqstm1 was indispensable for the aggregates formation. Furthermore, defective proteasome function led to transcriptional activation of the Nrf2, which served as a physiological adaptation. Our in vivo data suggest that cells contain networks of cellular defense mechanisms against defective proteostasis., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic) subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.

Neurodegenerative diseases are characterized by progressive degeneration of selective neurones in the nervous system, but the underlying mechanisms involved in neuroprotection and neurodegeneration remain unclear. Dysfunction of the ubiquitin proteasome system is one of the proposed hypotheses for the cause and progression of neuronal loss. We have performed quantitative two-dimensional fluorescence difference in-gel electrophoresis combined with peptide mass fingerprinting to reveal proteome changes associated with neurodegeneration following 26S proteasomal depletion in mouse forebrain neurones. Differentially expressed proteins were validated by Western blotting, biochemical assays and immunohistochemistry. Of significance was increased expression of the antioxidant enzyme peroxiredoxin 6 (PRDX6) in astrocytes, associated with oxidative stress. Interestingly, PRDX6 is a bifunctional enzyme with antioxidant peroxidase and phospholipase A2 (PLA2) activities. The PLA2 activity of PRDX6 was also increased following 26S proteasomal depletion and may be involved in neuroprotective or neurodegenerative mechanisms. This is the first in vivo report of oxidative stress caused directly by neuronal proteasome dysfunction in the mammalian brain. The results contribute to understanding neuronal-glial interactions in disease pathogenesis, provide an in vivo link between prominent disease hypotheses and importantly, are of relevance to a heterogeneous spectrum of neurodegenerative diseases., (© 2013. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is characterized by the progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurones and the formation of Lewy bodies (LB) in a proportion of the remaining neurones. α-synuclein is the main component of LB, but the pathological mechanisms that lead to neurodegeneration associated with LB formation remain unclear. Three pivotal elements have emerged in the development of PD: α-synuclein, mitochondria and protein degradation systems. We previously reported a unique model, created by conditional genetic depletion of 26S proteasomes in the SNpc of mice, which mechanistically links these three elements with the neuropathology of PD: progressive neurodegeneration and intraneuronal inclusion formation. Using this model, we tested the hypothesis that α-synuclein was essential for the formation of inclusions and neurodegeneration caused by 26S proteasomal depletion. We found that both of these processes were independent of α-synuclein. This provides an important insight into the relationship between the proteasome, α-synuclein, inclusion formation and neurodegeneration. We also show that the autophagy-lysosomal pathway is not activated in 26S proteasome-depleted neurones. This leads us to suggest that the paranuclear accumulation of mitochondria in inclusions in our model may reflect a role for the ubiquitin proteasome system in mitochondrial homeostasis and that neurodegeneration may be mediated through mitochondrial factors linked to inclusion biogenesis.

The ubiquitin proteasome system (UPS) is a fundamental cellular pathway, degrading most unwanted intracellular soluble proteins. Dysfunction of the UPS has been associated with normal aging as well as various age-related pathological conditions, including chronic human neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, leading to a significant interest in the involvement of this degradative system in neurones. We previously reported that the 26S proteasome was essential for neuronal homeostasis and survival in mouse brains following conditional genetic homozygous knockout of a key subunit of the multi-meric 26S proteasome (19S ATPase Psmc1). Here, we investigated the effects of Psmc1 heterozygosity in the mouse brain and primary mouse embryonic fibroblasts. Neuropathologically and biochemically, Psmc1 heterozygous (Psmc1(+/-)) knockout mice were indistinguishable from wild-type mice. However, we report a novel age-related accumulation of intraneuronal lysine 48-specific polyubiquitin-positive granular staining in both wild-type and heterozygous Psmc1 knockout mouse brain. In Psmc1(+/-) MEFs, we found a significant decrease in PSMC1 levels, altered 26S proteasome assembly and a notable G2/M cell cycle arrest that was not associated with an increase in the cell cycle regulatory protein p21. The disturbance in cell cycle progression may be responsible for the growth inhibitory effects in Psmc1(+/-) MEFs., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Chronic neurodegenerative disease is characterized by extensive regional loss of neurons in the brain and neuropathological hallmarks in surviving neurones. Genetic modelling by overexpression of hallmark proteins does not produce extensive neurodegeneration, whereas genetic deletion of neuronal 26S proteasomes does, as well as some hallmarks of human disease.

To what extent are nurses willing to learn with technology-enhanced tools, such as online education, podcasts, webcasts, mobile learning, and realistic simulations? What factors influence their willingness? This article includes a description of a mixed methodology study that addressed these questions. Nurses of all ages indicated a willingness to learn with a variety of technological tools. Primary determinants of willingness were associated with ease of use, familiarity, convenience, and perceived benefit.

A generality has been that polyubiquitin chain linkage can differentially address proteins for various physiological processes. 26S proteasomal degradation is the most established function of ubiquitin signalling, classically linked to Lys48 polyubiquitin chains. The other well-characterised polyubiquitin linkage, via Lys63, mediates nonproteolytic functions. However, there are five other lysine residues and ubiquitin's amino terminus which can participate in polyubiquitination. Our 26S proteasome knockout mouse provides a unique opportunity to comprehensively investigate the ubiquitin signals in their physiological context in neurones following genetic inhibition of the proteasome, using quantitative mass spectrometry of ubiquitin linkage-specific signature peptides. We provide the first evidence for diverse polyubiquitin chains in mammalian neurones in vivo and show that polyubiquitin linked via Lys6, Lys11, Lys29 and Lys48, but not Lys63, accumulates upon 26S proteasome dysfunction. This adaptable nature of ubiquitin signals for proteasomal targeting could reflect the extensive cellular processes which are regulated by proteasome proteolysis and/or may involve specific ubiquitin linkage preferences for subsets of proteins in mammalian neurones. Our molecular pathological findings make a significant contribution to the understanding of ubiquitin signalling in ubiquitin-proteasome function., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that regulates neurite outgrowth. It is phosphorylated by Cdk5 and GSK3, and these modifications are abnormally high in the brains of Alzheimer's disease (AD) patients. Increased phosphorylation of CRMP2 is also apparent in mouse models of AD that express mutated AβPP and PSEN1, but not AβPP or tau alone, where it is detectable before the appearance of amyloid plaques and neurofibrillary tangles, suggesting it is an early event in AD pathogenesis. Here, we have extended these observations by showing that CRMP2 is not hyperphosphorylated in mice overexpressing mutated PSEN1 alone, or in cultured neurons treated with soluble, oligomeric Aβ42 peptide. Similarly, CRMP2 phosphorylation was not increased in a mouse model of severe neurodegeneration (PMSC-1 knockout) or in cultured neurons subjected to neurotoxic concentrations of NMDA or staurosporine. Most interestingly, CRMP2 phosphorylation was not increased in frontal cortex from patients with frontotemporal lobar degeneration associated with mutations in MAPT or with Pick bodies. Together, these observations are consistent with the hypothesis that abnormal phosphorylation of CRMP2 is specific to AD and occurs downstream of excessive processing of AβPP, but that neither excessive Aβ42 peptide nor neurotoxicity alone are sufficient to promote hyperphosphorylation.

The ubiquitin-proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.

ADVANCES IN TECHNOLOGY HAVE expanded the educational tools and learning options available to today's nurses. Among these technologically enhanced tools and strategies are online learning, podcasts, vodcasts, webcasts, webinars, discussion forums, mobile learning, realistic simulations, and others. What exactly are these options? Which ones are the most effective? This is the first topic we will address in a new column on educational strategies in the NICU, a column designed to familiarize NICU nurse educators, clinical nurse specialists, managers, and preceptors with innovative and evidenced-based teaching strategies that promote optimal learning among NICU nurses. The purpose of this first column is to provide an introduction to innovative teaching tools and strategies-some technologically enhanced, some not-including such nontechnological interactive educational activities as problem-based learning, games, and concept maps. Future columns will discuss many of these strategies in more detail.

The 26S proteasome is a large multiprotein complex involved in the regulated degradation of ubiquitinated proteins in the cell. The 26S proteasome has been shown to control an increasing number of essential biochemical mechanisms of the cellular lifecycle including DNA synthesis, repair, transcription, translation, and cell signal transduction. Concurrently, it is increasingly seen that malfunction of the ubiquitin proteasome system contributes to the pathogenesis of disease. The recent identification of four molecular chaperones, in addition to five previously identified chaperones, have provided mechanistic insight into how this cellular megastructure is assembled in the cell. These data, together with new insights into the structure and function of the proteasome, provide a much better understanding of this complex protease., (Crown Copyright 2010. Published by Elsevier Ltd. All rights reserved.)

The significance of the accumulation of ubiquitin-positive intraneuronal inclusions in the brains of those affected with different neurodegenerative diseases is currently unclear. While one interpretation is that the disease mechanism(s) involves dysfunction of an ubiquitin-mediated process, such as the ubiquitin-proteasome system, the inclusions are also found in surviving neurones, suggesting a possible neuroprotective role. Here we review recent evidence in support of these seemingly opposing notions gleaned from cell and animal models as well as investigations of patient samples, with particular emphasis on studies relevant to Parkinson's disease.

The major human neurodegenerative diseases are characterised by ubiquitin-positive intraneuronal inclusions, however the precise nature of the ubiquitin modifications in these structures is unclear. Using a monoclonal antibody specific for Lys63-linked polyubiquitin we have performed the first immunohistochemical analysis of linkage-specific ubiquitination in vivo associated with neurodegeneration. Immunoreactivity was detected within the pathological lesions of Alzheimer's, Huntington's and Parkinson's disease brains, although staining of Lewy bodies in the substantia nigra in Parkinson's disease was rare, indicating a selective involvement of Lys63-linked polyubiquitin in inclusion biogenesis in this disorder. Immunoreactivity was also a feature in neurons of proteasome-depleted mice, suggesting a proteasomal contribution to the degradation of Lys63-linked polyubiquitinated proteins in vivo.

In the past twenty years, evidence has accumulated to show that ubiquitinated proteins are a consistent feature of the intraneuronal protein aggregates (inclusions) that characterize chronic neurodegenerative disease. These findings may indicate that age-related dysfunction of the 26S proteasome may be central to disease pathogenesis. The aggregate-prone proteins can also be eliminated by autophagy. We have used the Cre-recombinase/loxP genetic approach to ablate the proteasomal Psmc1 ATPase gene and deplete 26S proteasomes in neurons in different regions of the brain to mimic neurodegeneration. Deletion of the gene in dopaminergic neurons in the substantia nigra generates a new model of Parkinson disease. Ablation of the gene in the forebrain creates the first model of dementia with Lewy bodies. In both neuroanatomical regions, gene ablation causes the formation of Lewy-like inclusions together with extensive neurodegeneration. There is some evidence for neuronal autophagy in areas adjacent to inclusions. The models indicate that neuronal loss in neurodegenerative diseases can be attributed to proteasomal malfunction accompanied by Lewy-like inclusions as seen in dementia with Lewy bodies and Parkinson disease.

Objective: The authors assessed short-term effectiveness of a Web-based alcohol education program on entering freshmen., Participants: 3,216 incoming first-year students were randomized to a control or intervention group., Methods: Controls completed a survey and knowledge test the summer before college; 4 to 6 weeks after arrival on campus, they completed a follow-up survey of behaviors and harms followed by an invitation to complete the online course. Intervention students completed the precourse survey and test, the online course, and final exam prior to coming to campus. This was followed by a survey 4 to 6 weeks after arrival on campus., Results: Although the intervention group showed significantly higher alcohol-related postcourse knowledge compared to the control group, protective behavior, risk-related behavior, high-risk drinking, and alcohol-related harm did not favor the intervention group, with the sole exception of playing drinking games., Conclusions: Alcohol knowledge alone was insufficient to mitigate alcohol-related high-risk behaviors in this student population.

Neuropathological investigations have identified major hallmarks of chronic neurodegenerative disease. These include protein aggregates called Lewy bodies in dementia with Lewy bodies and Parkinson's disease. Mutations in the alpha-synuclein gene have been found in familial disease and this has led to intense focused research in vitro and in transgenic animals to mimic and understand Parkinson's disease. A decade of transgenesis has lead to overexpression of wild type and mutated alpha-synuclein, but without faithful reproduction of human neuropathology and movement disorder. In particular, widespread regional neuronal cell death in the substantia nigra associated with human disease has not been described. The intraneuronal protein aggregates (inclusions) in all of the human chronic neurodegenerative diseases contain ubiquitylated proteins. There could be several reasons for the accumulation of ubiquitylated proteins, including malfunction of the ubiquitin proteasome system (UPS). This hypothesis has been genetically tested in mice by conditional deletion of a proteasomal regulatory ATPase gene. The consequences of gene ablation in the forebrain include extensive neuronal death and the production of Lewy-like bodies containing ubiquitylated proteins as in dementia with Lewy bodies. Gene deletion in catecholaminergic neurons, including in the substantia nigra, recapitulates the neuropathology of Parkinson's disease.

The authors hypothesized that experienced and imagined intergenerational contact should improve older people's math test performance under stereotype threat. In Experiment 1 (N=51, mean age=69 years), positive prior contact with grandchildren eliminated stereotype threat, which was mediated partially by reduced test-related anxiety. In Experiment 2 (N=84, mean age=72 years), the effect of threat on performance was significantly improved when participants merely imagined intergenerational contact, a situation again mediated by reduced anxiety. Previous research established that intergroup contact improves intergroup attitudes. The findings show that intergroup (intergenerational) contact also provides a defense against stereotype threat., (Copyright (c) 2009 APA, all rights reserved.)

Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and alpha-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.

In the laboratory, horseshoe crabs express a circadian rhythm of visual sensitivity as well as daily and circatidal rhythms of locomotion. The major goal of this investigation was to determine whether the circadian clock underlying changes in visual sensitivity also modulates locomotion. To address this question, we developed a method for simultaneously recording changes in visual sensitivity and locomotion. Although every animal (24) expressed consistent circadian rhythms of visual sensitivity, rhythms of locomotion were more variable: 44% expressed a tidal rhythm, 28% were most active at night, and the rest lacked statistically significant rhythms. When exposed to artificial tides, 8 of 16 animals expressed circatidal rhythms of locomotion that continued after tidal cycles were stopped. However, rhythms of visual sensitivity remained stable and showed no tendency to be influenced by the imposed tides or locomotor activity. These results indicate that horseshoe crabs possess at least two biological clocks: one circadian clock primarily used for modulating visual sensitivity, and one or more clocks that control patterns of locomotion. This arrangement allows horseshoe crabs to see quite well while mating during both daytime and nighttime high tides.