Advanced engineering of third-generation lysins and formulation strategies for clinical applications

One of the possible solutions for the current antibiotic resistance crisis may be found in (often bacteriophage-derived) peptidoglycan hydrolases. The first clinical trials of these natural enzymes, coined here as first-generation lysins, are currently ongoing. Moving beyond natural endolysins with protein engineering established the second generation of lysins. In second-generation lysins, the focus lies on improving antibacterial and biochemical properties such as antimicrobial activity and stability, as well as expanding their activities towards Gram-negative pathogens. However, solutions to particular key challenges regarding clinical applications are only beginning to emerge in the third generation of lysins, in which protein and biochemical engineering efforts focus on improving properties relevant under clinical conditions. In addition, increasingly advanced formulation strategies are developed to increase the bioavailability, antibacterial activity, and half-life, and to reduce pro-inflammatory responses. This review focuses on third-generation and advanced formulation strategies that are developed to treat infections, ranging from topical to systemic applications. Together, these efforts may fully unlock the potential of lysin therapy and will propel it as a true antibiotic alternative or supplement

In‐treatment HDL cholesterol levels and development of new diabetes mellitus in hypertensive patients: The LIFE Study

Aims Although hypertensive patients with low baseline HDL cholesterol levels have a higher incidence of diabetes mellitus, whether changing levels of HDL over time are more strongly related to the risk of new diabetes in hypertensive patients has not been examined. Methods Incident diabetes mellitus was examined in relation to baseline and in‐treatment HDL levels in 7485 hypertensive patients with no history of diabetes randomly assigned to losartan‐ or atenolol‐based treatment. Results During 4.7 ± 1.2 years follow‐up, 520 patients (6.9%) developed new diabetes. In univariate Cox analyses, compared with the highest quartile of HDL levels (> 1.78 mmol/l), baseline and in‐treatment HDL in the lowest quartile ( 5‐fold and > 9 fold higher risks of new diabetes, respectively; patients with baseline or in‐treatment HDL in the 2nd and 3rd quartiles had intermediate risk of diabetes. In multivariable Cox analyses, adjusting for randomized treatment, age, sex, race, prior anti‐hypertensive therapy, baseline uric acid, serum creatinine and glucose entered as standard covariates, and in‐treatment non‐ HDL cholesterol, Cornell product left ventricular hypertrophy, diastolic and systolic pressure, BMI , hydrochlorothiazide and statin use as time‐varying covariates, the lowest quartile of in‐treatment HDL remained associated with a nearly 9‐fold increased risk of new diabetes (hazard ratio 8.7, 95%  CI 5.0–15.2), whereas the risk of new diabetes was significantly attenuated for baseline HDL < 1.21 mmol/l (hazard ratio 3.9, 95%  CI 2.8–5.4). Conclusions Lower in‐treatment HDL is more strongly associated with increased risk of new diabetes than baseline HDL level.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108303/1/dme12213.pd

Alcohol abstinence and drinking among African women: data from the World Health Surveys

<p>Abstract</p> <p>Background</p> <p>Alcohol use is increasing among women in Africa, and comparable information about women's current alcohol use is needed to inform national and international health policies relevant to the entire population. This study aimed to provide a comparative description of alcohol use among women across 20 African countries.</p> <p>Methods</p> <p>Data were collected as part of the WHO World Health Survey using standardized questionnaires. In total, 40,739 adult women were included in the present study. Alcohol measures included lifetime abstinence, current use (≥1 drink in previous week), heavy drinking (15+ drinks in the previous week) and risky single-occasion drinking (5+ drinks on at least one day in the previous week). Country-specific descriptives of alcohol use were calculated, and K-means clustering was performed to identify countries with similar characteristics. Multiple logistic regression models were fitted for each country to identify factors associated with drinking status.</p> <p>Results</p> <p>A total of 33,841 (81%) African women reported lifetime abstinence. Current use ranged from 1% in Malawi to 30% in Burkina Faso. Among current drinkers, heavy drinking varied between 4% in Ghana to 41% in Chad, and risky single-occasion drinking ranged from <1% in Mauritius to 58% in Chad. Increasing age was associated with increased odds of being a current drinker in about half of the countries.</p> <p>Conclusions</p> <p>A variety of drinking patterns are present among African women with lifetime abstention the most common. Countries with hazardous consumption patterns require serious attention to mitigate alcohol-related harm. Some similarities in factors related to alcohol use can be identified between different African countries, although these are limited and highlight the contextual diversity of female drinking in Africa.</p

Prevalence and causes of musculoskeletal impairment in Fundong District, North-West Cameroon: results of a population-based survey.

OBJECTIVES: Epidemiological data on musculoskeletal conditions such as degenerative joint diseases and bone fractures are lacking in low- and middle-income countries. This survey aimed to estimate the prevalence and causes of musculoskeletal impairment in Fundong Health District, North-West Cameroon. METHODS: Fifty-one clusters of 80 people (all ages) were selected using probability proportionate to size sampling. Households within clusters were selected by compact segment sampling. Six screening questions were asked to identify participants likely to have a musculoskeletal impairment (MSI). Participants screening positive to any screening question underwent a standardised examination by a physiotherapist to assess presence, cause, diagnosis and severity of impairment. RESULTS: In total, 3567 of 4080 individuals enumerated for the survey were screened (87%). The all-age prevalence of MSI was 11.6% (95% CI: 10.1-13.3). Prevalence increased with age, from 2.9% in children to 41.2% in adults 50 years and above. The majority of MSI cases (70.4%) were classified as mild, 27.2% as moderate and 2.4% as severe. Acquired non-trauma comprised 67% of the diagnoses. The remainder included trauma (14%), neurological (11%), infection (5%) and congenital (3%). The most common individual diagnosis was degenerative joint disease (43%). Over one-third (38%) of individuals with MSI had never received medical care or rehabilitation for their condition. CONCLUSIONS: This survey contributes to the epidemiological data on MSI in low- and middle-income countries. Nearly half of adults aged over 50 years had an MSI. There is a need to address the treatment and rehabilitative service gap for people with MSI in Cameroon

The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

BACKGROUND: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. OBJECTIVES: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. STUDY DESIGN: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. PARTICIPANTS: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. INTERVENTIONS: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. MAIN OUTCOME MEASURES: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. METHODS: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. RESULTS: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. CONCLUSIONS: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. LIMITATIONS: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. FUTURE WORK: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Update of the Scientific Opinion on opium alkaloids in poppy seeds

The CONTAM Panel wishes to thank the hearing experts: Pavel Cihlar, Daniel Doerge and Vaclav Lohr for the support provided to this scientific output. The CONTAM Panel acknowledges all European competent institutions and other stakeholders that provided occurrence data on opium alkaloids in food, and supported the data collection for the Comprehensive European Food Consumption Database. Adopted: 22 March 2018 Reproduction of the images listed below is prohibited and permission must be sought directly from the copyright holder:Figure A.1 in Appendix A: © Elsevier.Peer reviewedPublisher PD