Preventing adolescent substance use and youth violence are public health priorities. Positive youth development interventions are widely deployed often with the aim of preventing both. However, the theorised mechanisms by which PYD is intended to reduce substance use and violence are not clear and existing evaluated interventions are under-theorised. Using innovative methods, we systematically searched for and synthesised published theoretical literature describing what is meant by positive youth development and how it might reduce substance use and violence, as part of a broader systematic review examining process and outcomes of PYD interventions.

Genetic recombination between pathogens derived from humans and livestock has the potential to create novel pathogen strains, highlighted by the influenza pandemic H1N1/09, which was derived from a re-assortment of swine, avian and human influenza A viruses. Here we investigated whether genetic recombination between subspecies of the protozoan parasite, Trypanosoma brucei, from humans and animals can generate new strains of human pathogen, T. b. rhodesiense (Tbr) responsible for sleeping sickness (Human African Trypanosomiasis, HAT) in East Africa. The trait of human infectivity in Tbr is conferred by a single gene, SRA, which is potentially transferable to the animal pathogen Tbb by sexual reproduction. We tracked the inheritance of SRA in crosses of Tbr and Tbb set up by co-transmitting genetically-engineered fluorescent parental trypanosome lines through tsetse flies. SRA was readily transferred into new genetic backgrounds by sexual reproduction between Tbr and Tbb, thus creating new strains of the human pathogen, Tbr. There was no evidence of diminished growth or transmissibility of hybrid trypanosomes carrying SRA. Although expression of SRA is critical to survival of Tbr in the human host, we show that the gene exists as a single copy in a representative collection of Tbr strains. SRA was found on one homologue of chromosome IV in the majority of Tbr isolates examined, but some Ugandan Tbr had SRA on both homologues. The mobility of SRA by genetic recombination readily explains the observed genetic variability of Tbr in East Africa. We conclude that new strains of the human pathogen Tbr are being generated continuously by recombination with the much larger pool of animal-infective trypanosomes. Such novel recombinants present a risk for future outbreaks of HAT.

Natalizumab is an effective treatment for relapsing multiple sclerosis. Return of disease activity upon natalizumab discontinuance creates the need for follow-up therapeutic strategies.

The methodological quality and completeness of reporting of the systematic reviews (SRs) is fundamental to optimal implementation of evidence-based health care and the reduction of research waste. Methods exist to appraise SRs yet little is known about how they are used in SRs or where there are potential gaps in research best-practice guidance materials. The aims of this study are to identify reports assessing the methodological quality (MQ) and/or reporting quality (RQ) of a cohort of SRs and to assess their number, general characteristics, and approaches to 'quality' assessment over time.

New approaches to evidence synthesis, which use human effort and machine automation in mutually reinforcing ways, can enhance the feasibility and sustainability of living systematic reviews. Human effort is a scarce and valuable resource, required when automation is impossible or undesirable, and includes contributions from online communities ("crowds") as well as more conventional contributions from review authors and information specialists. Automation can assist with some systematic review tasks, including searching, eligibility assessment, identification and retrieval of full-text reports, extraction of data, and risk of bias assessment. Workflows can be developed in which human effort and machine automation can each enable the other to operate in more effective and efficient ways, offering substantial enhancement to the productivity of systematic reviews. This paper describes and discusses the potential-and limitations-of new ways of undertaking specific tasks in living systematic reviews, identifying areas where these human/machine "technologies" are already in use, and where further research and development is needed. While the context is living systematic reviews, many of these enabling technologies apply equally to standard approaches to systematic reviewing.

Endoplasmic reticulum (ER) stress occurs when unfolded proteins accumulate in the lumen of the organelle, triggering signal transduction events that contribute either to cellular adaptation and recovery or alternatively to cellular dysfunction and death. ER stress has been implicated in numerous diseases. To identify novel modulators of ER stress, we undertook a siRNA library screen of the kinome, revealing Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) as a contributor to unfolded protein response (UPR) signaling and ER stress-induced cell death. Knocking down expression of IRAK2 (but not IRAK1) in cultured mammalian cells suppresses ER stress-induced expression of the pro-apoptotic transcription factor CHOP and activation of stress kinases. Similarly, RNAi-mediated silencing of the IRAK family member Tube (but not Pelle) suppresses activation of stress kinase signaling induced by ER stress in Drosophila cells. The action of IRAK2 maps to the IRE1 pathway, rather than the PERK or ATF6 components of the UPR. Interestingly, ER stress also induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, suggesting a mutually supporting amplification loop involving IRAK2 and IRE1. In vivo, ER stress induces Irak2 expression in mice. Moreover, Irak2 gene knockout mice display defects in ER stress-induced CHOP expression and IRE1 pathway signaling. These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway.

Selective allocation of patients into the compared groups of a randomised trial may cause allocation bias, but the mechanisms behind the bias and its directionality are incompletely understood. We therefore analysed the mechanisms and directionality of allocation bias in randomised clinical trials.

There is an increasing recognition that health intervention research requires methods and approaches that can engage with the complexity of systems, interventions, and the relations between systems and interventions. One approach which shows promise to this end is qualitative comparative analysis (QCA), which examines casual complexity across a medium to large number of cases (between 10 and 60+), whilst also being able to generalise across those cases. Increasingly, QCA is being adopted in public health intervention research. However, there is a limited understanding of how it is being adopted. This systematic review will address this gap, examining how it is being used to understand complex causation; for what settings, populations and interventions; and with which datasets to describe cases.

Background: School closures have been a recommended non-pharmaceutical intervention in pandemic response owing to the potential to reduce transmission of infection between children, school staff and those that they contact. However, given the many roles that schools play in society, closure for any extended period is likely to have additional impacts. Literature reviews of research exploring school closure to date have focused upon epidemiological effects; there is an unmet need for research that considers the multiplicity of potential impacts of school closures. Methods: We used systematic searching, coding and synthesis techniques to develop a systems-based logic model. We included literature related to school closure planned in response to epidemics large and small, spanning the 1918-19 'flu pandemic through to the emerging literature on the 2019 novel coronavirus. We used over 170 research studies and a number of policy documents to inform our model. Results: The model organises the concepts used by authors into seven higher level domains: children's health and wellbeing, children's education, impacts on teachers and other school staff, the school organisation, considerations for parents and families, public health considerations, and broader economic impacts. The model also collates ideas about potential moderating factors and ethical considerations. While dependent upon the nature of epidemics experienced to date, we aim for the model to provide a starting point for theorising about school closures in general, and as part of a wider system that is influenced by contextual and population factors. Conclusions: The model highlights that the impacts of school closures are much broader than those related solely to health, and demonstrates that there is a need for further concerted work in this area. The publication of this logic model should help to frame future research in this area and aid decision-makers when considering future school closure policy and possible mitigation strategies.

Excessive anterior pelvic tilt is suspected of causing femoroacetabular impingement, low back pain, and sacroiliac joint pain. Non-surgical treatment may decrease symptoms and is seen as an alternative to invasive and complicated surgery. However, the effect of non-surgical modalities in adults is unclear. The aim of this review was to investigate patient- and observer-reported outcomes of non-surgical intervention in reducing clinical symptoms and/or potential anterior pelvic tilt in symptomatic and non-symptomatic adults with excessive anterior pelvic tilt, and to evaluate the certainty of evidence.MEDLINE, EMBASE, Web of Science and Cochrane (CENTRAL) databases were searched up to March 2019 for eligible studies. Two reviewers assessed risk of bias independently, using the Cochrane Risk of Bias tool for randomized trials and the ROBINS-I tool for non-randomized studies. Data were synthesized qualitatively. The GRADE approach was used to assess the overall certainty of evidence.Of 2013 citations, two randomized controlled trials (RCTs) (n = 72) and two non-RCTs (n = 23) were included. One RCT reported a small reduction (< 2°) in anterior pelvic tilt in non-symptomatic men. The two non-RCTs reported a statistically significant reduction in anterior pelvic tilt, pain, and disability in symptomatic populations. The present review was based on heterogeneous study populations, interventions, and very low quality of evidence.No overall evidence for the effect of non-surgical treatment in reducing excessive anterior pelvic tilt and potentially related symptoms was found. High-quality studies targeting non-surgical treatment as an evidence-based alternative to surgical interventions for conditions related to excessive anterior pelvic tilt are warranted. Cite this article: EFORT Open Rev 2020;5:37-45. DOI: 10.1302/2058-5241.5.190017.

Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2.

Chronic widespread pain (CWP) including fibromyalgia has a prevalence of up to 15% and is associated with substantial morbidity. Supporting psychosocial and behavioural self-management is increasingly important for CWP, as pharmacological interventions show limited benefit. We systematically reviewed the effectiveness of interventions applying self-management principles for CWP including fibromyalgia.

Randomized controlled trials (RCTs) are the gold standard method for evaluating whether a treatment works in health care but can be difficult to find and make use of. We describe the development and evaluation of a system to automatically find and categorize all new RCT reports.

The minimum clinically important difference (MCID) is used to interpret the clinical relevance of results reported by trials and meta-analyses as well as to plan sample sizes in new studies. However, there is a lack of consensus about the size of MCID in acute pain, which is a core symptom affecting patients across many clinical conditions.

Background: The extraction of data from the reports of primary studies, on which the results of systematic reviews depend, needs to be carried out accurately. To aid reliability, it is recommended that two researchers carry out data extraction independently. The extraction of statistical data from graphs in PDF files is particularly challenging, as the process is usually completely manual, and reviewers need sometimes to revert to holding a ruler against the page to read off values: an inherently time-consuming and error-prone process. Methods: To mitigate some of the above problems we integrated and customised two existing JavaScript libraries to create a new web-based graphical data extraction tool to assist reviewers in extracting data from graphs. This tool aims to facilitate more accurate and timely data extraction through a user interface which can be used to extract data through mouse clicks. We carried out a non-inferiority evaluation to examine its performance in comparison with participants' standard practice for extracting data from graphs in PDF documents. Results: We found that the customised graphical data extraction tool is not inferior to users' (N=10) prior standard practice. Our study was not designed to show superiority, but suggests that, on average, participants saved around 6 minutes per graph using the new tool, accompanied by a substantial increase in accuracy. Conclusions: Our study suggests that the incorporation of this type of tool in online systematic review software would be beneficial in facilitating the production of accurate and timely evidence synthesis to improve decision-making.

To simulate possible changes in systematic review results if rapid review methods were used.

Adverse Childhood Experiences (ACEs) such as abuse, neglect or household adversity may have a range of serious negative impacts. There is a need to understand what interventions are effective to improve outcomes for people who have experienced ACEs.

We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low; therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.

The impact of delayed discharge on patients, health-care staff and hospital costs has been incompletely characterized.

Ideally, health conditions causing the greatest global disease burden should attract increased research attention. We conducted a comprehensive global study investigating the number of randomised controlled trials (RCTs) published on different health conditions, and how this compares with the global disease burden that they impose.