Whole-genome sequencing reveals fine-scale environment-associated divergence near the range limits of a temperate reef fish.

Environmental variation is increasingly recognized as an important driver of diversity in marine species despite the lack of physical barriers to dispersal and the presence of pelagic stages in many taxa. A robust understanding of the genomic and ecological processes involved in structuring populations is lacking for most marine species, often hindering management and conservation action. Cunner (Tautogolabrus adspersus) is a temperate reef fish with both pelagic early life-history stages and strong site-associated homing as adults; the species is also of interest for use as a cleaner fish in salmonid aquaculture in Atlantic Canada. We aimed to characterize genomic and geographic differentiation of cunner in the Northwest Atlantic. To achieve this, a chromosome-level genome assembly for cunner was produced and used to characterize spatial population structure throughout Atlantic Canada using whole-genome sequencing. The genome assembly spanned 0.72 Gbp and 24 chromosomes; whole-genome sequencing of 803 individuals from 20 locations from Newfoundland to New Jersey identified approximately 11 million genetic variants. Principal component analysis revealed four regional Atlantic Canadian groups. Pairwise FST and selection scans revealed signals of differentiation and selection at discrete genomic regions, including adjacent peaks on chromosome 10 across multiple pairwise comparisons (i.e. FST 0.5-0.75). Redundancy analysis suggested association of environmental variables related to benthic temperature and oxygen range with genomic structure. Results suggest regional scale diversity in this temperate reef fish and can directly inform the collection and translocation of cunner for aquaculture applications and the conservation of wild populations throughout the Northwest Atlantic.

Duration of Protection After Vaccination Against Yellow Fever: A Systematic Review and Meta-Analysis.

The duration of protection after a single dose of yellow fever vaccine is a matter of debate. To summarize the current knowledge, we performed a systematic literature review and meta-analysis. Studies on the duration of protection after 1 and ≥2 vaccine doses were reviewed. Data were stratified by time since vaccination. In our meta-analysis, we used random-effects models. We identified 36 studies from 20 countries, comprising more than 17 000 participants aged 6 months to 85 years. Among healthy adults and children, pooled seroprotection rates after single vaccination dose were close to 100% by 3 months and remained high in adults for 5 to 10 years. In children vaccinated before age 2 years, the seroprotection rate was 52% within 5 years after primary vaccination. For immunodeficient persons, data indicate relevant waning. The extent of waning of seroprotection after yellow fever vaccination depends on age and immune status at primary vaccination.

Environmentally associated chromosomal structural variation influences fine-scale population structure of Atlantic Salmon (Salmo salar).

Chromosomal rearrangements (e.g., inversions, fusions, and translocations) have long been associated with environmental variation in wild populations. New genomic tools provide the opportunity to examine the role of these structural variants in shaping adaptive differences within and among wild populations of non-model organisms. In Atlantic Salmon (Salmo salar), variations in chromosomal rearrangements exist across the species natural range, yet the role and importance of these structural variants in maintaining adaptive differences among wild populations remains poorly understood. We genotyped Atlantic Salmon (n = 1429) from 26 populations within a highly genetically structured region of southern Newfoundland, Canada with a 220K SNP array. Multivariate analysis, across two independent years, consistently identified variation in a structural variant (translocation between chromosomes Ssa01 and Ssa23), previously associated with evidence of trans-Atlantic secondary contact, as the dominant factor influencing population structure in the region. Redundancy analysis suggested that variation in the Ssa01/Ssa23 chromosomal translocation is strongly correlated with temperature. Our analyses suggest environmentally mediated selection acting on standing genetic variation in genomic architecture introduced through secondary contact may underpin fine-scale local adaptation in Placentia Bay, Newfoundland, Canada, a large and deep embayment, highlighting the importance of chromosomal structural variation as a driver of contemporary adaptive divergence.

Genomic basis of deep-water adaptation in Arctic Charr (Salvelinus alpinus) morphs.

The post-glacial colonization of Gander Lake in Newfoundland, Canada, by Arctic Charr (Salvelinus alpinus) provides the opportunity to study the genomic basis of adaptation to extreme deep-water environments. Colonization of deep-water (>50 m) habitats often requires extensive adaptation to cope with novel environmental challenges from high hydrostatic pressure, low temperature, and low light, but the genomic mechanisms underlying evolution in these environments are rarely known. Here, we compare genomic divergence between a deep-water morph adapted to depths of up to 288 m and a larger, piscivorous pelagic morph occupying shallower depths. Using both a SNP array and resequencing of whole nuclear and mitochondrial genomes, we find clear genetic divergence (FST  = 0.11-0.15) between deep and shallow water morphs, despite an absence of morph divergence across the mitochondrial genome. Outlier analyses identified many diverged genomic regions containing genes enriched for processes such as gene expression and DNA repair, cardiac function, and membrane transport. Detection of putative copy number variants (CNVs) uncovered 385 genes with CNVs distinct to piscivorous morphs, and 275 genes with CNVs distinct to deep-water morphs, enriched for processes associated with synapse assembly. Demographic analyses identified evidence for recent and local morph divergence, and ongoing reductions in diversity consistent with postglacial colonization. Together, these results show that Arctic Charr morph divergence has occurred through genome-wide differentiation and elevated divergence of genes underlying multiple cellular and physiological processes, providing insight into the genomic basis of adaptation in a deep-water habitat following postglacial recolonization.

Peer review of searches for studies for health technology assessments, systematic reviews, and other evidence syntheses.

INTRODUCTION: Peer review of searches is a process whereby both the search strategies and the search process description are reviewed, ideally using an evidence-based checklist. RATIONALE: As the search strategy underpins any well-conducted evidence synthesis, its quality could affect the final result. Evidence shows, however, that search strategies are prone to error. FINDINGS: There is increasing awareness and use of the PRESS Evidence-Based Checklist and peer review of search strategies, at the outset of evidence syntheses, prior to the searches being run, and this is now recommended by a number of evidence synthesis organizations. RECOMMENDATIONS AND CONCLUSIONS: Searches for evidence syntheses should be peer reviewed by a suitably qualified and experienced librarian or information specialist after being designed, ideally, by another suitably qualified and experienced librarian or information specialist. Peer review of searches should take place at two important stages in the evidence synthesis process; at the outset of the project prior to the searches being run and at the prepublication stage. There is little empirical evidence, however, to support the effectiveness of peer review of searches. Further research is required to assess this. Those wishing to stay up to date with the latest developments in information retrieval, including peer review of searches, should consult the SuRe Info resource (http://www.sure-info.org), which seeks to help information specialists and others by providing easy access to the findings from current information retrieval methods research and thus support more research-based information retrieval practice.

Systematic review search methods evaluated using the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses and the Risk Of Bias In Systematic reviews tool.

OBJECTIVES: To evaluate the methodological and reporting characteristics of search methods of systematic reviews (SRs) using the Preferred Reporting of Systematic Reviews and Meta-Analyses (PRISMA) checklist and the Risk Of Bias In Systematic reviews (ROBIS) tool. METHODS: A sample of 505 SRs published in 2016 was taken from KSR Evidence, a database of SRs, and analyzed to assess compliance with Information sources and Search of the PRISMA checklist. Domain 2 (D2) (Identification and Selection of Studies) of the ROBIS tool was used to judge the risk of bias in search methods. RESULTS: Regarding Information sources and Search of PRISMA, twenty percent of SRs which claimed to be PRISMA-compliant in their methods, were compliant; twenty-four percent of SRs published in journals that require PRISMA reporting were compliant; nineteen percent in total were found to be compliant. Twenty-eight percent of SRs were judged to be at a low risk of bias in D2 and so searched widely with an effective strategy and, finally, ten percent were both compliant with the reporting of Information sources and with Search of PRISMA and were judged to be at a low risk of bias in D2. CONCLUSIONS: Ninety percent of SRs are failing to report search methods adequately and to conduct comprehensive searches using a wide range of resources. Editors of journals and peer reviewers need to ensure that they understand the requirements of PRISMA and that compliance is adhered to. Additionally, the comprehensiveness of search methods for SRs needs to be given more critical consideration.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

Environmental extremes drive population structure at the northern range limit of Atlantic salmon in North America.

Conservation of exploited species requires an understanding of both genetic diversity and the dominant structuring forces, particularly near range limits, where climatic variation can drive rapid expansions or contractions of geographic range. Here, we examine population structure and landscape associations in Atlantic salmon (Salmo salar) across a heterogeneous landscape near the northern range limit in Labrador, Canada. Analysis of two amplicon-based data sets containing 101 microsatellites and 376 single nucleotide polymorphisms (SNPs) from 35 locations revealed clear differentiation between populations spawning in rivers flowing into a large marine embayment (Lake Melville) compared to coastal populations. The mechanisms influencing the differentiation of embayment populations were investigated using both multivariate and machine-learning landscape genetic approaches. We identified temperature as the strongest correlate with genetic structure, particularly warm temperature extremes and wider annual temperature ranges. The genomic basis of this divergence was further explored using a subset of locations (n = 17) and a 220K SNP array. SNPs associated with spatial structuring and temperature mapped to a diverse set of genes and molecular pathways, including regulation of gene expression, immune response, and cell development and differentiation. The results spanning molecular marker types and both novel and established methods clearly show climate-associated, fine-scale population structure across an environmental gradient in Atlantic salmon near its range limit in North America, highlighting valuable approaches for predicting population responses to climate change and managing species sustainability.

Supplementary searches of PubMed to improve currency of MEDLINE and MEDLINE In-Process searches via Ovid.

OBJECTIVE: The research investigated whether conducting a supplementary search of PubMed in addition to the main MEDLINE (Ovid) search for a systematic review is worthwhile and to ascertain whether this PubMed search can be conducted quickly and if it retrieves unique, recently published, and ahead-of-print studies that are subsequently considered for inclusion in the final systematic review. METHODS: Searches of PubMed were conducted after MEDLINE (Ovid) and MEDLINE In-Process (Ovid) searches had been completed for seven recent reviews. The searches were limited to records not in MEDLINE or MEDLINE In-Process (Ovid). RESULTS: Additional unique records were identified for all of the investigated reviews. Search strategies were adapted quickly to run in PubMed, and reviewer screening of the results was not time consuming. For each of the investigated reviews, studies were ordered for full screening; in six cases, studies retrieved from the supplementary PubMed searches were included in the final systematic review. CONCLUSION: Supplementary searching of PubMed for studies unavailable elsewhere is worthwhile and improves the currency of the systematic reviews.

Systematic review of the economic evidence on home visitation programmes for vulnerable pregnant women.

INTRODUCTION: A systematic review of the economic evidence on home visitation programmes for young or vulnerable pregnant women was undertaken to provide a summary of the existing literature of these interventions. SOURCES OF DATA: Relevant studies were identified from a number of sources including large databases, free text search on Google Scholar as well as hand-searching of the obtained references. The search yielded a large number of papers, of which 12 were considered appropriate to be included in the review. These were either full or partial economic evaluations: four studies were cost-benefit analyses, three were cost-effectiveness analyses and the remaining were costing studies. AREAS OF AGREEMENT: The review highlighted the paucity of good quality economic evaluations in the area of home visiting programmes for young or vulnerable pregnant women. Methods varied substantially between the studies spanning from differing data sources (e.g. single randomized trials or meta-analyses) to different perspectives taken, cost items and outcomes included in the analysis. AREAS OF CONTROVERSY: It is difficult to establish a coherent body of economic evidence for these interventions and draw a firm conclusion on their value for money. GROWING POINTS: Home visiting programmes are complex interventions, with impact on the lives of mothers and their children. The funding of such interventions should be based on rigorous effectiveness and economic evidence. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need for well-designed economic evaluations which will follow the appropriate methodological guidelines and also take into account the complexity of such interventions. These analyses should preferably consider multiple perspectives and allow for the fact that the majority of the benefits accrue in the long-term future.

Cannabinoids for Medical Use: A Systematic Review and Meta-analysis.

IMPORTANCE: Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. OBJECTIVE: To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. DATA SOURCES: Twenty-eight databases from inception to April 2015. STUDY SELECTION: Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. RESULTS: A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. CONCLUSIONS AND RELEVANCE: There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis.

Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38-0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45-0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31-0.51 and HR = 0.50; 95 % CrI 0.37-0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38-0.58 and HR = 0.55; 95 % CrI 0.40-0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor.

Interventions for drug-using offenders with co-occurring mental illness.

BACKGROUND: This is an updated version of an original Cochrane review published in Issue 3 2006 (Perry 2006). The review represents one from a family of four reviews focusing on interventions for drug-using offenders. This specific review considers interventions aimed at reducing drug use or criminal activity, or both for drug-using offenders with co-occurring mental illness. OBJECTIVES: To assess the effectiveness of interventions for drug-using offenders with co-occurring mental illness in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases (searched between 2004 and 21 March 2013) and five internet resources (searched between 2004 and 11 November 2009). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials designed to reduce, eliminate or prevent relapse in drug-using offenders with co-occurring mental illness. We also reported data on the cost and cost effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified 76 trials across the four reviews. Following a process of pre-screening, we judged eight trials to meet the inclusion criteria for this specific review (three of the five trials are awaiting classification). The five included 1502 participants. The interventions reported on case management via a mental health drugs court, a therapeutic community, and an evaluation of a motivational interviewing technique and cognitive skills in comparison to relaxation training. The methodological quality of the trials was generally difficult to rate due to a lack of clear reporting. On most risk of bias items, we rated the majority of studies as unclear. Overall, the combined interventions did not show a statistically significant reduction in self reported drug use (2 studies, 715 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.44 to 1.55). A statistically significantly reduction was shown for re-incarceration (4 studies, 627 participants; RR 0.40, 95% CI 0.24 to 0.67 and mean difference (MD) 28.72, 95% CI 5.89 to 51.54) but not re-arrest (2 studies, 518 participants; RR 1.00, 95% CI 0.90 to 1.12). A specific subgroup analysis combining studies using therapeutic community interventions showed a statistically significant reduction in re-incarceration (2 studies, 266 participants; RR 0.29, 95% CI 0.16 to 0.54) but not re-arrest (1 study, 428 participants; RR 0.90, 95% CI 0.61 to 1.33). Case management via a mental health court and motivational interviewing with cognitive skills did not show a statistically significant reduction in criminal activity (1 study, 235 participants; RR 1.05, 95% CI 0.90 to 1.22) or self reported drug misuse (1 study, 162 participants; MD -7.42, 95% CI -20.12 to 5.28). Due to the small number of studies, we were unable to analyse the impact of setting on outcome. Some cost information was provided in the trials but not sufficient to be able to evaluate the cost effectiveness of the interventions. AUTHORS' CONCLUSIONS: This review highlights the paucity of evidence for drug misusing offenders with co-occurring mental health problems. Two of the five trials showed some promising results for the use of therapeutic communities and aftercare, but only in relation to reducing subsequent re-incarceration. The studies overall, showed a high degree of statistical variation demonstrating a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. More evaluations are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems.

Interventions for female drug-using offenders.

BACKGROUND: This is an updated version of a Cochrane review first published in Issue 3, 2006 (Perry 2006). The review represents one in a family of four reviews focusing on the effectiveness of interventions in reducing drug use and criminal activity for offenders. This specific review considers interventions for female drug-using offenders. OBJECTIVES: To assess the effectiveness of interventions for female drug-using offenders in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases (between 2004 and 21st March 2013) and five additional web resources (between 2004 and November 2011). We contacted experts in the field for further information. SELECTION CRITERIA: We include randomised controlled trials designed to reduce, eliminate or prevent relapse in female drug-using offenders. We also report data on the cost and cost effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. MAIN RESULTS: We identified 76 trials across the four reviews. Following a process of prescreening, we judged that 11 trials met the inclusion criteria of the specified review; four of the 11 trials are awaiting classification in the review. The remaining seven trials cover 1236 participants. The interventions included in this review report on therapeutic communities (TCs), gender-responsive treatment (GRT), use of case management and cognitive skills, and a pharmacological intervention using buprenorphine. Trial quality and risks of bias varied across each study. The majority of studies were rated as being at 'unclear' risk of bias due to a lack of descriptive information. Overall the interventions showed statistically significant reductions in self-reported drug use, (four studies, 734 participants, risk ratio (RR) 0.68; 95% confidence interval (CI) 0.58 to 0.80) and re-incarceration, (four studies, 745 participants, RR 0.55; 95% CI 0.41 to 0.72). We found a statistically non-significant result for re-arrest (three studies, 803 participants, RR 0.80; 95% CI 0.53 to 1.19). Individual treatment results found that TCs and a GRT programme showed a statistically significant reduction in re-incarceration (one study, 509 participants, RR 0.42; 95% CI 0.29 to 0.60) but not for re-arrest, (one study, 314 participants, RR 0.73; 95% CI 0.52 to 1.03) and self-reported drug use (two studies, 825 participants, RR 0.47; 95% CI 0.14 to 1.53). Case management and cognitive skills programmes did not significantly reduce re-arrests, (one study, 183 participants RR 1.12; 95% CI 0.89 to 1.41) or self-reported drug use, (one study, 77 participants, RR 0.65; 95% CI 0.20 to 2.12), but did show a statistically significant reduction in re-incarceration, (three studies, 236 participants, RR 0.63; 95% CI 0.49 to 0.81). Buprenorphine did not significantly reduce self-reported drug use (RR 0.58; 95% CI 0.25 to 1.35), but this result came from a single study with only 36 participants. Due to the small number of studies we were unable to analyse the impact of treatment setting on outcome. No cost and cost effectiveness evidence was reported in the studies. AUTHORS' CONCLUSIONS: The seven trials show some positive results for the use of treatments to reduce self-reported drug use and subsequent re-incarceration. However, the studies overall showed a high degree of statistical variation, requiring a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. Descriptions of treatment modalities are required to identify the important elements for treatment success in drug-using female offenders. More trials are required to increase the confidence with which we can draw conclusions about the effectiveness of treatments for female drug-using offenders.

Cultures of evidence across policy sectors: systematic review of qualitative evidence.

BACKGROUND: It is important to understand the decision-making process, and the role of research evidence within it, across sectors other than health, as interventions delivered within these sectors may have substantial impacts on public health and health inequalities. METHODS: Systematic review of qualitative evidence. Twenty-eight databases covering a range of sectors were searched. Studies were eligible if they included local decision-makers in a policy field relevant to the social determinants of health (including housing, transport, urban planning and regeneration, crime, licensing or trading standards), were conducted in a high-income country, and reported primary qualitative data on perceptions of research evidence. Study quality was assessed and a thematic synthesis undertaken. RESULTS: Sixteen studies were included, most using interview designs, and most focusing on planning or transport policy. Several factors are seen to influence decision-makers' views of evidence, including practical factors such as resources or organizational support; the credibility of the evidence; its relevance or applicability to practice; considerations of political support or feasibility; and legislative constraints. There are limited data on how evidence is used: it is sometimes used to not only support decision-making, but also to lend legitimacy to decisions that have already been made. CONCLUSION: Although cultures of evidence in non-health sectors are similar to those in health in some ways, there are some key differences, particularly as regards the political context of decision-making. Intersectoral public health research could benefit from taking into account non-health decision makers' needs and preferences, particularly around relevance and political feasibility.

Mania-like behavior induced by genetic dysfunction of the neuron-specific Na+,K+-ATPase α3 sodium pump.

Bipolar disorder is a debilitating psychopathology with unknown etiology. Accumulating evidence suggests the possible involvement of Na(+),K(+)-ATPase dysfunction in the pathophysiology of bipolar disorder. Here we show that Myshkin mice carrying an inactivating mutation in the neuron-specific Na(+),K(+)-ATPase α3 subunit display a behavioral profile remarkably similar to bipolar patients in the manic state. Myshkin mice show increased Ca(2+) signaling in cultured cortical neurons and phospho-activation of extracellular signal regulated kinase (ERK) and Akt in the hippocampus. The mood-stabilizing drugs lithium and valproic acid, specific ERK inhibitor SL327, rostafuroxin, and transgenic expression of a functional Na(+),K(+)-ATPase α3 protein rescue the mania-like phenotype of Myshkin mice. These findings establish Myshkin mice as a unique model of mania, reveal an important role for Na(+),K(+)-ATPase α3 in the control of mania-like behavior, and identify Na(+),K(+)-ATPase α3, its physiological regulators and downstream signal transduction pathways as putative targets for the design of new antimanic therapies.

Searching ClinicalTrials.gov and the International Clinical Trials Registry Platform to inform systematic reviews: what are the optimal search approaches?

BACKGROUND: Since 2005, International Committee of Medical Journal Editors (ICMJE) member journals have required that clinical trials be registered in publicly available trials registers before they are considered for publication. OBJECTIVES: The research explores whether it is adequate, when searching to inform systematic reviews, to search for relevant clinical trials using only public trials registers and to identify the optimal search approaches in trials registers. METHODS: A search was conducted in ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) for research studies that had been included in eight systematic reviews. Four search approaches (highly sensitive, sensitive, precise, and highly precise) were performed using the basic and advanced interfaces in both resources. RESULTS: On average, 84% of studies were not listed in either resource. The largest number of included studies was retrieved in ClinicalTrials.gov and ICTRP when a sensitive search approach was used in the basic interface. The use of the advanced interface maintained or improved sensitivity in 16 of 19 strategies for Clinicaltrials.gov and 8 of 18 for ICTRP. No single search approach was sensitive enough to identify all studies included in the 6 reviews. CONCLUSIONS: Trials registers cannot yet be relied upon as the sole means to locate trials for systematic reviews. Trials registers lag behind the major bibliographic databases in terms of their search interfaces. IMPLICATIONS: For systematic reviews, trials registers and major bibliographic databases should be searched. Trials registers should be searched using sensitive approaches, and both the registers consulted in this study should be searched.

Reporting methodological search filter performance comparisons: a literature review.

BACKGROUND: Methodological search filters are tools for retrieving database records reporting studies which use a specific research method. Choosing a filter is likely to be based on filter performance data. This review examines which measures are reported, and the way that filter performance is presented, in filter comparisons. METHODS: Studies were identified from the current content and pending update (2010) of a filter website. Eligible studies compared two or more methodological search filters designed to identify randomised controlled trials, diagnostic test accuracy studies, systematic reviews or economic evaluations. RESULTS: Eighteen studies met the inclusion criteria. The number of filters compared in a single study ranged from 2 to 38. The most commonly reported measures were sensitivity/recall and precision. All studies displayed results in tables and gave results as percentages or proportions. Two studies supplemented results tables with graphical displays of data: a bar graph of the proportion of retrieved and missed gold standard references per filter; a forest plot of the overall sensitivity and specificity of each filter. CONCLUSIONS: Sensitivity/recall and precision are the most frequently reported performance measures. This review highlights the potential for presenting results in novel and innovative ways to aid filter selection.

Choosing and using methodological search filters: searchers' views.

BACKGROUND: Search filters or hedges are search strategies developed to assist information specialists and librarians to retrieve different types of evidence from bibliographic databases. The objectives of this project were to learn about searchers' filter use, how searchers choose search filters and what information they would like to receive to inform their choices. METHODS: Interviews with information specialists working in, or for, the National Institute for Health and Care Excellence (NICE) were conducted. An online questionnaire survey was also conducted and advertised via a range of email lists. RESULTS: Sixteen interviews were undertaken and 90 completed questionnaires were received. The use of search filters tends to be linked to reducing a large amount of literature, introducing focus and assisting with searches that are based on a single study type. Respondents use numerous ways to identify search filters and can find choosing between different filters problematic because of knowledge gaps and lack of time. CONCLUSIONS: Search filters are used mainly for reducing large result sets (introducing focus) and assisting with searches focused on a single study type. Features that would help with choosing filters include making information about filters less technical, offering ratings and providing more detail about filter validation strategies and filter provenance.

Variable parallelism in the genomic basis of age at maturity across spatial scales in Atlantic Salmon.

Complex traits often exhibit complex underlying genetic architectures resulting from a combination of evolution from standing variation, hard and soft sweeps, and alleles of varying effect size. Increasingly, studies implicate both large-effect loci and polygenic patterns underpinning adaptation, but the extent that common genetic architectures are utilized during repeated adaptation is not well understood. Sea age or age at maturation represents a significant life history trait in Atlantic Salmon (Salmo salar), the genetic basis of which has been studied extensively in European Atlantic populations, with repeated identification of large-effect loci. However, the genetic basis of sea age within North American Atlantic Salmon populations remains unclear, as does the potential for a parallel trans-Atlantic genomic basis to sea age. Here, we used a large single-nucleotide polymorphism (SNP) array and low-coverage whole-genome resequencing to explore the genomic basis of sea age variation in North American Atlantic Salmon. We found significant associations at the gene and SNP level with a large-effect locus (vgll3) previously identified in European populations, indicating genetic parallelism, but found that this pattern varied based on both sex and geographic region. We also identified nonrepeated sets of highly predictive loci associated with sea age among populations and sexes within North America, indicating polygenicity and low rates of genomic parallelism. Despite low genome-wide parallelism, we uncovered a set of conserved molecular pathways associated with sea age that were consistently enriched among comparisons, including calcium signaling, MapK signaling, focal adhesion, and phosphatidylinositol signaling. Together, our results indicate parallelism of the molecular basis of sea age in North American Atlantic Salmon across large-effect genes and molecular pathways despite population-specific patterns of polygenicity. These findings reveal roles for both contingency and repeated adaptation at the molecular level in the evolution of life history variation.