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.