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In this concluding article, we take stock of the diverse and stimulating contributions comprising this special issue. Using concept mapping, we identify eight evaluation themes and concepts central to John Mayne’s collective work: evaluation utilization, results-based management, organizational learning, accountability, evaluation culture, contribution analysis, theory-based evaluation, and causation. The overarching contribution story is that John’s work served to bridge the gaps between evaluation practice and theory; to promote cross-disciplinary synergies across program evaluation, performance auditing, and monitoring; and to translate central themes in evaluation into a cogent system for using evaluative information more sensibly. In so doing, John left a significant institutional and academic legacy in evaluation and in results-based management.

ObjectiveTo evaluate the associations between the evolution of household use of cleaning products with the asthma symptom score and its evolution over 8 years.MethodsOur study is based on 509 women participating in the last two surveys of the Epidemiological study on the Genetics and Environment of Asthma (EGEA) study (EGEA2: 2003–2007 (44 years, 19% current smokers) and EGEA3: 2011–2013). We assessed an asthma symptom score and the use of household cleaning products through standardised questionnaires. We studied longitudinal associations of the evolution of weekly use of irritant or spayed cleaning products with (1) the asthma symptom score at EGEA3 and a stable symptom score between EGEA2-EGEA3 (negative binomial models) and (2) the incidence/evolution of asthma symptoms between EGEA2-EGEA3 (logistic/polytomous logistic regressions). Models accounted for familial dependence and were adjusted for age, smoking status, body mass index and occupational exposure to asthmagens.ResultsPersistent and increased (40% and 16%, respectively) weekly use of irritants or sprays were associated with a higher risk of asthma symptoms at EGEA3 (Mean Score Ratio (MSR)=1.51 (95% CI 1.06 to 2.14) and 1.33 (95% CI 0.85 to 2.08), respectively). A decreased use (19%) was associated with a lower risk of symptoms at EGEA3, compared with a persistent use (MSR=0.59 (95% CI 0.39 to 0.88)). We also observed an association between an increased use of sprays and the incidence of asthma symptoms (OR=2.30 (95% CI 1.08 to 4.91)), compared with no weekly use of irritants/sprays.ConclusionsThis longitudinal study, with repeated assessment of exposure and respiratory health, supports the hypothesis that a persistent or increased weekly use of sprayed cleaning products over time may have an adverse effect on the evolution of asthma symptoms.

Small bowel obstruction (SBO) is a known complication after congenital diaphragmatic hernia (CDH) repair, which can require surgery and even extensive bowel resection causing short bowel syndrome (SBS). We investigate whether specific bowel rotation and fixation can be used as a predictor for SBO including volvulus.A retrospective review of 256 CDH survivors following repair from 2003 to 2020 was performed. Operative notes and upper gastrointestinal series (UGI) were screened to determine the rotation and fixation of the bowel. Primary outcomes included SBO occurrence, SBO treated surgically, and volvulus. For statistical analysis Fisher's exact test was utilized.Twenty-two (9%) patients presented with SBO and majority, 19 (86%), required surgery. Adhesion were observed in 10 (45%), recurrence in 5 (23%), and extensive volvulus leading to SBS in 3 (14%). Both rotation and fixation were recorded in 117 (46%). Presence of left CDH with malrotation and nonfixation was a significant predictor for SBO requiring surgery (P0.05 vs all other groups). All 3 patients with extensive volvulus had left CDH with nonfixed bowel (100%), however only 1 had malrotation (33%).Malrotation and nonfixation are associated with increased SBO in CDH. Normal rotation is not protective and patients are still at risk for volvulus resulting in SBS. SBO requiring surgical intervention is common in CDH. Bowel rotation and fixation are important determinants that, should be routinely documented and education about the risk of SBO should be included in family counseling.Level IV - Case Series.

Evaluation capacity building (ECB) continues to attract the attention and interest of scholars and practitioners. Over the years, models, frameworks, strategies, and practices related to ECB have been developed and implemented. Although ECB is highly contextual, the evolution of knowledge in this area depends on learning from past efforts in a structured approach. The purpose of the present article is to integrate the ECB literature in evaluation journals. More specifically, the article aims to answer three questions: What types of articles and themes comprise the current literature on ECB? How are current practices of ECB described in the literature? And what is the current status of research on ECB? Informed by the findings of the review, the article concludes with suggestions for future ECB practice and scholarship.

Évaluer le risque cardiovasculaire global des patients en prévention primaire est un acte quotidien en médecine générale. La situation du patient jugé à risque intermédiaire est la plus délicate, car source d’incertitude sur la stratégie thérapeutique la plus appropriée. Le score calcique (coronary artery calcium, CAC) est un marqueur d’évaluation du risque cardiovasculaire global complémentaire de l’approche proposée par les références habituelles (SCORE, Framingham). Alors que ces références validées à l’échelle populationnelles peuvent être prises en défaut à l’échelle personnelle, le score calcique pourrait être un marqueur plus individuel. Quatre valeurs seuils semblent intéressantes en pratique clinique : CAC = 0, CAC > 100 ou charge calcaire modérée, CAC > 400 ou charge calcaire importante et CAC > 1 000 ou charge calcaire majeure. Sous certaines conditions, un CAC = 0 permettrait de reclasser en risque faible un patient jugé à risque intermédiaire. À l’inverse, un CAC élevé pourrait inciter à une attitude plus interventionniste adaptée à la singularité du patient, visant à réduire le risque cardiovasculaire global (prescription d’une statine et/ou d’activité physique, etc.). Pour autant, y recourir nécessite de connaître les situations dans lesquelles son résultat doit être considéré avec précaution. Il doit aussi être réservé aux situations dans lesquelles le résultat est réellement susceptible de modifier l’attitude thérapeutique. Des études prospectives sont nécessaires pour préciser son intérêt en routine de médecine générale.

Le développement des environnements numériques d’apprentissage (ENA), en plus de permettre un accès plus facile au savoir pour tous, présente un nouvel éventail de possibilités pédagogiques. Les infrastructures de données intrinsèquement liées aux technologies du Web favorisent l’apprentissage adaptatif et la personnalisation des parcours. C’est le cas de la plateforme en ligne Gérer ma douleur, qui propose un ensemble de ressources pour les personnes souffrant de douleurs chroniques afin de les aider à mieux les gérer. Dans le cadre du développement de cette plateforme, l’équipe de recherche-développement a procédé à l’étude de l’usage de ces infrastructures de données, pour proposer de nouvelles offres et fonctionnalités de façon à soutenir les parcours d’apprentissage. Un module de suivi de parcours d’apprentissage a été développé en partenariat avec de potentiels futurs utilisateurs, en suivant une méthodologie de prototypage rapide. De plus, un système de collecte et d’observation des données d’interactions des utilisateurs avec la plateforme a été mis en place en utilisant la norme xAPI, dans l’optique d’améliorer le fonctionnement du dispositif d’apprentissage et les différentes ressources éducatives.

Implementation fidelity is the degree of compliance with which the core elements of program or intervention practices are used as intended. The scientific literature reveals gaps in defining and assessing implementation fidelity in early intervention: lack of common definitions and conceptual framework as well as their lack of application. Through a critical review of the scientific literature, this article aims to identify information that can be used to develop a common language and guidelines for assessing implementation fidelity. An analysis of 46 theoretical and empirical papers about early intervention implementation, published between 1998 and 2018, identified four conceptual frameworks, in addition to that of Dane and Schneider. Following analysis of the conceptual frameworks, a four-component conceptualization of implementation fidelity (adherence, dosage, quality and participant responsiveness) is proposed.

The introduction of clinical exome sequencing (ES) has provided a unique opportunity to decrease the diagnostic odyssey for patients living with a rare genetic disease (RGD). ES has been shown to provide a diagnosis in 29%-57% of patients with a suspected RGD, with as many as 70% remaining undiagnosed. There is a need to advance the clinical model of care by more formally integrating approaches that were previously considered research into an enhanced diagnostic workflow. We developed an Exome Clinic, which set out to evaluate a workflow for improving the diagnostic yield of ES for patients with an undiagnosed RGD. Here, we report the outcomes of 47 families who underwent clinical ES in the first year of the clinic. The diagnostic yield from clinical ES was 40% (19/47). Families who remained undiagnosed after ES had the opportunity for follow-up studies that included phenotyping and candidate variant segregation in relatives, genomic matchmaking, and ES reanalysis. This enhanced diagnostic workflow increased the diagnostic yield to 55% (26/47), predominantly through the resolution of variants and genes of uncertain significance. We advocate that this approach be integrated into mainstream clinical practice and highlight the importance of a coordinated translational approach for patients with RGD.

MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.

Les pratiques d’intervention naturalistes dont l’activity-based intervention (ABI) utilisent le jeu et les activités quotidiennes pour soutenir le développement d’habiletés chez les jeunes enfants. Cet article documente les défis et facilitateurs rencontrés par quatre éducatrices en milieu de garde ayant reçu de la formation et de l’accompagnement pour implanter l’ABI en soutien au développement d’habiletés en littératie. Les principaux défis relèvent du manque de temps et de la gestion des défis socio-émotionnels. Dans les facilitateurs se retrouvent les adaptations de l’environnement et les intérêts des enfants. Cet article met en lumière, l’importance d’offrir du matériel en littératie diversifié et accessible.

Housing conditions are a key driver of asthma incidence and severity. Previous studies have shown increased emergency department visits for asthma among residents living in poor-quality housing. Interventions to improve housing conditions have been shown to reduce emergency department visits for asthma, but identification and remediation of poor housing conditions is often delayed or does not occur. This study evaluates whether emergency department visits for asthma can be used to identify poor-quality housing to support proactive and early intervention.We conducted a retrospective cohort study of children and adults living in and around New Haven, CT, USA, who were seen for asthma in an urban, tertiary emergency department between March 1, 2013, and Aug 31, 2017. We geocoded and mapped patient addresses to city parcels, and calculated a composite estimate of the incidence of emergency department use for asthma for each parcel (N11 429 asthma-related emergency department visits from 6366 unique patients were included in the analysis. Mean patient age was 32·4 years (SD 12·8); 3836 (60·3%) patients were female, 2530 (39·7%) were male, 3461 (57·2%) were Medicaid-insured, and 2651 (41·6%) were Black. Incidence of emergency department use for asthma was strongly correlated with lower housing inspection scores (Pearson's r=-0·55 [95% CI -0·70 to -0·35], p=3·5 × 10Emergency department visits for asthma are an early indicator of failed housing inspections. This approach represents a novel method for the early identification of poor housing conditions and could help to reduce asthma-related morbidity and mortality.Harvard-National Institute of Environmental Health Sciences (NIEHS) Center for Environmental Health.

Objective To estimate the prevalence of iron deficiency (ID) and anemia and study their main distal and proximal protective and risk factors among Nunavimmiut 16 years and older in 2017. Methods In a cross-sectional participatory survey of 831 women and 436 men from the Qanuilirpitaa? 2017 Nunavik Inuit Health Survey, venous blood samples were collected to measure various indicators of iron status and anemia as well as biomarkers of nutritional and inflammatory status and contaminant exposures. Sociodemographic, food security status, anthropometric, lifestyle, dietary, and health data were collected using questionnaires, clinical sessions, and a medical chart review. ID and anemia diagnoses were based on serum ferritin (SF) and hemoglobin (Hb), respectively. Multiple regressions were used to assess correlates of anemia and iron status. Results Prevalence of ID was highest among women of childbearing age (16–49 years old, 33%) and anemia among adults aged 50 years and older (31%). These estimates are prone to biases due to the relatively low participation rate (37%). Serum vitamin D, omega-3 polyunsaturated fatty acid content of erythrocyte membranes, blood selenium, inflammation, higher socioeconomic status (SES), obesity, and alcohol consumption were all positively associated with SF, while Helicobacter pylori infection and a recent pregnancy were negatively associated with Hb among women of childbearing age. Among older adults, food insecurity was associated with lower SF. Conclusion While data reported here provide some indication of an improvement since the previous survey conducted in 2004, additional efforts should be devoted to further increasing the SES and access to country foods and nutritious market foods in this population, the two main protective factors against ID and anemia identified in the present study.

Objectives To assess the prevalence of arterial hypertension among Inuit adults living in Nunavik (northern Quebec, Canada) in 2017 and identify its sociodemographic and lifestyle determinants. Methods We used data obtained from 1177 Inuit adults aged ≥ 18 years who participated in the cross-sectional Qanuilirpitaa? Nunavik Inuit Health Survey during late summer-early fall of 2017. Resting blood pressure (BP) and anthropometric characteristics were measured during a clinical session, while sociodemographic characteristics and lifestyle habits were documented using validated questionnaires. Information on current medication was retrieved from medical files. Sex-stratified population-weighted log-binomial regressions were conducted to identify determinants of hypertension, adjusting for potential confounders. Results Hypertension (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mmHg or taking antihypertensive medication) was present in 23% of the adult population and was more frequent in men than women (29% vs. 18%). About a third of hypertensive individuals (34%) were taking antihypertensive medication. These estimates are prone to biases due to the relatively low participation rate (37%). As expected, the prevalence of hypertension increased with age, but values were surprisingly elevated in 18 to 29-year-old men and women (18% and 8%, respectively) compared with 20 to 39-year-old adults of the general Canadian population (3% in both sexes, according to data from the Canadian Health Measures Survey, 2012–2015). Hypertension was associated with obesity and alcohol consumption in both men and women, and with higher socioeconomic status among men. Conclusion This survey revealed a high prevalence of hypertension among young Nunavimmiut adults in 2017 and the need to improve hypertension diagnosis and treatment in the region. Curbing obesity and alcohol consumption, two actionable determinants of hypertension, will require improving food security and addressing the consequences of historical trauma linked to colonization.

INTRODUCTIONMillions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.RATIONALEAs a result of the short evolutionary distance between humans and nonhuman primates, our proteins share near-perfect amino acid sequence identity. Hence, the effects of a protein-altering mutation found in one species are likely to be concordant in the other species. By systematically cataloging common variants of nonhuman primates, we aimed to annotate these variants as being unlikely to cause human disease as they are tolerated by natural selection in a closely related species. Once collected, the resulting resource may be applied to infer the effects of unobserved variants across the genome using machine learning.RESULTSFollowing the strategy outlined above we obtained whole-genome sequencing data for 809 individuals from 233 primate species and cataloged 4.3 million common missense variants. We confirmed that human missense variants seen in at least one nonhuman primate species were annotated as benign in the ClinVar clinical variant database in 99% of cases. By contrast, common variants from mammals and vertebrates outside the primate lineage were substantially less likely to be benign in the ClinVar database (71 to 87% benign), restricting this strategy to nonhuman primates. Overall, we reclassified more than 4 million human missense variants of previously unknown consequence as likely benign, resulting in a greater than 50-fold increase in the number of annotated missense variants compared to existing clinical databases.To infer the pathogenicity of the remaining missense variants in the human genome, we constructed PrimateAI-3D, a semisupervised 3D-convolutional neural network that operates on voxelized protein structures. We trained PrimateAI-3D to separate common primate variants from matched control variants in 3D space as a semisupervised learning task. We evaluated the trained PrimateAI-3D model alongside 15 other published machine learning methods on their ability to distinguish between benign and pathogenic variants in six different clinical benchmarks and demonstrated that PrimateAI-3D outperformed all other classifiers in each of the tasks.CONCLUSIONOur study addresses one of the key challenges in the variant interpretation field, namely, the lack of sufficient labeled data to effectively train large machine learning models. By generating the most comprehensive primate sequencing dataset to date and pairing this resource with a deep learning architecture that leverages 3D protein structures, we were able to achieve meaningful improvements in variant effect prediction across multiple clinical benchmarks. Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

Insertion and deletion mutations (indels) are important mechanisms of generating protein diversity. Indels in coding sequences are under considerable selective pressure to maintain reading frames and to preserve protein function, but once generated, indels provide raw material for the acquisition of new protein properties and functions. We reported recently that coding sequence insertions in theCandida albicansNDU1 protein, a mitochondrial protein involved in the assembly of the NADH:ubiquinone oxidoreductase are imperative for respiration, biofilm formation and pathogenesis. NDU1 inserts are specific to CTG-clade fungi, absent in human ortholog and successfully harnessed as drug targets. Here, we present the first comprehensive report investigating indels and clade-defining insertions (CDIs) in fungal proteomes. We investigated 80 ascomycete proteomes encompassing CTG clade species, the Saccharomycetaceae family, the Aspergillaceae family and the Herpotrichiellaceae (black yeasts) family. We identified over 30,000 insertions, 4,000 CDIs and 2,500 clade-defining deletions (CDDs). Insert sizes range from 1 to over 1,000 residues in length, while maximum deletion length is 19 residues. Inserts are strikingly over-represented in protein kinases, and excluded from structural domains and transmembrane segments. Inserts are predicted to be highly disordered. The amino acid compositions of the inserts are highly depleted in hydrophobic residues and enriched in polar residues. An indel in theSaccharomyces cerevisiaeSth1 protein, the catalytic subunit of the RSC (Remodel the Structure of Chromatin) complex is predicted to be disordered until it forms a ß-strand upon interaction. This interaction performs a vital role in RSC-mediated transcriptional regulation, thereby expanding protein function.

Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57+ FcϵRγ−NKG2C+ adaptive (CD56+CD3−) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNγ production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNγ production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy. Cancer Immunol Res; 6(7); 766–75. ©2018 AACR.

Supplemental Figures and Tables

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

Background Persistent organic pollutant exposures are well-documented in the Arctic, but fewer studies examined non-persistent chemicals, despite increased market food and consumer product consumption. Objective To measure phenol, paraben, phthalate, and alternative plasticizer concentrations in Inuit adults. Methods The study included 30 pooled urine samples from Qanuilirpitaa? 2017 Nunavik Inuit Health Survey (Q2017) participants. Creatinine-adjusted geometric mean concentrations (GM) and 95% confidence intervals (CI) were compared across sex, age, and regions, and compared to those in the Canadian Health Measures Survey (CHMS) and the First Nations Biomonitoring Initiative (FNBI). Results Q2017 bisphenol-A concentrations were double the CHMS 2018–2019 concentrations [GM (95% CI): 1.98 (1.69–2.31) versus 0.71 (0.60–0.84) µg/g creatinine], but in line with FNBI [1.74 (1.41–2.13) µg/g creatinine]. Several phthalate concentrations were higher in Q2017 versus CHMS, particularly monobenzyl phthalate, which was was 19-fold higher in Q2017 versus CHMS 2018–2019 [45.26 (39.35–52.06) versus 2.4 (2.0–2.9) µg/g creatinine] and four-fold higher than FNBI. There were also four-fold higher concentrations of the two alternate plasticizer 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TIXB) metabolites in Q2017 compared to CHMS 2018–2019. Women and people living in Ungava Bay had generally higher concentrations of non-persistent chemicals. Significance The results suggest higher concentrations of certain non-persistent chemicals in Inuit versus the general Canadian population. Impact Few studies have explored non-persistent chemical distributions in Northern communities, despite the increasing consumer product and market food consumption. We analyzed 30 pooled samples from the Qanuilirpitaa? Nunavik Inuit Health Survey 2017 to assess exposures to common plasticizes and plastic constituents and compare their levels with the general Canadian population and First Nation groups. We observed particularly higher levels of bisphenol-A, of monobenzyl phthalate, and of two 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB) metabolites among Nunavimmiut compared to the general Canadian population, notably among women and Ungava Bay residents. Larger studies are required to confirm our findings and identify potential adverse health effects from these exposures.

Objective:To document perfluoroalkyl acids (PFAA) and bisphenol-A (BPA) exposure in four First Nation communities in northern Quebec compared with the Canadian Health Measures Survey (CHMS Cycle 5 2016–2017) and examine the associations between dietary consumption and chemical exposure.Design:We used cross-sectional data from the JES-YEH! project conducted in collaboration with four First Nation communities in 2015. A FFQ collected information on diet, and PFAA and BPA were measured in biological samples. We used generalised linear models to test the associations between food intake and chemical biomarkers.Setting:Northern Quebec.Participants:Youth aged 3–19 years (n 198).Results:Mean perfluorononanoic acid (PFNA) levels were significantly higher in JES-YEH! than CHMS, and BPA levels were higher among those aged 12–19 years compared with CHMS. Dairy products were associated with PFNA among Anishinabe and Innu participants (geometric mean ratio 95 % CI: 1·53 (95 % CI 1·03, 2·29) and 1·52 (95 % CI 1·05, 2·20), respectively). PFNA was also associated with ultra-processed foods (1·57 (95 % CI 1·07, 2·31)) among Anishinabe, and with wild fish and berries (1·44 (95 % CI 1·07, 1·94); 1·75 (95 % CI 1·30, 2·36)) among Innu. BPA was associated with cheese (1·72 (95 % CI 1·19, 2·50)) and milk (1·53 (95 % CI 1·02, 2·29)) among Anishinabe, and with desserts (1·71 (95 % CI 1·07, 2·74)), processed meats (1·55 (95 % CI 1·00, 2·38)), wild fish (1·64 (95 % CI 1·07, 2·49)) and wild berries (2·06 (95 % CI 1·37, 3·10)) among Innu.Conclusions:These results highlight the importance of better documenting food-processing and packaging methods, particularly for dairy products, and their contribution to endocrine disruptors exposures as well as to promote minimally processed and unpackaged foods to provide healthier food environments for youth in Indigenous communities and beyond.

Bloom and cuckoo filters provide fast approximate set membership while using little memory. Engineers use them to avoid expensive disk and network accesses. The recently introduced xor filters can be faster and smaller than Bloom and cuckoo filters. The xor filters are within 23% of the theoretical lower bound in storage as opposed to 44% for Bloom filters. Inspired by Dietzfelbinger and Walzer, we build probabilistic filters—called binary fuse filters —that are within 13% of the storage lower bound—without sacrificing query speed. As an additional benefit, the construction of the new binary fuse filters can be more than twice as fast as the construction of xor filters. By slightly sacrificing query speed, we further reduce storage to within 8% of the lower bound. We compare the performance against a wide range of competitive alternatives such as Bloom filters, blocked Bloom filters, vector quotient filters, cuckoo filters, and the recent ribbon filters. Our experiments suggest that binary fuse filters are superior to xor filters.

Climate change is disproportionally impacting the Circumpolar North, with particular impacts among Indigenous populations. Environmental changes are felt in many aspects of daily life of Northern communities, including both physical and mental health. Thus, health institutions from around the Arctic must meet emerging needs, while the phenomenon remains marginal to their southern counterparts. In this systematic review, we aimed to review current scientific knowledge on the mental health impacts of climate change in Indigenous Peoples across the Circumpolar North. Seven databases were searched. Original peer-reviewed research articles were included if they addressed links between climate change and mental health in Arctic or Subarctic Indigenous Populations. After extraction, data were synthesized using thematic analysis. Of the 26 articles that met inclusion criteria, 16 focused on Canadian Inuit communities and 21 were exclusively qualitative. Being on the land was identified as a central determinant of wellbeing. Immediate impacts of climate change on mental health were felt through restricted mobility and disrupted livelihoods. Effects on mental health were further felt through changes in culture and identity, food insecurity, interpersonal stress and conflicts, and housing problems. Various ways in how communities and individuals are coping with these effects were reported. Understanding climate-related pathways of mental health risks in the Arctic is crucial to better identify vulnerable groups and to foster resilience. Clinicians can play a role in recognizing and providing support for patients affected by these disruptions. Policies sensitive to the climate–mental health relationship must be advocated for.

Contains more detailed information on the individual cohorts contributing to the study and their genotyping results; Supplemental Tables 1 and 2

Purpose: To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures.Results: Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19–52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype (P = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients.Conclusions: Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. Clin Cancer Res; 24(6); 1344–54. ©2017 AACR.

Background: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.Methods: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS).Results: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately.Conclusions: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk.Impact: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D. Cancer Epidemiol Biomarkers Prev; 22(11); 2037–46. ©2013 AACR.

Supplementary Methods, Tables and Figures Supplementary Table 1: Summary of whole genome sequencing results including performance metrics and time to reporting (N=62). Supplementary Table 2: Summary of GATA6 RNA in situ results and its correlation with RNA subtype and histologic grade. Supplementary Figure 1: WGS Performance Characteristics. Supplementary Figure 2: Both COMP-0037 and COMP-0057 had germline BRCA2 p.S1982fs mutations but only COMP-0037 had a second hit (somatic LOH of wild type allele) and showed hallmarks of double strand break repair deficiency. Supplementary Figure 3: BRCA2 mutation status of COMP-0057. Supplementary Figure 4: Subtypes of advanced PDAC by Moffitt tumour classification Supplementary Figure 5: Correlation between Moffitt tumor RNA subtypes and GATA6 gene expression. Supplementary Figure 6: Correlation between GATA6 expression measured by RNASeq and RNA in situ hybridization. Supplementary Figure 7: Differentially expressed pathways between Moffitt's basal like and classical RNA subtypes Supplementary Figure 8: CDK4 amplification identified in COMP-0008 (A) and CDK6 amplification identified in COMP-0010 (B) validated by fluorescence in-situ hybridization.

Supplemental Table 3. Environmental Factors and colorectal cancer: associations by study design

Background: Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene–environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279.Methods: Data on 9,160 cases and 9,280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, postmenopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons.Results: None of the permutation-adjusted P values reached statistical significance.Conclusions: The associations between recently identified genetic susceptibility loci and colorectal cancer are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors.Impact: Results suggest no evidence of strong gene–environment interactions involving the recently identified 16 susceptibility loci for colorectal cancer taken one at a time. Cancer Epidemiol Biomarkers Prev; 23(9); 1824–33. ©2014 AACR.

PDF file - 77K, All GxE interaction results.

PDF file - 55K, Study specific definitions of regular aspirin/NSAID use.

PDF file - 96K, All GxE interactions stratified by cancer site.

PDF file - 52K, Forest plots for meta-analysis results with GxE interaction p < 0.01

PDF file - 67K, Descriptives for smoking, BMI, height, dietary variables, alcohol, sex, and NSAID use.

PDF file - 55K, Further information about main finding

PDF file - 168K, SNP details by study.