The NCI/NIH Cancer Moonshot BioBank (CMB) and the Maine Cancer Genetics/Genomics Education Core (ME-CGEC) Collaborate to Improve Cancer Care in Maine

Goal: To better understand drug resistance and sensitivity in patients with late stage (Stage III & IV) cancers that are receiving standard of care molecularly targeted therapies through next generation sequencing (NGS) of biopsy and blood samples collected longitudinally (diagnosis-- treatment--progression).https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1053/thumbnail.jp

A Period Seroprevalence (SARS-CoV-2) Survey in MHCCN Cancer Healthcare Workers (HCWs) Providing Patient Care during the Height of the Outbreak: A Registry Study (Initial Progress)

Introduction: There is little information on the basic epidemiologic and serologic profile(s) of the novel SARSCoV- 2 coronavirus especially in HCWs employed in rural settings. We embarked on a period seroprevalence study in the MaineHealth Cancer Network (MHCCN) to document Covid-19 exposure in our rural cancer care workforce. Our fundamental hypothesis is that despite implementing procedures to safeguard patients and the use of appropriate PPE in the care of known source patients/PUIs in both the inpatient and outpatient cancer care settings a small, but not insignificant number of cancer care providers (hereafter referred to as cancer HCWs) will have evidence of exposure by virtue of plasma antibody seroconversion.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1001/thumbnail.jp

Le FORUM, Vol. 34 No. 2

https://digitalcommons.library.umaine.edu/francoamericain_forum/1026/thumbnail.jp

Contributions and perspectives of Indigenous Peoples to the study of mercury in the Arctic

Arctic Indigenous Peoples are among the most exposed humans when it comes to foodborne mercury (Hg). In response, Hg monitoring and research have been on-going in the circumpolar Arctic since about 1991; this work has been mainly possible through the involvement of Arctic Indigenous Peoples. The present overview was initially conducted in the context of a broader assessment of Hg research organized by the Arctic Monitoring and Assessment Programme. This article provides examples of Indigenous Peoples' contributions to Hg monitoring and research in the Arctic, and discusses approaches that could be used, and improved upon, when carrying out future activities. Over 40 mercury projects conducted with/by Indigenous Peoples are identified for different circumpolar regions including the U.S., Canada, Greenland, Sweden, Finland, and Russia as well as instances where Indigenous Knowledge contributed to the understanding of Hg contamination in the Arctic. Perspectives and visions of future Hg research as well as recommendations are presented. The establishment of collaborative processes and partnership/co-production approaches with scientists and Indigenous Peoples, using good communication practices and transparency in research activities, are key to the success of research and monitoring activities in the Arctic. Sustainable funding for community-driven monitoring and research programs in Arctic countries would be beneficial and assist in developing more research/ monitoring capacity and would promote a more holistic approach to understanding Hg in the Arctic. These activities should be well connected to circumpolar/international initiatives to ensure broader availability of the information and uptake in policy development

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function

The unique contribution of a local response group in the field investigation and management of a trichinellosis outbreak in Nunavik (Québec, Canada)

Setting : Consumption of raw game meats is important for Inuit health and well-being but may sometimes increase risk of exposure to parasites. In Nunavik, following trichinellosis outbreaks in the 1980s caused by raw walrus consumption, a diagnostic test was developed for the region and offered to all Inuit communities by 1997. Despite this prevention program, an important trichinellosis outbreak occurred in 2013, affecting 18 inhabitants of Inukjuak. Intervention : Because the classical outbreak investigation did not rapidly converge toward a common food source or specific event, a local response group, composed of four community members appointed by the Municipal Council as well as the regional public health physician, nurse and wildlife parasitologist, was created. Their objective was to investigate potential sources of infection related to the outbreak, hence the investigation of the types of meats consumed, the movement of meats between and within the community, and the local practices of processing game meat. Outcomes : Though the source of infection was not fully confirmed, this local investigation identified the distribution of transformed polar bear meat as the most probable source of infection. The creation of this unique, intersectoral and intercultural local response group fostered the use of local knowledge to better understand aspects of the modern food system, and is one of the most innovative outcomes of this investigation. Implications : Integrating multiple ways of knowing was critical for the management of this important public health issue and contributed to community members’ mobilization and empowerment with respect to local food safety issues.Contexte : La consommation de viandes de gibier crues est importante pour la santé et le bien-être des Inuits, mais elle peut parfois augmenter leur risque d'exposition à certains parasites. Au Nunavik, après quelques éclosions de trichinellose causées par la consommation de viande de morse crue dans les années 1980, un test diagnostic a été développé localement et offert à toutes les communautés, à partir de 1997. Malgré la mise en place de ce programme de prévention, une importante éclosion de trichinellose est survenue en 2013, affectant 18 habitants d'Inukjuak. Intervention : Comme l’enquête épidémiologique classique n’a pas rapidement convergé vers une source alimentaire commune ou un événement spécifique, un groupe d’intervention local a été créé. Il se composait de quatre membres de la communauté nommés par le conseil municipal ainsi que d’un médecin de santé publique, d’une infirmière et d’un parasitologue spécialisé dans la faune sauvage. L’objectif du groupe était d'étudier les sources potentielles d'infection liées à l'épidémie dont l'enquête sur les types de viande consommée, le mouvement de viande au sein de la communauté et avec les autres villages, ainsi que les pratiques locales de préparation de la viande de gibier. Résultats : Bien que la source de l'infection n'ait pas été confirmée avec certitude, l’enquête du groupe a ciblé la distribution de viande d'ours polaire transformée comme la source d'infection la plus probable. La création de ce groupe d’intervention local unique, intersectoriel et interculturel a favorisé l’utilisation des connaissances locales pour mieux comprendre les aspects du système alimentaire et constitue l’un des résultats les plus novateurs de cette enquête. Implications : L’intégration de connaissances locales et scientifiques était essentielle à la gestion de cet important problème de santé publique et a contribué à la mobilisation et à la responsabilisation des membres de la communauté concernant les problèmes locaux de sécurité alimentaire

Implementation of an Electronic Data Collection Tool to Monitor Nursing-Sensitive Indicators in a Large Academic Health Sciences Centre

Monitoring the quality of nursing care is essential to identify patients at risk, measure adherence to hospital policies and evaluate the effectiveness of best practice interventions. However, monitoring nursing-sensitive indicators (NSI) is a challenge. Prevalence surveys are one method used by some organizations to monitor NSI, which are patient outcomes that are directly affected by the quantity or quality of nursing care that the patient receives

Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder

Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10-8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p's < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (rg = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery

A Period Seroprevalence(SARS-CoV-2) Survey in MHCCN Cancer Healthcare Workers (HCWs) Providing Patient Care during the Height of the Outbreak: A Registry Study (Second Year Progress)

In December 2019, emergence of a new coronavirus in Wuhan, China heralded the onset of a global pandemic (aka Covid-19) that is well into its third year. At the outset, the initial first wave of the alpha variant in 2020 had less impact on our state and HCWs. In December 2020, Covid-19 vaccinations became available. By fall and winter 2021-2022, the delta and subsequent omicron variants nearly overwhelmed Maine healthcare systems and work force. In June 2020, we embarked on a period seroprevalencestudy in the MaineHealthCancer Network (MHCCN) to document Covid-19 exposure in our rural cancer care workforce. Enrollment continues over two discrete periods during our study, essentially pre-and post-vaccination and with two discrete SARS-CoV-2 antibody-testing platforms as the pandemic evolved. This ongoing study provides additional insight into viral antibody (Ab) response across the settings of potential occupational exposure, rapid community spread, and vaccination.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2022/1001/thumbnail.jp