Day in the Life: Indian Health Service - Zuni, NM

Outline: Zuni Pueblo (Geographics/ Demographics/ History and Culture) Rural Medicine (Full spectrum/ Day in the Life) Working for the Indian Health Service New Mexico Livin

A video-based educational intervention for providers regarding colorectal cancer screening

Methods: Email sent to providers asking them to complete a 7 question survey regarding knowledge and self-reported comfort in screening for colorectal cancer using a shared decision-making approach.https://jdc.jefferson.edu/patientsafetyposters/1045/thumbnail.jp

Risk factors of insulin refusal among type 2 diabetes mellitus patients with poor glycaemic control at Tanglin Health Clinic, Kuala Lumpur

Introduction: The number of patients with poor glycaemic control who refuse insulin therapy is alarming. Factors that contribute to insulin refusal are important to study to identify high risk groups so that appropriate measures can be taken to prevent progression of uncontrolled diabetes. The objective of this study is to determine the risk factors of insulin refusal among type 2 diabetes mellitus patients with poor glycaemic control at Tanglin Health Clinic, Kuala Lumpur, Malaysia. Methods: A case control study was conducted among 216 cases and 230 controls using stratified sampling method. Cases were defined as patients with HbA1C more than 7.5% but not on insulin therapy despite being offered by the doctor whereas controls consist of patients with HbA1C of more than 7.5% but already on insulin therapy. Data was collected from April until May 2018, using a self-administered questionnaire. Analysis was done via IBM SPSS version 23.0. Results: Response rate for cases was 93.9% and response rate for controls was 100%. Risk factors of insulin refusal among poor glycaemic control includes age above 60 years old, tertiary level education, duration of diabetes less than 10 years, poor level of knowledge on insulin, fear on injection pain and fear to bruising due to injections. Conclusion: Hence, efforts must be taken to tackle the modifiable factors such as knowledge on insulin and diabetes, and fear on injections and bruises

Demographic and Psychosocial Factors Associated with Suicide Mortality Among Childbearing-Aged Individuals: A Case-Control Study

Objective: Examine pregnancy-related, demographic, psychosocial and healthcare utilization factors associated with suicide mortality among childbearing-aged women. Methods: Data from nine health care systems in the Mental Health Research Network were included. A case-control study design was used in which 290 childbearing-age women who died by suicide (cases) from 2000-2015 were matched with 2,900 childbearing-age women from the same healthcare system and enrolled during the same time period who did not die by suicide. Conditional logistic regression was used to analyze associations between patient characteristics and suicide. Results: Women who died by suicide were more likely to have mental health or substance use disorders (aOR = 2.36, 95%CI: 1.46, 3.82) and to have visited the emergency department in the year prior to index date (aOR = 3.35, 95%CI: 2.39, 4.68). Pregnancy (aOR = 0.17, 95% CI: 0.04, 0.78) and delivery of a liveborn baby (aOR = 0.39, 95% CI: 0.16, 0.92) within a year before index date were associated with lower risk of suicide mortality. Women who experienced pregnancy loss were more likely to die by suicide (aOR = 1.41, 95% CI: 0.49, 4.06), but this was not statistically significant potentially due to small sample size (n = 6 cases; n = 21 control). Conclusions: Childbearing-aged women with mental health and/or substance use disorders, prior emergency department encounters may benefit from routine screening and monitoring for suicide risk. Future research should further examine the relationship between pregnancy loss and suicide mortality

Association of Autism With Induced or Augmented Childbirth in North Carolina Birth Record (1990-1998) and Education Research

IMPORTANCE One in 88 children in the United States is diagnosed as having autism spectrum disorder. Significant interest centers on understanding the environmental factors that may contribute to autism risk. OBJECTIVE To examine whether induced (stimulating uterine contractions prior to the onset of spontaneous labor) and/or augmented (increasing the strength, duration, or frequency of uterine contractions with spontaneous onset of labor) births are associated with increased odds of autism. DESIGN, SETTING, AND PARTICIPANTS We performed an epidemiological analysis using multivariable logistic regression modeling involving the North Carolina Detailed Birth Record and Education Research databases. The study featured 625 042 live births linked with school records, including more than 5500 children with a documented exceptionality designation for autism. EXPOSURES Induced or augmented births. MAIN OUTCOMES AND MEASURES Autism as assessed by exceptionality designations in child educational records. RESULTS Compared with children born to mothers who received neither labor induction nor augmentation, children born to mothers who were induced and augmented, induced only, or augmented only experienced increased odds of autism after controlling for potential confounders related to socioeconomic status, maternal health, pregnancy-related events and conditions, and birth year. The observed associations between labor induction/augmentation were particularly pronounced in male children. CONCLUSIONS AND RELEVANCE Our work suggests that induction/augmentation during childbirth is associated with increased odds of autism diagnosis in childhood. While these results are interesting, further investigation is needed to differentiate among potential explanations of the association including underlying pregnancy conditions requiring the eventual need to induce/augment, the events of labor and delivery associated with induction/augmentation, and the specific treatments and dosing used to induce/augment labor (eg, exogenous oxytocin and prostaglandins)

The SOCS-Box of HIV-1 Vif Interacts with ElonginBC by Induced-Folding to Recruit Its Cul5-Containing Ubiquitin Ligase Complex

The HIV-1 viral infectivity factor (Vif) protein recruits an E3 ubiquitin ligase complex, comprising the cellular proteins elongin B and C (EloBC), cullin 5 (Cul5) and RING-box 2 (Rbx2), to the anti-viral proteins APOBEC3G (A3G) and APOBEC3F (A3F) and induces their polyubiquitination and proteasomal degradation. In this study, we used purified proteins and direct in vitro binding assays, isothermal titration calorimetry and NMR spectroscopy to describe the molecular mechanism for assembly of the Vif-EloBC ternary complex. We demonstrate that Vif binds to EloBC in two locations, and that both interactions induce structural changes in the SOCS box of Vif as well as EloBC. In particular, in addition to the previously established binding of Vif's BC box to EloC, we report a novel interaction between the conserved Pro-Pro-Leu-Pro motif of Vif and the C-terminal domain of EloB. Using cell-based assays, we further show that this interaction is necessary for the formation of a functional ligase complex, thus establishing a role of this motif. We conclude that HIV-1 Vif engages EloBC via an induced-folding mechanism that does not require additional co-factors, and speculate that these features distinguish Vif from other EloBC specificity factors such as cellular SOCS proteins, and may enhance the prospects of obtaining therapeutic inhibitors of Vif function

Genomic Hotspots for Adaptation: The Population Genetics of Müllerian Mimicry in the Heliconius melpomene Clade

Wing patterning in Heliconius butterflies is a longstanding example of both Müllerian mimicry and phenotypic radiation under strong natural selection. The loci controlling such patterns are “hotspots” for adaptive evolution with great allelic diversity across different species in the genus. We characterise nucleotide variation, genotype-by-phenotype associations, linkage disequilibrium, and candidate gene expression at two loci and across multiple hybrid zones in Heliconius melpomene and relatives. Alleles at HmB control the presence or absence of the red forewing band, while alleles at HmYb control the yellow hindwing bar. Across HmYb two regions, separated by ∼100 kb, show significant genotype-by-phenotype associations that are replicated across independent hybrid zones. In contrast, at HmB a single peak of association indicates the likely position of functional sites at three genes, encoding a kinesin, a G-protein coupled receptor, and an mRNA splicing factor. At both HmYb and HmB there is evidence for enhanced linkage disequilibrium (LD) between associated sites separated by up to 14 kb, suggesting that multiple sites are under selection. However, there was no evidence for reduced variation or deviations from neutrality that might indicate a recent selective sweep, consistent with these alleles being relatively old. Of the three genes showing an association with the HmB locus, the kinesin shows differences in wing disc expression between races that are replicated in the co-mimic, Heliconius erato, providing striking evidence for parallel changes in gene expression between Müllerian co-mimics. Wing patterning loci in Heliconius melpomene therefore show a haplotype structure maintained by selection, but no evidence for a recent selective sweep. The complex genetic pattern contrasts with the simple genetic basis of many adaptive traits studied previously, but may provide a better model for most adaptation in natural populations that has arisen over millions rather than tens of years

A Survey of New Temperature-Sensitive, Embryonic-Lethal Mutations in C. elegans: 24 Alleles of Thirteen Genes

To study essential maternal gene requirements in the early C. elegans embryo, we have screened for temperature-sensitive, embryonic lethal mutations in an effort to bypass essential zygotic requirements for such genes during larval and adult germline development. With conditional alleles, multiple essential requirements can be examined by shifting at different times from the permissive temperature of 15°C to the restrictive temperature of 26°C. Here we describe 24 conditional mutations that affect 13 different loci and report the identity of the gene mutations responsible for the conditional lethality in 22 of the mutants. All but four are mis-sense mutations, with two mutations affecting splice sites, another creating an in-frame deletion, and one creating a premature stop codon. Almost all of the mis-sense mutations affect residues conserved in orthologs, and thus may be useful for engineering conditional mutations in other organisms. We find that 62% of the mutants display additional phenotypes when shifted to the restrictive temperature as L1 larvae, in addition to causing embryonic lethality after L4 upshifts. Remarkably, we also found that 13 out of the 24 mutations appear to be fast-acting, making them particularly useful for careful dissection of multiple essential requirements. Our findings highlight the value of C. elegans for identifying useful temperature-sensitive mutations in essential genes, and provide new insights into the requirements for some of the affected loci

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance.

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.Whole-genome sequencing of esophageal adenocarcinoma samples was performed as part of the International Cancer Genome Consortium (ICGC) through the oEsophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium and was funded by Cancer Research UK. We thank the ICGC members for their input on verification standards as part of the benchmarking exercise. We thank the Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital and UCL. Also the University Hospital of Southampton Trust and the Southampton, Birmingham, Edinburgh and UCL Experimental Cancer Medicine Centres and the QEHB charities. This study was partly funded by a project grant from Cancer Research UK. R.C.F. is funded by an NIHR Professorship and receives core funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Cancer Medicine Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited. We would like to thank Dr. Peter Van Loo for providing the NGS version of ASCAT for copy number calling. We are grateful to all the patients who provided written consent for participation in this study and the staff at all participating centres. Some of the work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. The work at UCLH/UCL was also supported by the CRUK UCL Early Cancer Medicine Centre.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.365