The Expectations and Challenges of Wildlife Disease Research in the Era of Genomics: Forecasting with a Horizon Scan-like Exercise.

The outbreak and transmission of disease-causing pathogens are contributing to the unprecedented rate of biodiversity decline. Recent advances in genomics have coalesced into powerful tools to monitor, detect, and reconstruct the role of pathogens impacting wildlife populations. Wildlife researchers are thus uniquely positioned to merge ecological and evolutionary studies with genomic technologies to exploit unprecedented "Big Data" tools in disease research; however, many researchers lack the training and expertise required to use these computationally intensive methodologies. To address this disparity, the inaugural "Genomics of Disease in Wildlife" workshop assembled early to mid-career professionals with expertise across scientific disciplines (e.g., genomics, wildlife biology, veterinary sciences, and conservation management) for training in the application of genomic tools to wildlife disease research. A horizon scanning-like exercise, an activity to identify forthcoming trends and challenges, performed by the workshop participants identified and discussed 5 themes considered to be the most pressing to the application of genomics in wildlife disease research: 1) "Improving communication," 2) "Methodological and analytical advancements," 3) "Translation into practice," 4) "Integrating landscape ecology and genomics," and 5) "Emerging new questions." Wide-ranging solutions from the horizon scan were international in scope, itemized both deficiencies and strengths in wildlife genomic initiatives, promoted the use of genomic technologies to unite wildlife and human disease research, and advocated best practices for optimal use of genomic tools in wildlife disease projects. The results offer a glimpse of the potential revolution in human and wildlife disease research possible through multi-disciplinary collaborations at local, regional, and global scales.

Nutritional Status in Childhood as a Prognostic Factor in Patients with Cystic Fibrosis.

INTRODUCTION: There is a strong association between cystic fibrosis and malnutrition, mainly because of the higher energy needs combined with lower intake. There is also a well-established correlation between good nutritional status and better lung function. To date, however, there are no studies examining nutritional status in childhood and adult lung function. To respond to this need, this innovative study explored the long-term correlations between nutritional status in childhood and lung function in adulthood for the same patient population. METHODS: A retrospective patient file study was conducted to identify putative correlations between nutritional status in childhood and lung function in adulthood. The medical archives at Sheba Medical Center were examined for a period of 31 years between 1986 and 2017 for age, gender, mutations, pancreatic sufficiency or insufficiency (PI/PS), sputum cultures, cystic fibrosis related diabetes, body mass index (BMI) at the age of 10, and FEV1 at 20 and 30 in patients who underwent or did not undergo lung transplantation. RESULTS: The database was composed of the records of sixty-five patients, thirteen of whom underwent lung transplantation. The correlations (R²) between BMI at age of 10 years and FEV1 at the age of 20 and 30 years were 0.35 and 0.28, respectively, p < 0.001. A BMI of lower than - 0.75 at the age of 10 emerged as a risk factor for lung transplantation (OR 3.42 p = 0.023) and had a negative predictive value of 90%. Kaplan-Meier survival curve showed significant lower lung transplantation rate in the group of BMI z score higher than - 0.75 at the age of 10 years. Logistic regression found nutritional at the age of 10 years as a dominant risk factor for lung transplantation. CONCLUSIONS: This study reports a clear, significant and important correlation for the first time between nutritional status in childhood and lung function for the same patients at adulthood. Hence, nutritional status sets a clear trajectory and should be treated aggressively. The findings emphasize the importance of new-born screening and early implementation of nutritional guidelines for cystic fibrosis patients.

Association Between Initial Opioid Prescribing Patterns and Subsequent Long-Term Use Among Opioid-Naïve Patients: A Statewide Retrospective Cohort Study.

BACKGROUND: Long-term efficacy of opioids for non-cancer pain is unproven, but risks argue for cautious prescribing. Few data suggest how long or how much opioid can be prescribed for opioid-naïve patients without inadvertently promoting long-term use. OBJECTIVE: To examine the association between initial opioid prescribing patterns and likelihood of long-term use among opioid-naïve patients. DESIGN: Retrospective cohort study; data from Oregon resident prescriptions linked to death certificates and hospital discharges. PARTICIPANTS: Patients filling opioid prescriptions between October 1, 2012, and September 30, 2013, with no opioid fills for the previous 365 days. Subgroup analyses examined patients under age 45 who did not die in the follow-up year, excluding most cancer or palliative care patients. MAIN MEASURES: Exposure: Numbers of prescription fills and cumulative morphine milligram equivalents (MMEs) dispensed during 30 days following opioid initiation ("initiation month"). OUTCOME: Proportion of patients with six or more opioid fills during the subsequent year ("long-term users"). KEY RESULTS: There were 536,767 opioid-naïve patients who filled an opioid prescription. Of these, 26,785 (5.0 %) became long-term users. Numbers of fills and cumulative MMEs during the initiation month were associated with long-term use. Among patients under age 45 using short-acting opioids who did not die in the follow-up year, the adjusted odds ratio (OR) for long-term use among those receiving two fills versus one was 2.25 (95 % CI: 2.17, 2.33). Compared to those who received < 120 total MMEs, those who received between 400 and 799 had an OR of 2.96 (95 % CI: 2.81, 3.11). Patients initiating with long-acting opioids had a higher risk of long-term use than those initiating with short-acting drugs. CONCLUSIONS: Early opioid prescribing patterns are associated with long-term use. While patient characteristics are important, clinicians have greater control over initial prescribing. Our findings may help minimize the risk of inadvertently initiating long-term opioid use.

Iatrogenic superior mesenteric vein injury: the perils of high ligation.

PURPOSE: The purpose of this review is to highlight the perils and pitfalls associated with high vascular ligation during right colectomies for adenocarcinoma and to identify the various mechanisms of injury to the superior mesenteric vein (SMV) and its tributaries. METHODS: This is a retrospective chart review of 304 right colectomies (159 open and 145 laparoscopic) performed over a period of 10 years (1 June 2006-31 May 2016) for right-sided colonic adenocarcinoma in an academic medical center. RESULTS: During a 10-year study period, we encountered five cases in which significant damage to the SMV and its tributaries occurred. This accounts for a total of 1.6 % of all right colectomies performed for colonic adenocarcinoma. CONCLUSIONS: Iatrogenic superior mesenteric vein injury is a rare, severe, and underreported complication of both open and laparoscopic right colectomy for colonic adenocarcinoma. We identified several mechanisms of injury such as anatomic misperception, excessive traction and pulling on the venous system, extensive tumor involvement of the mesentery, and uncontrolled suturing attempts at hemostasis. We believe that increased awareness of this complication with profound understanding of vascular anatomy and the different mechanisms of injury will allow surgeons to avoid this often devastating complication.

Corrected QT interval anomalies are associated with worse prognosis among patients suffering from sepsis.

BACKGROUND: Patients suffering from sepsis experience organ failure and metabolic derangements, with a negative impact on their prognosis and survival. Objective markers for dismal prognosis in this group of patients are sought. AIMS: To assess the potential role of corrected QT interval anomalies as surrogates for metabolic derangements leading to increased short and medium-term mortality in patients suffering from sepsis. METHODS: This study utilised a historic-cohort analysis of 257 septic patients admitted to internal medicine departments. Personal data, vital signs, laboratory results and electrocardiograms were collected. Patients were grouped according to QTc duration, weather mid-range (395-490 ms) or non-mid-range, and further defined as shorter (<395 ms) or longer (>490 ms). RESULTS: Mortality rates differed significantly between the mid-range QTc group and the non-mid-range groups at 14 days (23.7 vs 38.2%, respectively; P = 0.014) and at 3 months (38.5 vs 59.6%, respectively; P = 0.001). In a three-group analysis, the 14-day mortality was the highest in the longer QTc group and the lowest in the mid-range group compared with the shorter QTc group (44.4, 23.7 and 35.5%, respectively; P = 0.034), and this difference also remained at 3 months (74.1, 38.5 and 53.2%, respectively; P = 0.001). All differences remained statistically significant in a multivariate Cox regression analysis. CONCLUSIONS: QTc duration anomalies are associated with worse short- and medium-term prognosis and may act as a marker for more severe clinical sequelae.

Genome-wide association study of lung function phenotypes in a founder population.

BACKGROUND: Lung function is a long-term predictor of mortality and morbidity. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. METHODS: We performed a genome-wide association study (GWAS) of FEV1, forced vital capacity (FVC), and FEV1/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. RESULTS: Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 × 10(-8) to 3.4 × 10(-9)). Nine SNPs at or near 4 additional loci had P < 10(-5) with FEV1/FVC. Only 2 SNPs were found with P < 10(-5) for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of ß-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B. CONCLUSION: This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.

Sex-specific genetic architecture of human disease.

Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.

Racial/ethnic and insurance status disparities in discharge to posthospitalization care for patients with traumatic brain injury.

OBJECTIVES: Professional, posthospitalization care (PHC) can improve outcomes among patients with traumatic brain injury. We examined disparities in discharge to PHC by patients' race/ethnicity and insurance type. PARTICIPANTS: A total of 6061 adults hospitalized for unintentional traumatic brain injury in Oregon, 2008 to 2011. MAIN OUTCOME MEASURE: Posthospitalization care was assessed on the basis of discharge disposition. Multivariable logistic regression was used to estimate effects of race/ethnicity and insurance on referral to PHC while controlling for potential confounders. Generalized estimating equations were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), accounting for clustering of data by hospital. RESULTS: 28% of patients were discharged to PHC. While controlling for potential confounders, Hispanics were less likely to be discharged to PHC (OR, 0.62; CI, 0.40-0.96) than non-Hispanic whites. Compared with patients with private insurance, uninsured patients were less likely to be discharged to PHC (OR, 0.19; CI, 0.11-0.32) whereas patients with public insurance (OR, 1.65; CI, 1.33-2.05) and worker's compensation (OR, 1.66; CI, 1.09-2.52) were more likely to be discharged to PHC. CONCLUSIONS: Results suggest that racial/ethnic and insurance disparities exist in discharge to postacute care after hospitalization for traumatic brain injury. Future research should examine factors that might contribute to and reduce these inequities in care.

Opioid Overdose After Medication for Opioid Use Disorder Initiation Following Hospitalization or ED Visit.

Importance: Hospitalizations related to opioid use disorder (OUD) represent an opportunity to initiate medication for OUD (MOUD). Objective: To assess whether starting MOUD after a hospitalization or emergency department (ED) visit is associated with the odds of fatal and nonfatal opioid overdose at 6 and 12 months. Design, Setting, and Participants: This population-based cohort study used data from the Oregon Comprehensive Opioid Risk Registry, which links all payer claims data to other administrative health datasets, for individuals aged 18 years or older who had diagnosis codes related to OUD recorded at an index ED visit or hospitalization from January 2017 to December 2019. Data were analyzed between May 2023 and January 2024. Exposures: Receipt of MOUD within the 7 days after an OUD-related hospital visit. Main Outcomes and Measures: The primary outcome was fatal or nonfatal overdose at 6 and 12 months after discharge. Sample characteristics, including age, sex, insurance plan, number of comorbidities, and opioid-related overdose events, were stratified by receipt or nonreceipt of MOUD within 7 days after an OUD-related hospital visit. A logistic regression model was used to investigate the association between receipt of MOUD and having an opioid overdose event. Results: The study included 22 235 patients (53.1% female; 25.0% aged 25-39 years) who had an OUD-related hospital visit during the study period. Overall, 1184 patients (5.3%) received MOUD within 7 days of their ED visit or hospitalization. Of these patients, 683 (57.7%) received buprenorphine, 463 (39.1%) received methadone, and 46 (3.9%) received long-acting injectable naltrexone. Patients who received MOUD within 7 days after discharge had lower adjusted odds of fatal or nonfatal overdose at 6 months compared with those who did not (adjusted odds ratio [AOR], 0.63; 95% CI, 0.41-0.97). At 12 months, there was no difference in adjusted odds of fatal or nonfatal overdose between these groups (AOR, 0.79; 95% CI, 0.58-1.08). Patients had a lower risk of fatal or nonfatal overdose at 6 months associated with buprenorphine use (AOR, 0.50; 95% CI, 0.27-0.95) but not with methadone use (AOR, 0.57; 95% CI, 0.28-1.17). Conclusions and Relevance: In this cohort study of individuals with an OUD-related hospital visit, initiation of MOUD was associated with reduced odds of opioid-related overdose at 6 months. Hospitals should consider implementing programs and protocols to offer initiation of MOUD to patients with OUD who present for care.

The maternal HLA-G 1597ΔC null mutation is associated with increased risk of pre-eclampsia and reduced HLA-G expression during pregnancy in African-American women.

The non-classical major histocompatibility complex molecule, human leukocyte antigen (HLA)-G, is thought to contribute to maternal immune tolerance and successful placentation during pregnancy. Genetic polymorphisms in HLA-G are known to influence expression levels as well as the relative expression of individual protein isoforms. As diminished or aberrant HLA-G expression patterns may contribute to the development of certain pregnancy complications, we sought to investigate the association between functional HLA-G polymorphisms and the risk of pre-eclampsia (PE) in African-American women. The association between maternal and fetal genotype at six HLA-G polymorphisms and risk of PE was assessed in 372 pregnancies (314 normotensive; 58 pre-eclamptic). We observed an elevated risk of PE (P = 0.00027) in pregnancies where the mother carried the 1597ΔC allele, a null allele that abolishes expression of full-length HLA-G isoforms. Furthermore, the frequency of the maternal 1597ΔC allele was highest in the subset of pre-eclamptic pregnancies that were delivered preterm, suggesting an association between the null allele and the severity of PE. We then replicated the association between higher maternal 1597ΔC allele frequency and increased severity of PE (P = 0.038) in an independent sample of 533 African-American women. Finally, to investigate the mechanistic basis of this association, we measured circulating soluble HLA-G (sHLA-G) concentrations in maternal serum collected during pregnancy in 51 healthy, normotensive African-American control women and found significantly lower levels in women carrying the 1597ΔC allele (P = 0.012). These results demonstrate that maternal HLA-G genotype is significantly associated with risk of PE in African-American women and is predictive of circulating sHLA-G levels during pregnancy.

Human leukocyte antigen-G expression in differentiated human airway epithelial cells: lack of modulation by Th2-associated cytokines.

BACKGROUND: Human leukocyte antigen (HLA)-G is a nonclassical class I antigen with immunomodulatory roles including up-regulation of suppressor T regulatory lymphocytes. HLA-G was recently identified as an asthma susceptibility gene, and expression of a soluble isoform, HLA-G5, has been demonstrated in human airway epithelium. Increased presence of HLA-G5 has been demonstrated in bronchoalveolar lavage fluid recovered from patients with mild asthma; this suggests a role for this isoform in modulating airway inflammation though the mechanisms by which this occurs is unclear. Airway inflammation associated with Th2 cytokines such as IL-4 and IL-13 is a principal feature of asthma, but whether these cytokines elicit expression of HLA-G is not known. METHODS: We examined gene and protein expression of both soluble (G5) and membrane-bound (G1) HLA-G isoforms in primary differentiated human airway epithelial cells collected from normal lungs and grown in air-liquid interface culture. Cells were treated with up to 10 ng/ml of either IL-4, IL-5, or IL-13, or 100 ng/ml of the immunomodulatory cytokine IL-10, or 10,000 U/ml of the Th1-associated cytokine interferon-beta, for 24 hr, after which RNA was isolated for evaluation by quantitative PCR and protein was collected for Western blot analysis. RESULTS: HLA-G5 but not G1 was present in dAEC as demonstrated by quantitative PCR, western blot and confocal microscopy. Neither G5 nor G1 expression was increased by the Th2-associated cytokines IL-4, IL-5 or IL-13 over 24 hr, nor after treatment with IL-10, but was increased 4.5 ± 1.4 fold after treatment with 10,000 U/ml interferon-beta. CONCLUSIONS: These data demonstrate the constitutive expression of a T lymphocyte regulatory molecule in differentiated human airway epithelial cells that is not modulated by Th2-associated cytokines.

Association of Household Opioid Availability With Opioid Overdose.

Importance: Previous studies that examined the role of household opioid prescriptions in opioid overdose risk were limited to commercial claims, did not include fatal overdoses, and had limited inclusion of household prescription characteristics. Broader research is needed to expand understanding of the risk of overdose. Objective: To assess the role of household opioid availability and other household prescription factors associated with individuals' odds of fatal or nonfatal opioid overdose. Design, Setting, and Participants: A retrospective cohort study assessing patient outcomes from January 1, 2015, through December 31, 2018, was conducted on adults in the Oregon Comprehensive Opioid Risk Registry database in households of at least 2 members. Data analysis was performed between October 16, 2020, and January 26, 2023. Exposures: Household opioid prescription availability and household prescription characteristics. Main Outcomes and Measures: Opioid overdoses were captured from insurance claims, death records, and hospital discharge data. Household opioid prescription availability and prescription characteristics for individuals and households were modeled as 6-month cumulative time-dependent measures, updated monthly. To assess the association between household prescription availability, household prescription characteristics, and overdose, multilevel logistic regression models were developed, adjusting for demographic, clinical, household, and prescription characteristics. Results: The sample included 1 691 856 individuals in 1 187 140 households, of which most were women (53.2%), White race (70.7%), living in metropolitan areas (75.8%), and having commercial insurance (51.8%), no Elixhauser comorbidities (69.5%), and no opioid prescription fills in the study period (57.0%). A total of 28 747 opioid overdose events were observed during the study period (0.0526 per 100 person-months). Relative to individuals without personal or household opioid fills, the odds of opioid-related overdose increased by 60% when another household member had an opioid fill in the past 6 months (adjusted odds ratio [aOR], 1.60; 95% CI, 1.54-1.66) and were highest when both the individual and another household member had opioid fills in the preceding 6 months (aOR, 6.25; 95% CI, 6.09-6.40). Conclusions and Relevance: In this cohort study of adult Oregon residents in households of at least 2 members, the findings suggest that household prescription availability is associated with increased odds of opioid overdose for others in the household, even if they do not have their own opioid prescription. These findings underscore the importance of educating patients about proper opioid disposal and the risks of household opioids.

IFNG genotype and sex interact to influence the risk of childhood asthma.

BACKGROUND: Asthma is a complex disease characterized by sex-specific differences in incidence, prevalence, and severity, but little is known about the molecular basis of these sex-based differences. OBJECTIVE: To investigate the genetic architecture of sex differences in asthma risk, we evaluated (1) associations between polymorphisms in the IFNG gene and childhood-onset asthma in combined and sex-specific samples and (2) interactions between polymorphisms and sex on asthma risk. METHODS: Main and sex-interaction effects of IFNG genetic diversity on asthma risk and IFN-γ levels were examined in a birth cohort of children at high risk for asthma and allergic diseases. Replication of the genetic association was assessed in an independent sample of asthma cases. RESULTS: Significant genotype-sex interactions on asthma were observed for 2 IFNG single nucleotide polymorphisms, rs2069727 and rs2430561, which were in strong linkage disequilibrium with each other. In contrast, none of the 10 IFNG single nucleotide polymorphisms showed significant main effects on asthma. The observed genotype-sex interaction on asthma was characterized by nonadditivity; that is, heterozygous boys had the highest risk for asthma, and heterozygous girls had the lowest risk. The interaction effect was robust to other asthma risk factors but was limited to children who experienced wheezing illnesses with viral infections during the first 3 years of life. Genotype-sex interactions were also observed in the IFN-γ response to LPS in the first year of life. Finally, the sex-interaction effect was replicated in an independent population of childhood asthma cases. CONCLUSIONS: These results provide insight into the genetic basis of sex differences in asthma and highlight the potential importance of interactions among sex, genotype, and environmental factors in asthma pathogenesis.

Accuracy of behavioral health variables in Oregon national violent death reporting system data: a linked cohort study.

BACKGROUND: The National Violent Death Reporting System (NVDRS) collects data on the circumstances of violent deaths, and all firearm-related deaths, across states and territories in the USA. This surveillance system is critical to understanding patterns and risk factors for these fatalities, thereby informing targets for prevention. NVDRS variables include behavioral health conditions among decedents, but the validity of the reported behavioral health data is unknown. Using Department of Veterans Affairs (VA) healthcare records as a criterion standard, we examined the accuracy of NVDRS-reported behavioral health variables for veteran decedents in a sample state (Oregon) between 2003 and 2017. METHODS: We linked Oregon NVDRS data to VA healthcare data to identify veteran decedents who used VA services within two years of death. Veterans' VA diagnoses within this time frame, including depression, post-traumatic stress disorder (PTSD), anxiety, and substance use disorders, were compared to behavioral health variables identified in the Oregon NVDRS. Concordance, sensitivity, and correlates of sensitivity were examined over time and by decedent characteristics. RESULTS: We identified 791 VA-using veterans with violent and/or firearm-related fatal injuries documented in the Oregon NVDRS between 2003 and 2017. In this cohort, the Oregon NVDRS accurately identified only 49% of decedents who were diagnosed with depression, 45% of those diagnosed with PTSD, and 17% of those diagnosed with anxiety by the VA. Among 211 veterans diagnosed by the VA with a substance use disorder, the Oregon NVDRS coded only 56% as having a substance use problem. In general, the sensitivity of behavioral health variables in the Oregon NVDRS remained the same or decreased over the study period; however, the sensitivity of PTSD diagnoses increased from 21% in 2003-2005 to 54% in 2015-2017. Sensitivity varied by some decedent characteristics, but not consistently across behavioral health variables. CONCLUSIONS: NVDRS data from one state missed more than half of behavioral health diagnoses among VA-using veterans who died from violence or from firearm injuries. This suggests that reports of behavioral health conditions among decedents nationally may be severely undercounted. Efforts to improve validity of these variables in state NVDRS data are needed.

Factors Associated With Opioid Overdose After an Initial Opioid Prescription.

Importance: The opioid epidemic continues to be a public health crisis in the US. Objective: To assess the patient factors and early time-varying prescription-related factors associated with opioid-related fatal or nonfatal overdose. Design, Setting, and Participants: This cohort study evaluated opioid-naive adult patients in Oregon using data from the Oregon Comprehensive Opioid Risk Registry, which links all payer claims data to other health data sets in the state of Oregon. The observational, population-based sample filled a first (index) opioid prescription in 2015 and was followed up until December 31, 2018. Data analyses were performed from March 1, 2020, to June 15, 2021. Exposures: Overdose after the index opioid prescription. Main Outcomes and Measures: The outcome was an overdose event. The sample was followed up to identify fatal or nonfatal opioid overdoses. Patient and prescription characteristics were identified. Prescription characteristics in the first 6 months after the index prescription were modeled as cumulative, time-dependent measures that were updated monthly through the sixth month of follow-up. A time-dependent Cox proportional hazards regression model was used to assess patient and prescription characteristics that were associated with an increased risk for overdose events. Results: The cohort comprised 236 921 patients (133 839 women [56.5%]), of whom 667 (0.3%) experienced opioid overdose. Risk of overdose was highest among individuals 75 years or older (adjusted hazard ratio [aHR], 3.22; 95% CI, 1.94-5.36) compared with those aged 35 to 44 years; men (aHR, 1.29; 95% CI, 1.10-1.51); those who were dually eligible for Medicaid and Medicare Advantage (aHR, 4.37; 95% CI, 3.09-6.18), had Medicaid (aHR, 3.77; 95% CI, 2.97-4.80), or had Medicare Advantage (aHR, 2.18; 95% CI, 1.44-3.31) compared with those with commercial insurance; those with comorbid substance use disorder (aHR, 2.74; 95% CI, 2.15-3.50), with depression (aHR, 1.26; 95% CI, 1.03-1.55), or with 1 to 2 comorbidities (aHR, 1.32; 95% CI, 1.08-1.62) or 3 or more comorbidities (aHR, 1.90; 95% CI, 1.42-2.53) compared with none. Patients were at an increased overdose risk if they filled oxycodone (aHR, 1.70; 95% CI, 1.04-2.77) or tramadol (aHR, 2.80; 95% CI, 1.34-5.84) compared with codeine; used benzodiazepines (aHR, 1.06; 95% CI, 1.01-1.11); used concurrent opioids and benzodiazepines (aHR, 2.11; 95% CI, 1.70-2.62); or filled opioids from 3 or more pharmacies over 6 months (aHR, 1.38; 95% CI, 1.09-1.75). Conclusions and Relevance: This cohort study used a comprehensive data set to identify patient and prescription-related risk factors that were associated with opioid overdose. These findings may guide opioid counseling and monitoring, the development of clinical decision-making tools, and opioid prevention and treatment resources for individuals who are at greatest risk for opioid overdose.

An imprinted locus epistatically influences Nstr1 and Nstr2 to control resistance to nerve sheath tumors in a neurofibromatosis type 1 mouse model.

Cancer is a complex disease in which cells acquire many genetic and epigenetic alterations. We have examined how three types of alterations, mutations in tumor suppressor genes, changes in an imprinted locus, and polymorphic loci, interact to affect tumor susceptibility in a mouse model of neurofibromatosis type 1 (NF1). Mutations in tumor suppressor genes such as TP53 and in oncogenes such as KRAS have major effects on tumorigenesis due to the central roles of these genes in cell proliferation and cell survival. Imprinted genes expressed from only one parental chromosome affect tumorigenesis if their monoallelic expression is lost or duplicated. Because imprinted loci are within regions deleted or amplified in cancer, the parental origin of genomic rearrangements could affect tumorigenesis. Gene polymorphisms can vary tumor incidence by affecting rate-limiting steps in tumorigenesis within tumor cells or surrounding stroma. In our mouse model of NF1, the incidence of tumors mutant for the tumor suppressor genes Nf1 and Trp53 is strongly modified by a linked imprinted locus acting epistatically on two unlinked polymorphic loci, Nstr1 and Nstr2. This interaction of an imprinted locus and polymorphic susceptibility loci has profound implications for human mapping studies where the parental contribution of alleles is often unknown.

High prevalence of Lynx rufus gammaherpesvirus 1 in wild Vermont bobcats.

Gammaherpesviruses (GHVs) are host specific DNA viruses that infect a large range of mammalian species. These viruses preferentially target host lymphocyte cell populations and infection may lead to morbidity or mortality in immunocompromised, co-infected, or non-adapted hosts. In this study, we tested for the presence of Lynx rufus gammaherpesvirus 1 (LruGHV1) in a northeastern United States population of wild bobcats (L. rufus). We estimated prevalence of infection and viral load in infected individuals using quantitative real-time PCR analysis of spleen DNA from 64 Vermont bobcats. We observed an overall prevalence of 64% using this methodology. Bobcat age was significantly positively associated with GHV infection status, and we noted a trend for higher viral loads in young animals, but prevalence and viral load were similar in male and female bobcats. A single LruGHV1 variant was identified from the sequencing of the viral glycoprotein B gene of Vermont bobcats. This gene sequence was 100% similar to that reported in Florida bobcats and slightly variant from other isolates identified in the Western USA. Our work suggests broad geographic distribution and high prevalence of LruGHV1 in bobcat populations across the United States with infection attributes that suggest horizontal transmission of the agent. Geographic differences in viral genotype may reflect historical migration and expansion events among bobcat populations.

Use of prescription opioids before and after an operation for chronic pain (lumbar fusion surgery).

Lumbar fusion surgery is usually prompted by chronic back pain, and many patients receive long-term preoperative opioid analgesics. Many expect surgery to eliminate the need for opioids. We sought to determine what fraction of long-term preoperative opioid users discontinue or reduce dosage postoperatively; what fraction of patients with little preoperative use initiate long-term use; and what predicts long-term postoperative use. This retrospective cohort study included 2491 adults undergoing lumbar fusion surgery for degenerative conditions, using Oregon's prescription drug monitoring program to quantify opioid use before and after hospitalization. We defined long-term postoperative use as ≥4 prescriptions filled in the 7 months after hospitalization, with at least 3 occurring >30 days after hospitalization. Overall, 1045 patients received long-term opioids preoperatively, and 1094 postoperatively. Among long-term preoperative users, 77.1% continued long-term postoperative use, and 13.8% had episodic use. Only 9.1% discontinued or had short-term postoperative use. Among preoperative users, 34.4% received a lower dose postoperatively, but 44.8% received a higher long-term dose. Among patients with no preoperative opioids, 12.8% became long-term users. In multivariable models, the strongest predictor of long-term postoperative use was cumulative preoperative opioid dose (odds ratio of 15.47 [95% confidence interval 8.53-28.06] in the highest quartile). Cumulative dose and number of opioid prescribers in the 30-day postoperative period were also associated with long-term use. Thus, lumbar fusion surgery infrequently eliminated long-term opioid use. Opioid-naive patients had a substantial risk of initiating long-term use. Patients should have realistic expectations regarding opioid use after lumbar fusion surgery.

Association of Prescription Drug Monitoring Program Use With Opioid Prescribing and Health Outcomes: A Comparison of Program Users and Nonusers.

Prescription drug monitoring programs (PDMPs) are a response to the prescription opioid epidemic, but their effects on prescribing and health outcomes remain unclear, with conflicting reports. We sought to determine if prescriber use of Oregon's PDMP led to fewer high-risk opioid prescriptions or overdose events. We conducted a retrospective cohort study from October 2011 through October 2014, using statewide PDMP data, hospitalization registry, and vital records. Early PDMP registrants (n = 927) were matched with clinicians who never registered during the study period, using baseline prescribing metrics in a propensity score. Generalized estimating equations were used to examine prescribing trends after PDMP registration, using 2-month intervals. We found a statewide decline in measures of per capita opioid prescribing. However, compared with nonregistrants, PDMP registrants did not subsequently have significantly fewer patients receiving high-dose prescriptions, overlapping opioid and benzodiazepine prescriptions, inappropriate prescriptions, prescriptions from multiple prescribers, or overdose events. At baseline, frequent PDMP users wrote fewer high-risk opioid prescriptions than infrequent users; this persisted during follow-up with few significant group differences in trend. Thus, although opioid prescribing declined statewide after implementing the PDMP, registrants did not show greater declines than nonregistrants. PERSPECTIVE: Factors other than PDMP use may have had greater influence on prescribing trends. Refinements in the PDMP program and related policies may be necessary to increase PDMP effects.

Positive selection on MMP3 regulation has shaped heart disease risk.

BACKGROUND: The evolutionary forces of mutation, natural selection, and genetic drift shape the pattern of phenotypic variation in nature, but the roles of these forces in defining the distributions of particular traits have been hard to disentangle. To better understand the mechanisms contributing to common variation in humans, we investigated the evolutionary history of a functional polymorphism in the upstream regulatory region of the MMP3 gene. This single base pair insertion/deletion variant, which results in a run of either 5 or 6 thymidines 1608 bp from the transcription start site, alters transcription factor binding and influences levels of MMP3 mRNA and protein. The polymorphism contributes to variation in arterial traits and to the risk of coronary heart disease and its progression. RESULTS: Phylogenetic and population genetic analysis of primate sequences indicate that the binding site region is rapidly evolving and has been a hot spot for mutation for tens of millions of years. We also find evidence for the action of positive selection, beginning approximately 24,000 years ago, increasing the frequency of the high-expression allele in Europe but not elsewhere. Positive selection is evident in statistical tests of differentiation among populations and haplotype diversity within populations. Europeans have greater arterial elasticity and suffer dramatically fewer coronary heart disease events than they would have had this selection not occurred. CONCLUSIONS: Locally elevated mutation rates and strong positive selection on a cis-regulatory variant have shaped contemporary phenotypic variation and public health.