Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection.

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10-14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.

"It's important to foster open discussion about the topic": development, implementation, and evaluation of an ethics of abortion independent learning module for second year medical students.

PURPOSE: Despite the frequency of abortions, one-third of medical schools in the US and Canada did not include coverage of that topic, according to a survey conducted in 2002-2005. The purpose of this project was to develop, implement, and evaluate a module for second year medical students related to the ethics of abortion. METHODS: The module was designed as Independent Learning Time (ILT). The stated purpose was for students to consider some of the recent debate in the ethics literature related to conscientious objection and abortion and how personal views may influence future practice. The ILT included readings and Power Points to view. Students were asked to write a one-page reflection on one of three writing prompts. RESULTS: The most commonly selected writing prompt in three classes was on personal values in relation to abortion (56.5%), followed by information about nearest provider of reproductive services to rural preceptor site (34.7%), followed by conscientious objection (23.3%). We received many positive comments about the ILT, including: "First, I would like to acknowledge my gratitude for this assignment and its subject. I believe it is very important that future physicians learn the entirety of women's reproductive health care, including abortion and contraception, but unfortunately this is not always the case in medical training". CONCLUSIONS: There has been an extremely positive response to the ILT. With the exception of the prompt specific to our regional campus mission that includes rural preceptorships during the preclinical years, this module could be implementable at other medical schools.

Trends in Maternal Weight Disparities: Statewide Differences in Rural and Urban Minnesota Residents From 2012 to 2019.

INTRODUCTION: Despite research showing substantial weight disparities along the rural-urban continuum, little work has attempted to identify differences in prepregnancy weight status or gestational weight gain (GWG) outcomes between rural and urban birthing people. As such, the goals of this research were to 1) document the prevalence of prepregnancy overweight and obesity and excessive GWG in rural and urban birthing people and 2) examine changes in rural and urban prepregnancy overweight or obesity and excessive GWG over time. METHODS: Birth certificate data provided sociodemographic variables, prepregnancy body mass index, GWG, and rurality status on 465,709 respondents who gave birth in Minnesota from 2012 to 2019. A series of regression models estimated risk differences in 1) prepregnancy weight status and 2) excessive GWG between rural and urban respondents over time, controlling for relevant covariates. RESULTS: Rural individuals had a 4.9 percentage-point (95% confidence interval, 4.5-5.3) higher risk of having prepregnancy overweight or obesity compared with urban individuals, and a 2.6 percentage-point (95% confidence interval, 1.9-3.3) higher risk of gaining excessive gestational weight. The disparities in prepregnancy overweight or obesity and excessive gestational weight between rural and urban individuals widened over time. CONCLUSIONS: These findings contribute to accumulating evidence documenting notable health disparities between rural and urban individuals during the perinatal period and support the need to develop prevention and treatment efforts focused on improving the weight-related health of individuals living in rural communities.

Public Attitudes toward Pharmacogenomic Testing and Establishing a Statewide Pharmacogenomics Database in the State of Minnesota.

The clinical adoption and implementation of pharmacogenomics (PGx) beyond academic medical centers remains slow, restricting the general population from benefitting from this important component of personalized medicine. As an initial step in the statewide initiative of PGx implementation in Minnesota, we engaged community members and assessed attitudes towards PGx testing and acceptability of establishing a secure statewide PGx database for clinical and research use among Minnesota residents. Data was collected from 808 adult attendees at the 2021 Minnesota State Fair through an electronic survey. Eighty-four percent of respondents felt comfortable getting a PGx test for clinical care. Most respondents trusted health professionals (78.2%) and researchers (73.0%) to keep their PGx data private. The majority expressed their support and interest in participating in a statewide PGx database for clinical and research use (64-72%). Higher acceptability of the statewide PGx database was associated with younger age, higher education, higher health literacy, having health insurance, and prior genetic testing. The study sample representing Minnesota residents expressed high acceptability of receiving PGx testing and willingness to participate in PGx data sharing for clinical and research use. Community support and engagement are needed to advance PGx implementation and research on the state scale.

Development and Validation of the Minnesota Assessment of Pharmacogenomic Literacy (MAPL).

Ensuring that patients have an adequate understanding of pharmacogenomic (PGx) test results is a critical component of implementing precision medicine into clinical care. However, no PGx-specific validated literacy assessment has yet been developed. To address this need, we developed and validated the Minnesota Assessment of Pharmacogenomic Literacy (MAPLTM). Foundational work included a scoping review of patient and general public attitudes and experiences with pharmacogenomic testing, three focus groups, readability assessments, and review by experts and members of the general public. This resulted in a 15-item assessment designed to assess knowledge in four domains: underlying concepts, limitations, benefits, and privacy. For validation, 646 participants completed the MAPL as a part of a larger survey about pharmacogenomic research and statewide PGx implementation. Two items were deemed to be "too easy" and dropped. The remaining 13 items were retained in the final MAPL with good internal reliability (Cronbach's alpha = 0.75). Confirmatory factor analysis validated the four-domain construct of MAPL and suggested good model performance and high internal validity. The estimated coefficient loadings across 13 questions on the corresponding domains are all positive and statistically significant (p < 0.05). The MAPL covers multiple knowledge domains of specific relevance to PGx and is a useful tool for clinical and research settings where quantitative assessment of PGx literacy is of value.

Epidemiology of traumatic brain injuries at a rural-serving Level II trauma center, 2004 - 2016.

OBJECTIVE: To describe the epidemiology of traumatic brain injury (TBI) and quantify rural and urban differences. METHODS: Patient characteristics, injury characteristics, imaging, and outcomes were extracted from the trauma registry of the level II trauma center at Essentia Health-St. Mary's Medical Center, Duluth, MN, for patients admitted for a TBI from January 1, 2004, through December 31, 2016. Estimated relative risk (RR) per year, Wald 95% confidence intervals, and p-values were calculated. RESULTS: Of the 5,079 TBI admissions during the study period, just under half (2,510, 49.4%) resided in rural areas at the time of admission. Overall, there was a 3.8% unadjusted annual increase in TBI risk rom 2004-2016, with 2.9% and 4.7% annual increases among rural and urban U.S. residents, respectively. Rural residents had significant annual increases in risk of TBI admission resulting in 30-day post-discharge emergency department readmission and 30-day post-discharge combined inpatient/emergency department readmission of 35.2% and 22.4%, respectively. CONCLUSIONS: We found that risk of rural resident TBI admission due to MVC was significantly greater than that for urban residents. Public health and medical interventions to decrease the rural/urban disparity are warranted, including public health campaigns to increase seat belt use, and supportive care post-discharge into rural communities.

Development, Implementation, and Evaluation of an Early Mobility Protocol in a Regional Level II Trauma Center.

The purpose of this project was to develop and evaluate a collaborative nursing/therapist protocol for early mobility in a medical-surgical intensive care unit (MICU) in a regional level II trauma center. Data for patients in the MICU were compared for the periods August 3, 2015-August 2, 2016, and August 3, 2014-August 2, 2015. Semistructured interviews were conducted with 10 nurses and 1 therapist. Average MICU length of stay decreased from 3.81 to 3.50 days (P = .057). Mean time in mobility chairs did not change (0.12 days vs 0.11 days, P = .389). Mean number of days to first documented level 2-5 activity decreased significantly, from 1.81 to 1.51 days (P = .036). The percentage of hospitalizations with any documented level 3 or 4 activity increased significantly (from 3.8% to 7.4% and from 61.5% to 66.7%, P = .003 and P = .031, respectively). Barriers/challenges to implementation included having enough people to assist, space, documentation, having to coax the physician to place order for upright mobility, availability of therapists for later stages of protocol, patient variability, fear of patient falls, availability of therapy chairs, staff changes, time, and patient refusal. A multidisciplinary approach to protocol development for early mobility in an intensive care unit was successfully implemented at a regional level II trauma center.

Associations between CES1 variants and dosing and adverse effects in children taking methylphenidate.

Background: Methylphenidate is the most prescribed stimulant to treat attention deficit-hyperactivity disorder (ADHD). Despite its widespread usage, a fair proportion of children are classified as non-responders to the medication. Variability in response and occurrence of adverse events with methylphenidate use may be due to several factors, including drug-drug interactions as well as pharmacogenetic differences resulting in pharmacokinetic and/or pharmacodynamic variances within the general population. The objective of this study was to analyze the effect of carboxylesterase 1 (CES1) variants on the frequency of adverse effects and dosing requirements of methylphenidate in children with ADHD. Methods: This was a retrospective cohort study of children and adolescents who met the inclusion criteria and had a routine visit during the enrollment period were invited to participate. Inclusion criteria included: ADHD diagnosis by a healthcare provider, between 6 and 16 years of age at the time of permission/assent, had not previously been prescribed methylphenidate, and treatment with any methylphenidate formulation for at least three consecutive months. Three months of records were reviewed in order to assess changes in dose and frequency of discontinuing methylphenidate. Participants' ADHD symptoms, medication response, adverse effects, select vitals, and dose were extracted from the electronic health record. Saliva samples were collected by trained study coordinators. Haplotypes were assigned based on copy number in different portions of the CES1 gene. Due to limited numbers, diplotypes (combinations of two haplotypes) were grouped for analysis as CES1A1/CES1A1, CES1A1/CES1A1c and CES1A1c/CES1A1c. Results: A total of 99 participants (n = 30 female; n = 69 male) had both clinical data and CES1 sequencing data, with an average age of 7.7 years old (range 3-15 years). The final weight-based dose in all individuals was 0.79 mg/kg/day. The most common adverse effects reported were decreased appetite (n = 47), weight loss (n = 24), and sleep problems (n = 19). The mean final weight-based dose by haplotype was 0.92 mg/kg for CES1A2/CES1A2, 0.81 mg/kg for CES1A2/CES1P1, and 0.78 mg/kg for CES1P1/CES1P1. After correction for multiple hypothesis testing, only one SNV, rs114119971, was significantly associated with weight-based dosing in two individuals. The individuals with the rs114119971 SNV had a significantly lower weight-based dose (0.42 mg/kg) as compared to those without (0.88 mg/kg; p < 0.001). Discussion: Variation in CES1 activity may impact dose requirements in children who are prescribed methylphenidate, as well as other CES1 substrates. Although intriguing, this study is limited by the retrospective nature and relatively small sample size.

Pharmacogenomics education, research and clinical implementation in the state of Minnesota.

Several healthcare organizations across Minnesota have developed formal pharmacogenomic (PGx) clinical programs to increase drug safety and effectiveness. Healthcare professional and student education is strong and there are multiple opportunities in the state for learners to gain workforce skills and develop advanced competency in PGx. Implementation planning is occurring at several organizations and others have incorporated structured utilization of PGx into routine workflows. Laboratory-based and translational PGx research in Minnesota has driven important discoveries in several therapeutic areas. This article reviews the state of PGx activities in Minnesota including educational programs, research, national consortia involvement, technology, clinical implementation and utilization and reimbursement, and outlines the challenges and opportunities in equitable implementation of these advances.

Using the PhenX Toolkit to Select Standard Measurement Protocols for Your Research Study.

The goals of PhenX (consensus measures for Phenotypes and eXposures) are to promote the use of standard measurement protocols and to help investigators identify opportunities for collaborative research and cross-study analysis, thus increasing the impact of individual studies. The PhenX Toolkit (https://www.phenxtoolkit.org/) offers high-quality, well-established measurement protocols to assess phenotypes and exposures in studies with human participants. The Toolkit contains protocols representing 29 research domains and 6 specialty collections of protocols that add depth to the Toolkit in specific research areas (e.g., COVID-19, Social Determinants of Health [SDoH], Blood Sciences Research [BSR], Mental Health Research [MHR], Tobacco Regulatory Research [TRR], and Substance Abuse and Addiction [SAA]). Protocols are recommended for inclusion in the PhenX Toolkit by Working Groups of domain experts using a consensus process that includes input from the scientific community. For each PhenX protocol, the Toolkit provides a detailed description, the rationale for inclusion, and supporting documentation. Users can browse protocols in the Toolkit, search the Toolkit using keywords, or use Browse Protocols Tree to identify protocols of interest. The PhenX Toolkit provides data dictionaries compatible with the database of Genotypes and Phenotypes (dbGaP), Research Electronic Data Capture (REDCap) data submission compatibility, and data collection worksheets to help investigators incorporate PhenX protocols into their study design. The PhenX Toolkit provides resources to help users identify published studies that used PhenX protocols. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Using the PhenX Toolkit to support or extend study design.

A Trans-Ethnic Genome-Wide Association Study of Uterine Fibroids.

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.

Implementation, adoption, and utility of family health history risk assessment in diverse care settings: evaluating implementation processes and impact with an implementation framework.

PURPOSE: This paper describes the implementation outcomes associated with integrating a family health history-based risk assessment and clinical decision support platform within primary care clinics at four diverse healthcare systems. METHODS: A type III hybrid implementation-effectiveness trial. Uptake and implementation processes were evaluated using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. RESULTS: One hundred (58%) primary care providers and 2514 (7.8%) adult patients enrolled. Enrolled patients were 69% female, 22% minority, and 32% Medicare/Medicaid. Compared with their respective clinic's population, patient-participants were more likely to be female (69 vs. 59%), older (mean age 57 vs. 49), and Caucasian (88 vs. 69%) (all p values <0.001). Female (81.3% of females vs. 78.5% of males, p value = 0.018) and Caucasian (Caucasians 90.4% vs. minority 84.1%, p value = 0.02) patient-participants were more likely to complete the study once enrolled. Patient-participant survey responses indicated MeTree was easy to use (95%), and patient-participants would recommend it to family/friends (91%). Minorities and those with less education reported greatest benefit. Enrolled providers reflected demographics of underlying provider population. CONCLUSION: Family health history-based risk assessment can be effectively implemented in diverse primary care settings and can effectively engage patients and providers. Future research should focus on finding better ways to engage young adults, males, and minorities in preventive healthcare.

Evaluation of a protocol for early detection of delayed brain hemorrhage in head injured patients on warfarin.

PURPOSE: In 2007, Essentia Health St. Mary's Medical Center (SMMC), a Level II trauma center in northeastern Minnesota, implemented a protocol for patients who presented with blunt head trauma and were receiving warfarin for anticoagulation. The purpose of this study was to determine the incidence and risk factors of early delayed, warfarin-associated intracranial hemorrhage (ICH). METHODS: Adult patients with signs and symptoms of head injury on warfarin who were admitted by protocol to SMMC between March 2007 and June 2015 were included. Patients were observed for neurologic change and received a follow-up head CT scan within 24 h after an initial negative scan. RESULTS: Among the 232 episodes of care studied, there were 204 patients. The average age was 71; 51% of patients were female. Most patients presented with Glasgow Coma Scale score of 15 and had signs of head trauma. The majority of patients (63%) had a therapeutic International Normalized Ratio (INR) for their indicated condition, but 19% of patients had a supratherapeutic INR and 19% had a subtherapeutic INR. The incidence of early delayed ICH was 1.7%; none of these cases required operative intervention or were fatal. CONCLUSIONS: For patients who were anticoagulated with warfarin and had sustained minor traumatic brain injury, implementation of our protocol showed low incidence of early delayed ICH in the first 24 h. We believe withholding warfarin for several days and careful follow-up regarding its resumption is warranted, especially in the setting of supratherapeutic INR.

Consanguinity and its association with visual impairment in southern India: the Pavagada Pediatric Eye Disease Study 2.

To determine the association of consanguinity with the occurrence of genetically transmitted eye diseases in rural and urban populations in Pavagada and Madhugiri taluks, Karnataka state, south India. This study was part of a population based cross-sectional prevalence survey, "The Pavagada pediatric eye disease study 2." As a part of the demographic data, trained investigators collected information on consanguinity from the parents of children identified for the study. The children underwent visual acuity measurements and were examined by an ophthalmologist. Children with minor eye diseases were treated and those with major eye diseases were seen by a pediatric ophthalmologist. Eight thousand five hundred and fifty-three children were examined. The prevalence of ocular morbidity was 6.54% and blindness was 0.09%. The percentage of consanguineously married couples in the screened population was 34.33%. Among the blind children, 75% were blind with a disease with potential genetic etiology. Out of that, 66.67% were born out of consanguineous marriage (uncle-niece). Among children with diseases with a potential genetic etiology 54.29% of the children were born out of consanguineous union. Most of these children (71.43%) were born out of uncle-niece marriages. Further analysis showed that consanguineous parents were more likely to have children with disease with a potential genetic etiology as compared to nonconsanguineous parents (odds ratio: 2.551, p = 0.012). It is evident that consanguineous marriages, especially uncle-niece unions are common in the study area. Consanguinity is more likely to result in children with eye diseases with potential genetic etiology.

Ethics Committees: Team Perspectives and Organizational Responses.

Healthcare ethics committees can be valuable resources but are largely underutilized by nurses. The purpose of this project was to review ethics concerns and educational needs of nurses in a large, integrated healthcare delivery system. Seven themes were identified: organizational issues, nonbeneficial care, withdrawing life-sustaining therapies, discharge disposition, challenging patients and families, communication with physicians, and capacity versus competence. A process was then developed to better engage nurses in ethical discussions.

Enrichment sampling for a multi-site patient survey using electronic health records and census data.

Objective: We describe a stratified sampling design that combines electronic health records (EHRs) and United States Census (USC) data to construct the sampling frame and an algorithm to enrich the sample with individuals belonging to rarer strata. Materials and Methods: This design was developed for a multi-site survey that sought to examine patient concerns about and barriers to participating in research studies, especially among under-studied populations (eg, minorities, low educational attainment). We defined sampling strata by cross-tabulating several socio-demographic variables obtained from EHR and augmented with census-block-level USC data. We oversampled rarer and historically underrepresented subpopulations. Results: The sampling strategy, which included USC-supplemented EHR data, led to a far more diverse sample than would have been expected under random sampling (eg, 3-, 8-, 7-, and 12-fold increase in African Americans, Asians, Hispanics and those with less than a high school degree, respectively). We observed that our EHR data tended to misclassify minority races more often than majority races, and that non-majority races, Latino ethnicity, younger adult age, lower education, and urban/suburban living were each associated with lower response rates to the mailed surveys. Discussion: We observed substantial enrichment from rarer subpopulations. The magnitude of the enrichment depends on the accuracy of the variables that define the sampling strata and the overall response rate. Conclusion: EHR and USC data may be used to define sampling strata that in turn may be used to enrich the final study sample. This design may be of particular interest for studies of rarer and understudied populations.