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.

The PhenX Toolkit: standard measurement resources for cancer outcomes and survivorship research.

This brief report introduces the Cancer Outcomes and Survivorship domain in the PhenX Toolkit (consensus measures for Phenotypes and eXposures), which includes 15 validated measurement protocols for cancer survivorship research that were recommended for inclusion in this publicly available resource. Developed with input from the scientific community, the domain provides researchers with well-established measurement protocols for evaluating physical and psychological effects, financial toxicity, and patient experiences with cancer care. The PhenX Toolkit, funded by the National Human Genome Research Institute since 2007, is an online resource that provides high-quality standard measurement protocols for a wide range of research areas (eg, smoking cessation, harm reduction and biomarkers, and social determinants of health). Use of the PhenX Cancer Survivorship Outcomes and Survivorship domain can simplify the selection of measurement protocols, data sharing, and comparisons across studies investigating the cancer survivorship experience.

Rural health disparities in health care utilization for dementia in Minnesota.

PURPOSE: We visualized rural-urban differences in inpatient hospitalization and emergency department (ED) health care utilization (HCU) for older adults with dementia to understand the HCU of rural versus urban older adults in Minnesota and to examine in greater detail the variability of HCU in rural areas. METHODS: For 3 older adult age groups, we utilized Healthcare Cost and Utilization Project (H-CUP) datasets from 2016 to 2018 to profile hospital admission rates, and ED visit rates related to dementia stratified by rurality and regions. Rates were visualized by spatial interpolation method. We then used logistic regression analysis adjusted by multiple covariates to evaluate rural-urban differences of the chance of having a dementia diagnosis in HCU. FINDINGS: Minnesota rural areas showed 17.6% lower age-adjusted rate (AAR) of dementia mortality than urban areas. AARs of ED visits for dementia were 12.4% higher in rural ZIP codes, whereas AARs of hospitalization were 24.7% lower. After controlling for neighborhood-level risk factors, such as income, education, health behaviors, and provider access, the odds ratios of having dementia diagnosis are 12% lower if an ED visit patient lives in rural as opposed to an urban area (OR = 0.88, P<.0001). CONCLUSIONS: In comparison to AAR, the fully adjusted data showed larger rural-urban predictors of having dementia diagnoses in hospitalizations and ED utilizations and demonstrated differences between AAR of ED visit and odds ratios of having dementia diagnosis. A regional comparison revealed that dementia ED visits were higher for Northeast MN compared to Minnesota's largest metropolitan region.

Implementation-effectiveness trial of systematic family health history based risk assessment and impact on clinical disease prevention and surveillance activities.

BACKGROUND: Systematically assessing disease risk can improve population health by identifying those eligible for enhanced prevention/screening strategies. This study aims to determine the clinical impact of a systematic risk assessment in diverse primary care populations. METHODS: Hybrid implementation-effectiveness trial of a family health history-based health risk assessment (HRA) tied to risk-based guideline recommendations enrolling from 2014-2017 with 12 months of post-intervention survey data and 24 months of electronic medical record (EMR) data capture. SETTING: 19 primary care clinics at four geographically and culturally diverse U.S. healthcare systems. PARTICIPANTS: any English or Spanish-speaking adult with an upcoming appointment at an enrolling clinic. METHODS: A personal and family health history based HRA with integrated guideline-based clinical decision support (CDS) was completed by each participant prior to their appointment. Risk reports were provided to patients and providers to discuss at their clinical encounter. OUTCOMES: provider and patient discussion and provider uptake (i.e. ordering) and patient uptake (i.e. recommendation completion) of CDS recommendations. MEASURES: patient and provider surveys and EMR data. RESULTS: One thousand eight hundred twenty nine participants (mean age 56.2 [SD13.9], 69.6% female) completed the HRA and had EMR data available for analysis. 762 (41.6%) received a recommendation (29.7% for genetic counseling (GC); 15.2% for enhanced breast/colon cancer screening). Those with recommendations frequently discussed disease risk with their provider (8.7%-38.2% varied by recommendation, p-values ≤ 0.004). In the GC subgroup, provider discussions increased referrals to counseling (44.4% with vs. 5.9% without, P < 0.001). Recommendation uptake was highest for colon cancer screening (provider = 67.9%; patient = 86.8%) and lowest for breast cancer chemoprevention (0%). CONCLUSIONS: Systematic health risk assessment revealed that almost half the population were at increased disease risk based on guidelines. Risk identification resulted in shared discussions between participants and providers but variable clinical action uptake depending upon the recommendation. Understanding the barriers and facilitators to uptake by both patients and providers will be essential for optimizing HRA tools and achieving their promise of improving population health. TRIAL REGISTRATION: Clinicaltrials.gov number NCT01956773 , registered 10/8/2013.

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.

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.

Family satisfaction in a neuro trauma ICU.

OBJECTIVE: The purpose of this quality improvement initiative was to evaluate satisfaction of family members of patients in a neuro trauma ICU (NTICU). METHODS: Adult patients (age 18+) admitted to the NTICU for at least 24 hours between June 2017 and November 2018 were identified. Near or at the time of discharge from the NTICU, the health unit coordinator or registered nurse identified the family member who was either the next-of-kin, surrogate decision-maker, or person who had been most frequently present at the patient's bedside. This person was provided a packet containing a letter of consent and the Critical Care Family Satisfaction Survey (CCFSS). RESULTS: Surveys were completed by 78 family members, the majority of whom were the wife of the patient (n = 35, 44%), 60 years and older (n = 48, 60.8%). Fifty-seven percent of patients (n = 45) were in the ICU less than 3 days and 59% (n = 47) of medical events were injury-related. Total CCFSS scores ranged from 69 to 100 (median 95). The item with the largest number of dissatisfied responses was "Noise level in the critical care unit" (n = 4, 5.3% not satisfied). Open-ended question comments were primarily positive (n = 60, 66%), with 32% (n = 29) representing areas for improvement. CONCLUSIONS: Results of this satisfaction survey have been disseminated to leadership and have been taken into consideration in the planning of a new hospital building currently being built, including ICU patient rooms that allow for more privacy and reduced noise, and more comfortable family rooms. RELEVANCE TO CLINICAL PRACTICE: Family members are a very useful source of feedback for ICU care. Several concerns identified by family members in this study are likely to be relevant to other sites. These included: communication between health care providers and family about patient status, noise in the ICU, peaceful waiting areas for family, and slow transfers.

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.

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.

At the intersection of precision medicine and population health: an implementation-effectiveness study of family health history based systematic risk assessment in primary care.

BACKGROUND: Risk assessment is a precision medicine technique that can be used to enhance population health when applied to prevention. Several barriers limit the uptake of risk assessment in health care systems; and little is known about the potential impact that adoption of systematic risk assessment for screening and prevention in the primary care population might have. Here we present results of a first of its kind multi-institutional study of a precision medicine tool for systematic risk assessment. METHODS: We undertook an implementation-effectiveness trial of systematic risk assessment of primary care patients in 19 primary care clinics at four geographically and culturally diverse healthcare systems. All adult English or Spanish speaking patients were invited to enter personal and family health history data into MeTree, a patient-facing family health history driven risk assessment program, for 27 medical conditions. Risk assessment recommendations followed evidence-based guidelines for identifying and managing those at increased disease risk. RESULTS: One thousand eight hundred eighty-nine participants completed MeTree, entering information on N = 25,967 individuals. Mean relatives entered = 13.7 (SD 7.9), range 7-74. N = 1443 (76.4%) participants received increased risk recommendations: 597 (31.6%) for monogenic hereditary conditions, 508 (26.9%) for familial-level risk, and 1056 (56.1%) for risk of a common chronic disease. There were 6617 recommendations given across the 1443 participants. In multivariate analysis, only the total number of relatives entered was significantly associated with receiving a recommendation. CONCLUSIONS: A significant percentage of the general primary care population meet criteria for more intensive risk management. In particular 46% for monogenic hereditary and familial level disease risk. Adopting strategies to facilitate systematic risk assessment in primary care could have a significant impact on populations within the U.S. and even beyond. TRIAL REGISTRATION: Clinicaltrials.gov number NCT01956773 , registered 10/8/2013.

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.