Academic clinician frontline-worker wellbeing and resilience during the COVID-19 pandemic experience: Were there gender differences?

Prior research suggests COVID-19 has amplified stress on Academic Clinician Frontline-Workers (ACFW). The aim of this paper is: (1) to better understand the experiences of ACFW during the COVID-19 pandemic including their mental-emotional wellbeing, academic productivity, clinical experiences, and (2) to examine any gender differences. A cross-sectional survey was administered to University of Minnesota/M Health Fairview systems' faculty February-June 2021. Of the 291 respondents, 156 were clinicians, with 91 (58 %) identifying as Frontline-Workers (ACFW). Faculty wellbeing was assessed using validated measures in addition to measures of productivity and sociodemographics. For example, ACFW reported a higher Work-Family Conflict (WFC) scores compared to non-ACFW (26.5 vs. 24.1, p = 0.057) but did not report higher Family-Work Conflict (FWC) scores (17.7 vs. 16.3, p = 0.302). Gender sub-analyses, revealed that women ACFW compared to men ACFW reported higher WFC scores (27.7 vs. 24.1, p = 0.021) and FWC (19.3 vs. 14.3, p = 0.004). Academically, ACFW reported submitting fewer grants and anticipated delays in promotion and tenure due to the COVID-19 (p = 0.035). Results suggest COVID-19 has exacerbated ACFW stress and gender inequities. Reports of anticipated delay in promotion for ACFW may pose a challenge for the long-term academic success of ACFW, especially women ACFW. In addition, women may experience higher FWC and WFC as compared to men. Schools of academic medicine should consider re-evaluating promotion/tenure processes and creating resources to support women ACFW as well as ACFW caregivers.

Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Effect of hoof orientation and ballast on acceleration and vibration in the hoof and distal forelimb following simulated impacts ex vivo.

REASONS FOR PERFORMING STUDY: We wished to add to the existing baseline data on impact loading of the distal limb as a precursor to assessing the potential role of impact in injury and joint disease. OBJECTIVES: To examine the effect of 3 hoof-strike conditions (toe first, flat and heel first) and 2 specimen masses (with and without a ballast of ∼2% body mass) on impact deceleration and vibration frequencies and energies at the hoof, first phalanx and third metacarpal. STUDY DESIGN: Biomechanical experiments in cadaver material. METHODS: Eight cadaver limbs were subjected to randomised, repeated controlled trials, in which the hoof was struck by a pendulum impact-testing machine (impact velocity, 3.55 m/s) in the 3 strike and 2 mass conditions. Data from triaxial accelerometers on the hoof, first phalanx and third metacarpal quantified, for all trials, the peak impact acceleration, frequencies in the first 6.4 ms following impact, the frequency with the most energy, 95% of the total energy and the frequency at 95% cumulative energy. The effects of the strike and mass conditions on each variable were statistically tested using repeated-measures ANOVA (α = 0.05). RESULTS: Signal energy reaching the third metacarpal was 6-31% of that at the hoof. A heel-first strike produced the largest peak accelerations and highest frequencies among all strike conditions, and changing the mass had no effect regardless of strike condition. CONCLUSIONS: Large accelerations that occur upon impact of the hoof with the ground are attenuated by the distal structures of the equine limb, but still carry considerable energy within the signal that could be damaging to tissue and are dependent on hoof-strike condition but not ballast. Our results suggest that impact loading on the hoof could be a factor in contributing to bone injury and joint disease in the distal limb.

Effect of hoof angle on joint contact area in the equine metacarpophalangeal joint following simulated impact loading ex vivo.

REASONS FOR PERFORMING STUDY: To add to the existing data on impact loading of the metacarpophalangeal (MCP) joint as a precursor to assessing the potential role of impact in joint disease. OBJECTIVES: To examine the effect of impact loading on contact areas of the first phalanx (P1) and proximal sesamoids (PS) with the third metacarpal (McIII) under 3 hoof-strike conditions (toe-first, flat, heel-first). STUDY DESIGN: Randomised, repeated controlled experiment using cadaver material. METHODS: Eight cadaver limbs were subjected to randomised, repeated controlled trials where the hoof was struck by a pendulum impact machine (impact velocity 3.55 m/s) under 3 strike conditions. Data from pressure sensitive film placed over medial and lateral McIII condyles and lateromedially across the dorsal aspect of McIII were quantified: total areas of P1 and PS contact (cm(2) ) at maximum recorded pressure; centroid locations of contact areas relative to the sagittal ridge (cm) and transverse ridge (cm) and dispersion of pixels (cm(4) ) for each McIII condyle (medial/lateral). The effect of the strike conditions on each variable were statistically tested using repeated-measures ANOVA (α = 0.05). RESULTS: Contact area between P1 and McIII condyles fell in well-defined areas bounded by the sagittal and transverse ridge, contact areas from PS were smaller and widely dispersed across McIII palmar border. Ratio of contact area of P1 to PS was 2.83 (P<0001). Hoof strike had no significant effect on contact area (P>0.54) CONCLUSIONS: Contact at impact (primarily from P1 and distally situated on McIII), contrasts with contact areas at midstance from both P1 and PS, symmetrically placed. Under impact, the greatest contact area was on the dorsal aspect of the medial condyle and coincides with the area subjected to the greatest increase in subchondral bone stiffening in joint disease.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems.

We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Characterization of statin dose response in electronic medical records.

Efforts to define the genetic architecture underlying variable statin response have met with limited success, possibly because previous studies were limited to effect based on a single dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 preselected variants. Two large biobanks were used to construct dose-response curves for 2,026 and 2,252 subjects on simvastatin and atorvastatin, respectively. Atorvastatin was more efficacious, was more potent, and demonstrated less interindividual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in subjects homozygous for the minor allele vs. 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand the genetic factors contributing to drug response.

The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T → C, rs2252281) and MATE2 (g.-130G → A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

Coronary risk assessment among intermediate risk patients using a clinical and biomarker based algorithm developed and validated in two population cohorts.

BACKGROUND: Many coronary heart disease (CHD) events occur in individuals classified as intermediate risk by commonly used assessment tools. Over half the individuals presenting with a severe cardiac event, such as myocardial infarction (MI), have at most one risk factor as included in the widely used Framingham risk assessment. Individuals classified as intermediate risk, who are actually at high risk, may not receive guideline recommended treatments. A clinically useful method for accurately predicting 5-year CHD risk among intermediate risk patients remains an unmet medical need. OBJECTIVE: This study sought to develop a CHD Risk Assessment (CHDRA) model that improves 5-year risk stratification among intermediate risk individuals. METHODS: Assay panels for biomarkers associated with atherosclerosis biology (inflammation, angiogenesis, apoptosis, chemotaxis, etc.) were optimized for measuring baseline serum samples from 1084 initially CHD-free Marshfield Clinic Personalized Medicine Research Project (PMRP) individuals. A multivariable Cox regression model was fit using the most powerful risk predictors within the clinical and protein variables identified by repeated cross-validation. The resulting CHDRA algorithm was validated in a Multiple-Ethnic Study of Atherosclerosis (MESA) case-cohort sample. RESULTS: A CHDRA algorithm of age, sex, diabetes, and family history of MI, combined with serum levels of seven biomarkers (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3, and sFas) yielded a clinical net reclassification index of 42.7% (p < 0.001) for MESA patients with a recalibrated Framingham 5-year intermediate risk level. Across all patients, the model predicted acute coronary events (hazard ratio = 2.17, p < 0.001), and remained an independent predictor after Framingham risk factor adjustments. LIMITATIONS: These include the slightly different event definition with the MESA samples and inability to include PMRP fatal CHD events. CONCLUSIONS: A novel risk score of serum protein levels plus clinical risk factors, developed and validated in independent cohorts, demonstrated clinical utility for assessing the true risk of CHD events in intermediate risk patients. Improved accuracy in cardiovascular risk classification could lead to improved preventive care and fewer deaths.

A common 5'-UTR variant in MATE2-K is associated with poor response to metformin.

Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.

The emerging role of electronic medical records in pharmacogenomics.

Health-care information technology and genotyping technology are both advancing rapidly, creating new opportunities for medical and scientific discovery. The convergence of these two technologies is now facilitating genetic association studies of unprecedented size within the context of routine clinical care. As a result, the medical community will soon be presented with a number of novel opportunities to bring functional genomics to the bedside in the area of pharmacotherapy. By linking biological material to comprehensive medical records, large multi-institutional biobanks are now poised to advance the field of pharmacogenomics through three distinct mechanisms: (i) retrospective assessment of previously known findings in a clinical practice-based setting, (ii) discovery of new associations in huge observational cohorts, and (iii) prospective application in a setting capable of providing real-time decision support. This review explores each of these translational mechanisms within a historical framework.

Intake of meat, meat mutagens, and iron and the risk of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: Epidemiological evidence on meat intake and breast cancer is inconsistent, with little research on potentially carcinogenic meat-related exposures. We investigated meat subtypes, cooking practices, meat mutagens, iron, and subsequent breast cancer risk. METHODS: Among 52 158 women (aged 55-74 years) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, who completed a food frequency questionnaire, 1205 invasive breast cancer cases were identified. We estimated meat mutagen and haem iron intake with databases accounting for cooking practices. Using Cox proportional hazards regression, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) within quintiles of intake. RESULTS: Comparing the fifth to the first quintile, red meat (HR=1.23; 95% CI=1.00-1.51, P trend=0.22), the heterocyclic amine (HCA), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), (HR=1.26; 95% CI=1.03-1.55; P trend=0.12), and dietary iron (HR=1.25; 95% CI=1.02-1.52; P trend=0.03) were positively associated with breast cancer. We observed elevated, though not statistically significant, risks with processed meat, the HCA 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), mutagenic activity, iron from meat, and haem iron from meat. CONCLUSION: In this prospective study, red meat, MeIQx, and dietary iron elevated the risk of invasive breast cancer, but there was no linear trend in the association except for dietary iron.

Characteristics of progression of early age-related macular degeneration: the cardiovascular health and age-related maculopathy study.

AIMS: To determine the risk of age-related macular degeneration (AMD) progression posed by the presence of each early AMD characteristic. METHODS: A prospective cohort study of 254 participants aged 50 years and older, all with early AMD features at their baseline visit followed for an average of 7 years. Stereoscopic colour fundus photographs were graded for early AMD features using the International Classification System. AMD status was stratified into six exclusive levels along a continuum of disease severity according to drusen type, pigmentary abnormalities, or late AMD. Progression was assessed according to three definitions: a change between or within a severity level, or by side by side grading. RESULTS: The progression rate of early AMD ranged between 3.4 and 4.67% per annum depending upon the definition used. In total, 15 (6%) cases progressed from early AMD to the late complication of AMD. After controlling for age and smoking, cases with soft indistinct drusen at baseline were at a greater risk of progressing from early to late AMD than were cases without this characteristic (OR=3.72, 95%CI 1.20-11.54; P=0.02). CONCLUSION: Our proposed definitions of AMD progression give rates that are consistent with current knowledge of progression and its determinants. Each early AMD characteristic conveys its own risk of progression to an eye, with soft indistinct drusen carrying the greater risk. An international consensus on what defines AMD progression would greatly help the research community when trying to assess the importance of new risk factors and the effectiveness of novel interventions.

Healthy People 2010 disease prevalence in the Marshfield Clinic Personalized Medicine Research Project cohort: opportunities for public health genomic research.

OBJECTIVES: The purpose of this study was to estimate the prevalence of Healthy People 2010 disease conditions in a large population-based cohort in central Wisconsin (WI, USA) and to consider how these conditions can be prioritized for research based on the use of healthcare services, the prevalence of various disease states and the resulting study power. METHODS: Healthy People 2010 diagnoses were estimated for participants in the Personalized Medicine Research Project (PMRP), a large population-based biobank for residents aged 18 years and older living in central Wisconsin. By interrogating the electronic medical record, three parameters were calculated for each diagnosis: mean number of concomitant diagnoses, mean number of annual clinic visits before diagnosis and mean number of clinic visits after diagnosis. RESULTS: A total of 18,239 adults enrolled in PMRP from September 2002 to May 2005 and were included in the study. They had a mean age of 49 years (standard deviation: 18.5), ranging from 18-98 years; 57% were female. At least one Healthy People 2010 disease was diagnosed in 86.4% of the participants; 13.6% had never been diagnosed with any of these conditions. The median number of diagnoses per subject was three (range: 1-15). The median number of annual visits after diagnosis was lowest for chronic obstructive pulmonary disease (9.1) and highest for sleep apnea (17.9). Subjects with a diabetic retinopathy diagnosis had the highest number of concomitant diagnoses (mean: 6.8). DISCUSSION: All of the diseases within the Healthy People 2010 list are purported to have at least some genetic component, with the exception of injuries. The PMRP cohort is large enough that diseases of public health importance can be studied in the context of a variety of clinical and environmental covariates. This database is being developed as a national resource and is particularly useful where the estimated disease prevalence is 5% or greater. For less common diseases, additional cases can be recruited from throughout the Marshfield Clinic system of care, with population-based controls selected from the main PMRP study cohort.