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Abstract Severe hypercholesterolemia/possible familial hypercholesterolemia (FH) is relatively common but underdiagnosed and undertreated. We investigated whether implementing clinical decision support (CDS) was associated with lower low-density lipoprotein cholesterol (LDL-C) in patients with severe hypercholesterolemia/possible FH (LDL-C ≥ 190 mg/dL). As part of a pre-post implementation study, a CDS alert was deployed in the electronic health record (EHR) in a large health system comprising 3 main sites, 16 hospitals and 53 clinics. Data were collected for 3 months before (‘silent mode’) and after (‘active mode’) its implementation. Clinicians were only able to view the alert in the EHR during active mode. We matched individuals 1:1 in both modes, based on age, sex, and baseline lipid lowering therapy (LLT). The primary outcome was difference in LDL-C between the two groups and the secondary outcome was initiation/intensification of LLT after alert trigger. We identified 800 matched patients in each mode (mean ± SD age 56.1 ± 11.8 y vs. 55.9 ± 11.8 y; 36.0% male in both groups; mean ± SD initial LDL-C 211.3 ± 27.4 mg/dL vs. 209.8 ± 23.9 mg/dL; 11.2% on LLT at baseline in each group). LDL-C levels were 6.6 mg/dL lower (95% CI, −10.7 to −2.5; P = 0.002) in active vs. silent mode. The odds of high-intensity statin use (OR, 1.78; 95% CI, 1.41–2.23; P

Abstract Parturition timing has long been a topic of interest in ungulate research. However, few studies have examined parturition timing at fine scale (e.g.,

Abstract Background Information on reproduction of harvested species such as mule deer (Odocoileus hemionus) is vital for conservation and management. Furthermore, parturition in ungulates may be detected using patterns of movement logged by GPS transmitters. Several movement-based methods have been developed to detect parturition in ungulates including the Peterson method, behavioral change point analysis (BCPA), rolling minimum convex polygons (rMCP), individual-based method (IBM), and population-based method (PBM). Our objectives were to (1) test the accuracy and the precision of each previously described method and (2) develop an improved method optimized for mule deer that incorporated aspects of the other methods. Methods We determined parturition timing and status for female mule deer fitted with GPS collars and implanted with vaginal implant transmitters (VITs). We used movement patterns before and after parturition to set movement thresholds for each movement-based method. Following model training, we used location and birth date data from an external dataset to test the effectiveness of each movement-based method. Additionally, we developed a novel method for detecting parturition called the analysis of parturition indicators (API). We used two regression analyses to determine the accuracy and precision of estimates generated by each method. Results The six methods we employed varied in accuracy, with the API, rMCP, and BCPA being most accurate. Precision also varied among methods, with the API, rMCP, and PBM generating the most precise estimates of parturition dates. The API and the rMCP performed similarly and better overall than any of the other existing methods. Conclusions We found that movement-based methods could be used to accurately and precisely detect parturition in mule deer. Further, we determined that the API and rMCP methods had the greatest overall success at detecting parturition in mule deer. The relative success of the API and rMCP may be attributed to the fact that both methods use home range size to detect parturition and are validated using known parturition dates of collared deer. We present the API as an efficient method of estimating birth status and timing of parturition of mule deer fitted with GPS transmitters, as well as affirm the effectiveness of a previously developed method, rMCP.

Climate and land-use change are modifying the availability of food and water resources, which is driving more wildlife to the wildland-urban interface. For many wildlife populations, use of these areas still requires habitat connectivity both within the interface and/or to wildland habitats. However, navigating these areas can be difficult due to human development and sensory pollutants, such as artificial night light. Determining how these components of urbanization influence the behaviors and functional connectivity of species is important for managing wildlife within these mixed-use landscapes. Here we used a movescape approach based on graph theory to characterize functional uses of the landscape using metrics for behavior, connectivity, and space use intensity. We found that mule deer (Odocoileus hemionus; n = 43) functional uses of anthropogenic landscapes in the Intermountain West, USA, were dependent not only on physical barriers, terrain, and sensory factors, but also the local levels of light exposure and vegetative greenness. Remotely sensed artificial light levels had a strong influence on how mule deer used the landscape by reducing the intensity of use in the most illuminated areas given forage availability. In contrast, relatively high local light levels were associated with increased use intensity within less developed areas—highlighting the foraging tradeoffs for species using the wildland-urban interface. Corridor use was reduced in areas where road and housing density were higher, and within-corridor movement was faster when artificial light was high and vegetative greenness was low. Developing a more mechanistic understanding of how species functionally use the landscape in relation to features of urbanization can enhance conservation by delineating areas important for connectivity and foraging, while providing insights into how future development and climate change may alter movement and behavior. Spatially-explicit estimates of functional uses can directly guide management decisions to maintain species resiliency and improve land-use planning.

Abstract Observed links between parasites, such as ticks, and climate change have aroused concern for human health, wildlife population dynamics, and broader ecosystem effects. The one‐host life history of the winter tick (Dermacentor albipictus) links each annual cohort to environmental conditions during three specific time periods when they are predictably vulnerable: spring detachment from hosts, summer larval stage, and fall questing for hosts. We used mixed‐effects generalized linear models to investigate the drivers of tick loads carried by moose (Alces alces) relative to these time periods and across 750 moose, 10 years, and 16 study areas in the western United States. We tested for the effects of biotic factors (moose density, shared winter range, vegetation, migratory behavior) and weather conditions (temperature, snow, humidity) during each seasonal period when ticks are vulnerable and off‐host. We found that warm climatic regions, warm seasonal periods across multiple partitions of the annual tick life cycle, and warm years relative to long‐term averages each contributed to increased tick loads. We also found important effects of snow and other biotic factors such as host density and vegetation. Tick loads in the western United States were, on average, lower than those where tick‐related die‐offs in moose populations have occurred recently, but loads carried by some individuals may be sufficient to cause mortality. Lastly, we found interannual variation in tick loads to be most correlated with spring snowpack, suggesting this environmental component may have the highest potential to induce change in tick load dynamics in the immediate future of this region.

Abstract The capture of neonate ungulates allows for the collection of valuable ecological data, including estimates of litter size. However, varied methods used to capture neonate ungulates can result in sampling biases. Our objective was to determine if opportunistic captures of neonate ungulates (i.e., locating neonates by visually scanning for adult females displaying postpartum behaviors) bias relative estimates of litter size and investigate potential causes if a bias does exist. We analyzed data from 161 litters of mule deer (Odocoileus hemionus) sampled using three different capture methods during 2019–2021 in Utah, USA. Estimates of litter size derived from opportunistic captures were smaller than estimates derived from movement-based captures or captures completed with the aid of vaginal implant transmitters (VITs). Age at capture was inversely related to estimates of litter size and likely influenced the detection bias associated with opportunistic captures. Neonates captured opportunistically were not older than neonates captured using movement-based methods, but were older than neonates captured with the aid of VITs. Distance between neonates from the same litter did not influence estimates of litter size. Researchers should be aware of the biases associated with different capture methods and use caution when interpreting data among multiple capture methods. Estimates of litter size derived from opportunistic captures should not be compared to estimates of litter size derived from alternative capture methods without accounting for the detection bias we observed.

Summary: Background: The identification of new uses for existing drug therapies has the potential to identify treatments for comorbid conditions that have the added benefit of glycemic control while also providing a rapid, low-cost approach to drug (re)discovery. Methods: We developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. This approach mapped genetically-predicted gene expression signals from the largest genome-wide association study for type 2 diabetes mellitus to drug targets using publicly available databases to identify drug–gene pairs. These drug–gene pairs were then validated using a two-step approach: 1) a self-controlled case-series (SCCS) using electronic health records from a discovery and replication population, and 2) Mendelian randomization (MR). Findings: After filtering on sample size, 20 candidate drug–gene pairs were validated and various medications demonstrated evidence of glycemic regulation including two anti-hypertensive classes: angiotensin-converting enzyme inhibitors as well as calcium channel blockers (CCBs). The CCBs demonstrated the strongest evidence of glycemic reduction in both validation approaches (SCCS HbA1c and glucose reduction: −0.11%, p = 0.01 and −0.85 mg/dL, p = 0.02, respectively; MR: OR = 0.84, 95% CI = 0.81, 0.87, p = 5.0 x 10–25). Interpretation: Our results support CCBs as a strong candidate medication for blood glucose reduction in addition to cardiovascular disease reduction. Further, these results support the adaptation of this approach for use in future drug-repurposing efforts for other conditions. Funding: National Institutes of Health, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK Medical Research Council, American Heart Association, and Department of Veterans Affairs (VA) Informatics and Computing Infrastructure and VA Cooperative Studies Program.

Urine marking, aggression, and other behavioral concerns are common reasons for cat owners to seek veterinary care. Empiric treatment for lower urinary tract disease or primary behavior disorders are commonly pursued, especially in those cases with normal routine laboratory evaluations. Herein, we report the clinicopathologic findings in eight sexually altered cats that were diagnosed with androgen-secreting adrenocortical tumors. Nearly all cats (n = 7) initially were evaluated for inappropriate urination and pungent urine, with additional behavioral concerns including aggression (n = 3) and excess vocalization (n = 4) commonly reported. Penile barbs (n = 5) were identified in all five male cats, and an enlarged clitoris was observed in one female cat. Testing of serum androgen concentrations revealed abnormally high androstenedione (n = 1) or testosterone (n = 7) concentrations. In the five cases with available adrenal tissue, histopathologic evaluation identified either an adrenocortical adenoma (n = 3) or adrenocortical carcinoma (n = 2). Hormonal abnormalities resolved and clinical signs improved in the four cats that underwent surgical adrenalectomy, with each of these cats surviving >1 year. However, clinical signs were minimally impacted with medical treatments, including one cat in which trilostane treatment failed to improve clinical signs or testosterone concentrations. This collection of cases underscores the importance of a detailed physical examination as well as the consideration of endocrine disturbances in cats undergoing evaluation for inappropriate urination or aggression. Furthermore, this report adds to the growing body of evidence that sex-hormone secreting adrenal tumors in cats may be an under-recognized syndrome.

Introduction: Plate distance is correlated with an increased incidence of adjacent segment pathologies (ASP). However, a correct plate-to-disk distance >5 mm is often not achieved. Therefore, this study aimed to quantify the effect of short plate-to-disk distance on the development of ASP using epidemiological measures in patients with cervical degenerative spine disease undergoing single-level anterior cervical discectomy and fusion (ACDFs). Methods: Medical records of all patients with cervical degeneration undergoing single-level ACDF with plating (between January 2015 and December 2017), and a follow-up of at least 1 year, were reviewed retrospectively. Radiologic and clinical outcomes were assessed preoperatively, postoperatively, and at last follow-up. The plate-to-adjacent disk distance was measured, and epidemiological measures were calculated to quantify the risk on adjacent-level ossification development (ALOD) and adjacent segment degeneration (ASD). Results: Thirty-eight (47.5%) of the 80 patients developed ALOD, and 12 (15.0%) developed ASD after a 2-year follow-up. The incidence of ALOD was significantly lower if the plate was >5 mm away from the adjacent disk space compared to 5 mm away from the adjacent disk.

Translocation of large mammals has become common practice for wildlife managers charged with conservation of animals and their genetic integrity on increasingly modified landscapes. Translocations of ungulates have occurred around the world with varying outcomes. Although translocations have been used to manage mule deer (Odocoileus hemionus) in western North America, only recently have the outcomes associated with this management practice been documented. Our objective was to evaluate survival of translocated mule deer in comparison to resident mule deer over multiple years following release and provide information useful in judging the relative value of translocation as a conservation strategy for this species. In January and March 2013, the Utah Division of Wildlife Resources (UDWR) captured and translocated 102 mule deer from winter range near Parowan, Utah to winter range near Holden, Utah (approximately 145 kilometers north of capture location). We fitted each deer with a radio transmitter (n = 102 total: 21 GPS collars, 81 VHF collars) prior to release. We also captured and marked a total of 70 resident deer (9 GPS collars, 61 VHF collars) to serve as a reference group. Survival of translocated deer in the first year was similar among release dates in January (0.51; 95% CI = 0.40–0.63) and March (0.53; 95% CI = 0.40–0.66). Annual survival of translocated deer, however, was lower than survival of resident deer (0.83; 95% CI = 0.72–0.90) in the first year after release. During the second year following release, however, survival of translocated animals (0.85; 95% CI = 0.71–0.93) was not different from that of resident deer (0.80; 95% CI = 0.69–0.88). Additionally, age strongly influenced the survival of translocated deer; young deer (e.g., 1.5 year olds) were more than twice as likely as old deer (e.g., 7.5 year olds) to survive the initial year following translocation. These data highlight the need to monitor translocated animals for multiple years following release and suggest that wildlife managers should expect to see higher survival rates during the second year following translocation and higher survival rates in younger deer compared to older deer.

Maternal effects are the influence of maternal phenotype and the maternally-provided environment on the phenotype (i.e., expression of traits) of offspring. Frequently, maternal effects are manifest both before and after parturition. Pre-parturition effects are primarily direct allocation of energy to the offspring that is in utero. Post-parturition effects can include direct (e.g., nursing and defending offspring) and indirect (e.g., selection of habitat that is relatively safe or has high nutritional value) influences. While both direct and indirect effects are often discussed, there is a paucity of information on the relative importance of each type on offspring due to the difficulty in monitoring mothers prior to parturition and mother-offspring relationships after parturition in free-ranging animals. Our objective was to determine the importance of direct maternal effects on birth weight, growth rates, and survival of mule deer (Odocoileus hemionus) fawns from birth through the first 18 months of life. We determined the effect of nutritional condition of the dam (mother) on birth weight (pre-parturition direct effect). We also examined the post-parturition direct effect of dam nutritional condition on growth rates and survival of fawns. Direct maternal effects were evident both before and after parturition; dams in better nutritional condition produced offspring with greater mass at birth, higher rates of growth, and increased survival. Our findings demonstrate that maternal nutritional condition influences fawn health from gestation through recruitment. These links highlight the importance of considering direct maternal effects when examining population dynamics and reproductive success in long-lived mammals. Management plans for ungulates should include assessment of nutritional condition of adult females to maximize likelihood of effective conservation.

Recent meta-analyses indicate that predator removal experiments result in marginal increases in prey abundance at best. However, most predator removal studies take place for less than the target prey’s generation time and lack a targeted spatial approach. Our objective was to determine how temporal and spatial aspects of predator control influenced neonate survival of a temperate ungulate. We conducted multiyear coyote (Canis latrans) removals using a crossover experimental design. We found that consecutive years of predator removal increased survival of neonate mule deer (Odocoileus hemionus) more than a single year of removal. We also found that removing coyotes from areas near fawn birth sites increased fawn survival, whereas removing coyotes from areas farther from birth sites did not influence fawn survival. Our results underscore the need for coyote removal programs to (1) employ removal efforts over consecutive years to maximize effectiveness, (2) conduct spatially explicit removal efforts targeting fawning habitat, and (3) occur when the likelihood of additive mortality is high and prey populations have the resources available to grow.

Background: Contemporary prevalence, awareness, and control of severe hypercholesterolemia (SH) and familial hypercholesterolemia (FH) and the associated atherosclerotic cardiovascular disease risk in the US are unknown. Method: Using electronic health records, we assessed the burden of SH and FH in Olmsted County, Minnesota, US, between 2004 and 2015. We defined SH as low-density lipoprotein cholesterol (LDL-C) level ≥190 mg/dl without secondary causes of hypercholesterolemia and FH as a Dutch Lipid Clinic Network score ≥6. Controls were age- and sex-matched individuals with LDL-C level

Abstract The phase offset of quantum oscillations is commonly used to experimentally diagnose topologically nontrivial Fermi surfaces. This methodology, however, is inconclusive for spin-orbit-coupled metals where π-phase-shifts can also arise from non-topological origins. Here, we show that the linear dispersion in topological metals leads to a T 2-temperature correction to the oscillation frequency that is absent for parabolic dispersions. We confirm this effect experimentally in the Dirac semi-metal Cd3As2 and the multiband Dirac metal LaRhIn5. Both materials match a tuning-parameter-free theoretical prediction, emphasizing their unified origin. For topologically trivial Bi2O2Se, no frequency shift associated to linear bands is observed as expected. However, the π-phase shift in Bi2O2Se would lead to a false positive in a Landau-fan plot analysis. Our frequency-focused methodology does not require any input from ab-initio calculations, and hence is promising for identifying correlated topological materials.

Abstract Background The frequency with which multiple corticosteroid abnormalities occur in cats with aldosterone secreting adrenocortical tumors is unknown. Objectives To evaluate adrenal‐derived corticosteroids in cats in which blood samples were submitted for measure of aldosterone. Animals Two hundred ninety‐seven cats. Methods Retrospective study. Analysis of a convenience sample of previously submitted serum or plasma. Progesterone, corticosterone, and cortisol were measured in feline serum or plasma samples submitted to an endocrinology laboratory for aldosterone measurements. Demographics and clinical history were retrieved from submittal forms when provided. Statistical testing was performed to investigate associations among the adrenal corticosteroids. Results Progesterone and corticosterone concentrations were strongly correlated (ρ = 0.74; P

Abstract Background Primary hyperaldosteronism caused by adrenal neoplasia has been well described in cats. Multiple corticosteroid abnormalities occur in a subset of affected cats, but characterizations of this syndrome are limited to several case reports. Objectives To describe a series of cats with adrenal tumors secreting aldosterone and additional corticosteroids. Animals Ten cats with multiple corticosteroid secreting adrenocortical tumors. Methods Retrospective case series. Medical records of cats with adrenal tumors secreting both aldosterone and progesterone were identified. Data concerning historical findings, clinicopathologic features, treatments, and outcomes were retrieved from medical records. Results All 10 cats had diabetes mellitus in addition to biochemical features of hyperaldosteronism such as hypokalemia. High corticosterone concentrations were observed in all 3 cats in which this corticosteroid was measured. Ultrasound examinations revealed unilateral adrenal tumors in all 10 cases, and the contralateral adrenal gland was either atrophied or not identified in 5 cats. Three of 4 cats developed hypoadrenocorticism after surgical adrenalectomy. Three cats achieved diabetic remission after adrenalectomy. Two cats treated with adrenalectomy survived >1 year, 1 cat survived 6.5 months, and 1 cat was alive 5.5 months after diagnosis. Survival >1 year occurred in 2 of 4 cats treated with medical management alone. Two cats were not treated. Conclusions and Clinical Importance The presence of multiple corticosteroid abnormalities should be considered in cats with aldosterone secreting adrenal tumors, especially those with concurrent diabetes mellitus. Both surgical and medical management can result in long‐term survival, although diabetic remission was documented only in cats undergoing adrenalectomy.

Background: Injured patients have early changes to normal coagulation that can impact long term risk for thrombotic complications. There is little known about how age impacts biomarkers of coagulation after traumatic injury. In this pilot study, we aimed to characterize thrombin generation kinetics, a known predictor of venous thromboembolism, in trauma patients across the age spectrum. Methods: Citrated plasma samples were collected from 174 trauma patients (3–94 years old). Thrombin generation kinetics were measured using calibrated automated thrombogram (CAT) and expressed as lag time (LT – minutes) and time to peak (ttPeak – minutes). Kruskal-Wallis, Spearman correlation, and multivariable regression analysis were carried out. Data in median and quartiles [Q1, Q3]. P

Abstract Background Conservation and management of migratory animals has gained attention in recent years, but the majority of research has focused on stereotypical ‘migrant’ and ‘resident’ behaviors, often failing to incorporate any atypical behaviors or characterize migratory behaviors beyond distance and timing of the migration. With migration threatened by anthropogenic development and climate change, it is crucial that we understand the full range of migratory behaviors. Our objective was to demonstrate and characterize the variation in migration strategies, including typical and atypical migratory behaviors for mule deer (Odocoileus hemionus) in Utah, USA. Methods Because calculation of common metrics such as distance, timing, and use of stopovers during migration did not adequately describe the variation we observed in migratory behavior for this species—particularly when animals visited multiple (> 3) ranges for extended lengths of time—we developed additional methods and categories to describe observed variation in migratory behavior. We first categorized trajectories based on the number of discrete, separate ranges and range shifts between them. Then, we further characterized the variation in migration strategies by examining the timing, duration, and distance traveled within each of the categories. We also examined if and how frequently individual deer switched among categories from year to year. Results We classified 1218 movement trajectories from 722 adult female mule deer, and found that 54.4% were dual-range migrants, who made one round-trip to one distinct range. Multi-range migrants (23.6%) made one round-trip during which they stayed at multiple discrete ranges. Commuters (1.0%) traveled to the same range multiple times, and poly migrants (1.5%) made multiple round-trips to different ranges. Gradual movers (2.5%) did not show a discrete range shift but moved gradually between ranges, whereas residents (12.6%) never left their home ranges, and dispersers (4.4%) left but never returned. Of the deer that we monitored for multiple years, 51.2% switched among categories. Conclusion We conclude that the substantial number of atypical migratory strategies, as well as the number of deer that switched categories, underlines the importance of studying these less-stereotyped behaviors that may be exhibited by large proportions of populations. Acknowledging and investigating the full complexity and diversity in migratory strategies might uncover unknowns with respect to underlying factors and drivers of migration, and can help shape effective conservation strategies.

Abstract Background Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer‐recommended dosing protocols can be cost‐prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive. Objective To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA. Animals Thirty‐seven dogs, including 19 test population dogs and 18 controls. Methods Randomized controlled double‐blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low‐dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days. Results Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016‐1.029) as compared to test population dogs (1.033, 1.023‐1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs. Conclusions and Clinical Importance Low‐dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard‐dose protocols are more likely to result in biochemical evidence of overtreatment.

Abstract Ecological context—the biotic and abiotic environment, along with its influence on population mixing dynamics and individual susceptibility—is thought to have major bearing on epidemic outcomes. However, direct comparisons of wildlife disease events in contrasting ecological contexts are often confounded by concurrent differences in host genetics, exposure histories, or pathogen strains. Here, we compare disease dynamics of a Mycoplasma ovipneumoniae spillover event that affected bighorn sheep populations in two contrasting ecological contexts. One event occurred on the herd's home range near the Rio Grande Gorge in New Mexico, while the other occurred in a captive facility at Hardware Ranch in Utah. While data collection regimens varied, general patterns of antibody signal strength and symptom emergence were conserved between the two sites. Symptoms appeared in the captive setting an average of 12.9 days postexposure, average time to seroconversion was 24.9 days, and clinical signs peaked at approximately 36 days postinfection. These patterns were consistent with serological testing and subsequent declines in symptom intensity in the free‐ranging herd. At the captive site, older animals exhibited more severe declines in body condition and loin thickness, higher symptom burdens, and slower antibody response to the pathogen than younger animals. Younger animals were more likely than older animals to clear infection by the time of sampling at both sites. The patterns presented here suggest that environment may not be a major determinant of epidemiological outcomes in the bighorn sheep—M. ovipneumoniae system, elevating the possibility that host‐ or pathogen‐factors may be responsible for observed variation.

Abstract Abnormal postprandial suppression of glucagon in Type 2 diabetes (T2DM) has been attributed to impaired insulin secretion. Prior work suggests that insulin and glucagon show an inverse coordinated relationship. However, dysregulation of α‐cell function in prediabetes occurs early and independently of changes in β‐cells, which suggests insulin having a less significant role on glucagon control. We therefore, sought to examine whether hepatic vein hormone concentrations provide evidence to further support the modulation of glucagon secretion by insulin. As part of a series of experiments to measure the effect of diabetes‐associated genetic variation in TCF7L2 on islet cell function, hepatic vein insulin and glucagon concentrations were measured at 2‐minute intervals during fasting and a hyperglycemic clamp. The experiment was performed on 29 nondiabetic subjects (age = 46 ± 2 years, BMI 28 ± 1 Kg/m2) and enabled post‐hoc analysis, using Cross‐Correlation and Cross‐Approximate Entropy (Cross‐ApEn) to evaluate the interaction of insulin and glucose. Mean insulin concentrations rose from fasting (33 ± 4 vs. 146 ± 12 pmol/L, p

Summary: Background: Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. Methods: Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). Findings: IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. Interpretation: Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. Funding: Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments.

Abstract Introduction Plasma thrombin generation kinetics as measured by the calibrated automated thrombogram (CAT) assay is a predictor of symptomatic venous thromboembolism after trauma. We hypothesized that data from a new prototype assay for measurement of thrombin generation kinetics in fresh whole blood (near patient testing of thrombin generation), will correlate with the standard CAT assay in the same patients, making it a potential tool in the future care of trauma patients. Methods Patients were enrolled from June 2018 to February 2020. Within 12 hours of injury, blood samples were collected simultaneously for both assays. Variables compared and correlated between assays were lag time, peak height, time to peak, and endogenous thrombin potential. Data are presented as median with interquartile range (IQR). Spearman and Pearson correlations were estimated and tested between both assays; a P value of

Clinical trials have shown that electric stimulation (ELSM) using either cardiac resynchronization therapy (CRT) or cardiac contractility modulation (CCM) approaches is an effective treatment for patients with moderate to severe heart failure, but the mechanisms are incompletely understood. Extracellular vesicles (EV) produced by cardiac mesenchymal stem cells (C-MSC) have been reported to be cardioprotective through cell-to-cell communication. In this study, we investigated the effects of ELSM stimulation on EV secretion from C-MSCs (C-MSCELSM). We observed enhanced EV-dependent cardioprotection conferred by conditioned medium (CM) from C-MSCELSM compared to that from non-stimulated control C-MSC (C-MSCCtrl). To investigate the mechanisms of ELSM-stimulated EV secretion, we examined the protein levels of neutral sphingomyelinase 2 (nSMase2), a key enzyme of the endosomal sorting complex required for EV biosynthesis. We detected a time-dependent increase in nSMase2 protein levels in C-MSCELSM compared to C-MSCCtrl. Knockdown of nSMase2 in C-MSC by siRNA significantly reduced EV secretion in C-MSCELSM and attenuated the cardioprotective effect of CM from C-MSCELSM in HL-1 cells. Taken together, our results suggest that ELSM-mediated increases in EV secretion from C-MSC enhance the cardioprotective effects of C-MSC through an EV-dependent mechanism involving nSMase2.

The coronavirus disease 2019 (COVID-19) pandemic created an extremely disruptive challenge for health care leaders that required a rapid, dynamic, and innovative response. The purpose of this manuscript is to share the leadership actions and decisions at Mayo Clinic in Florida during the first 6 months of the pandemic (February to July 2020). We note 4 strategies that contributed to an effective response: (1) leverage experience with disaster preparedness and mobilize regional and national networks; (2) use surge models to anticipate and to address supply chain issues as well as practical and financial effects of the pandemic; (3) adapt creatively to establish new safety and procedural protocols in various areas for various populations; and (4) communicate timely information effectively and be the common source of truth. Mayo Clinic in Florida was able to address the surges of patients with COVID-19, to provide ongoing tertiary care, and to restore function within the first 6 months with new, strengthened practices and protocols.

The low-complexity (LC) domain mediates liquid-liquid phase separation and fibril formation of the RNA-binding protein FUS (FUsed in Sarcoma). Here, the authors combine cryo-EM, solid-state NMR measurements and MD simulations to structurally characterise the fibrils formed by the C-terminal half of the FUS LC domain and discuss stabilizing interactions within the fibril core.

Multiple quantum critical behaviors exist in the heavy fermion material CeRhIn5, but their interrelation is less studied. Here, Helm et al. investigate the interrelation of two quantum critical points and other relevant orders, revealing a strongly non-mean-field-like phase diagram.

Background Von Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.Methods We assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.Results REAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0–264.0) vs. 92.0 (71.0–114.0), p

Aim To provide a contemporary analysis of incidence trends of infective endocarditis (IE) with its changing epidemiology over the past two decades in Europe.Methods A systematic review was conducted at the Mayo Clinic, Rochester. Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus and Web of Science were searched for studies published between 1 January 2000 and 30 November 2020. All studies were independently reviewed by four referees and those that included a population-based incidence of IE in patients, irrespective of age, in Europe were included. Least squares regression was used to estimate pooled temporal trends in IE incidence.Results Of 9138 articles screened, 18 studies were included in the review. Elderly men predominated in all studies. IE incidence increased 4.1% per year (95% CI 1.8% to 6.4%) in the pooled regression analysis of eight studies that included comprehensive and consistent trends data. When trends data were weighted according to population size of individual countries, an increase in yearly incidence of 0.27 cases per 100 000 people was observed. Staphylococci and streptococci were the most common pathogens identified. The rate of surgical intervention ranged from 10.2% to 60.0%, and the rate of inpatient mortality ranged from 14.3% to 17.5%. In six studies that examined the rate of injection drug use, five of them reported a rate of less than 10%.Conclusion Based on findings from our systematic review, IE incidence in Europe has doubled over the past two decades in Europe. Multiple factors are likely responsible for this striking increase.Trial registeration number CRD42020191196.

Background: COVID-19-associated coagulopathy is incompletely understood. Objectives: To characterize thrombin generation, Von Willebrand Factor (VWF), neutrophil extracellular traps (NETs), and their role in COVID-19 risk stratification in the emergency department (ED). Patients/methods: Plasma samples from 67 ED COVID-19 patients were compared to 38 healthy volunteers (HVs). Thrombin generation (calibrated automated thrombogram, CAT) was expressed as lag time (LT, min), peak height (PH, min), and time to peak (ttPeak, min). Citrullinated nucleosomes and histones were quantified with ELISA, VWF antigen and activity (IU/dL) through latex immunoassay, Factor VIII (IU/dL) through one-stage optical clot detection, and VWF multimers with Western blot densitometry. Wilcoxon testing and multivariable logistic regression were performed. Results presented as median [Q1, Q3]; p

Background Hypertriglyceridemia is associated with increased risk of coronary heart disease but the association is often attributed to concomitant metabolic abnormalities. We investigated the epidemiology of primary isolated hypertriglyceridemia (PIH) and associated cardiovascular risk in a population‐based setting. Methods and Results We identified adults with at least one triglyceride level ≥500 mg/dL between 1998 and 2015 in Olmsted County, Minnesota. We also identified age‐ and sex‐matched controls with triglyceride levels

European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.

Objective: To determine whether early Roux-en-Y gastric bypass surgery (RYGB) reduces the risk of Major adverse cardiovascular events (MACE) in patients with obesity.Patients and Methods: We conducted a study of patients with class II and III obesity [body mass index (BMI) > 35 kg/m2] from Olmsted County, Minnesota, who underwent obesity clinic consultation between the years 1993–2012, and had either RYGB surgery within 1 year (RYGB-1Y group), or medically managed (No-RYGB group). The composite endpoint of MACE (all-cause mortality, stroke, heart failure admission and acute myocardial infarction) was the primary endpoint, with new-onset AF as the secondary endpoint.Results: Of the 1,009 study patients, 308 had RYGB-1Y and 701 were medically managed (No-RYGB). Overall, the age was 44.0 ± 12.4 (mean ± SD) years; BMI was 45.0 ± 6.8 kg/m2. The RYGB-1Y group had a lower rate of MACE (adjusted hazard ratio (HR), 0.62; 95% CI, 0.44–0.88; P = 0.008) and lower mortality (adjusted HR, 0.51; 95% CI, 0.26–0.96; P = 0.04) than the No-RYGB group. The RYGB-1Y surgery was not associated with lower AF occurrence (HR, 0.66; 95% CI, 0.40–1.10; P = 0.11).Conclusion: An early RYGB approach for BMI reduction was associated with lower rates of MACE.

Abstract Objective: Clinical trials, which are mainly conducted in urban medical centers, may be less accessible to rural residents. Our aims were to assess participation and the factors associated with participation of rural residents in clinical trials. Methods: Using geocoding, the residential address of participants enrolled into clinical trials at Mayo Clinic locations in Arizona, Florida, and the Midwest between January 1, 2016, and December 31, 2017, was categorized as urban or rural. The distance travelled by participants and trial characteristics was compared between urban and rural participants. Ordinal logistic regression analyses were used to evaluate whether study location and risks were associated with rural participation in trials. Results: Among 292 trials, including 136 (47%) cancer trials, there were 2313 participants. Of these, 731 (32%) were rural participants, which is greater than the rural population in these 9 states (19%, P

Background Recent investigations suggest that inflammation and autoimmunity might have a role in the pathophysiology of atrial fibrillation (AF). Given that abnormal ventriculovascular coupling often coexists with AF, we hypothesize that autoimmune vasculitis plays a significant role in the pathogenetic mechanism of AF. Methods and Results A standardized retrospective population‐based case–control study was conducted to evaluate the association between autoimmune vasculitis and AF, and all‐cause mortality. The study included 8459 patients with a new diagnosis of AF and 8459 age‐, sex‐, and registration calendar year–matched controls in Olmsted County, Minnesota, between January 1, 1980 and December 31, 2010. The association of each clinical characteristic, diagnosis, and treatment was assessed using conditional logistic regression to account for the matched case–control study design. Cox proportional hazards regression models and Kaplan‐Meier curves were used to detect independent predictors of mortality and examine cumulative survival. Of a total of 16 918 patients (mean age 72.3+14.4 years; 48.7% women), 320 (1.9%) were diagnosed with autoimmune vasculitis before the index date during the 30‐year period. Among the cases, the prevalence of any autoimmune vasculitis was 2.3%, whereas the frequency of autoimmune vasculitis in controls was 1.5% (P

Abstract Climatic changes are affecting the distribution and viability of species worldwide, and the effects may be greatest for heat‐sensitive organisms in populations situated near the species’ equatorial range limit. We studied the population dynamics of a cold‐adapted large herbivore, moose (Alces alces shirasi), in a population located at the extreme southern range limit of the species in Utah, USA, using a long‐term dataset of aerial counts conducted between 1958 and 2013. We used a modeling approach that acknowledges the uncertainty in the number of moose counted. To determine how climate influenced this population, we tested four models corresponding to different hypotheses suggested by previous studies of moose population dynamics: (1) High summer rainfall increases population growth, (2) severe winters reduce population growth, (3) high summer and winter temperatures cause heat stress which reduces population growth, and (4) snow conditions favorable to winter ticks reduce population growth. We then ranked these models against two additional hypotheses that tested the combined effects of the best‐performing models. The best‐supported model included summer rainfall and the number of days with snow cover in late winter, which described the conditions influencing winter tick numbers, a common parasite of moose in the region. Reproductive female ticks drop off their hosts at the end of winter to lay eggs, and fewer ticks survive in years with abundant snow cover. Positive effects of snow and rainfall indicated that moose population growth was higher following summers with more rainfall and late winters with more days of snow cover, the latter because those conditions likely reduced winter tick numbers. In accordance with global patterns in which altered precipitation regimes are influencing the dynamics of many species, the top‐performing model suggested that both summer and winter precipitation acted together to explain the most variation in moose population growth. Our analysis demonstrates the multiple pathways by which climate and population density can affect the dynamics of temperate species living at their equatorial range limits, including potential parasite‐mediated effects.

Pressure from hunting can alter the behavior and habitat selection of game species. During hunting periods, cervids such as elk (Cervus canadensis) typically select for areas further from roads and closer to tree cover, while altering the timing of their daily activities to avoid hunters. Our objective was to determine the habitat characteristics most influential in predicting harvest risk of elk. We captured 373 female elk between January 2015 and March 2017 in the Uinta-Wasatch-Cache National Forest and surrounding area of central Utah, USA. We determined habitat selection during the hunting season using a resource selection function (RSF) for 255 adult cow elk. Additionally, we used a generalized linear mixed model to evaluate risk of harvest based on habitat use within home ranges (3rd order selection) as well as the location of the home range on the landscape to evaluate vulnerability on a broader scale. Female elk selected for areas that reduced hunter access (rugged terrain, within tree cover, on private land). Age, elevation and distance to roads within a home range were most influential in predicting harvest risk (top model accounted for 36.2% of AIC weight). Elevation and distance to trees were most influential in predicting risk when evaluating the location of the home range (top model accounted for 42.1% of AIC weight). Vulnerability to harvest was associated with proximity to roads. Additionally, survival in our landscape decreased with age of femaleelk.

PURPOSE:A recently identified and treatable cause of spontaneous intracranial hypotension (SIH) is cerebrospinal fluid (CSF)-venous fistula, and a recently described computed tomography myelogram (CTM) finding highly compatible with but not diagnostic of this entity is the hyperdense paraspinal vein sign. We aimed to retrospectively measure the prevalence of the hyperdense paraspinal vein sign on CTMs in SIH patients without dural CSF leak, in comparison with control groups.METHODS:Three CTM groups were identified: 1) SIH study group, which included dural CSF leak-negative standard CTMs performed for SIH, with early and delayed imaging; 2) Early control CTMs, which were performed for indications other than SIH, with imaging shortly after intrathecal contrast administration; 3) Delayed control CTMs, which included delayed imaging. CTMs were retrospectively reviewed for the hyperdense paraspinal vein sign by experienced neuroradiologists, blinded to the group assignment. All CTMs deemed by a single reader to be positive for the hyperdense paraspinal vein sign were independently reviewed by two additional neuroradiologists; findings were considered positive only if consensus was present among all three readers. For positive cases, noncontrast CTs and prior CTMs, if available, were reviewed for the presence of the sign.RESULTS:Seven of 101 (7%) SIH patients had contrast in a spinal/paraspinal vein consistent with the hyperdense paraspinal vein sign; no patient in either control group (total n=54) demonstrated the hyperdense paraspinal vein sign (P = 0.0463). The finding occurred only at thoracic levels. Each patient had a single level of involvement. Six (86%) occurred on the right. Four occurred in female patients (57%). The sign was seen on early images in 3 of 7 cases (43%) and on both early and delayed images in 4 of 7 cases (57%). In 2 of 7 patients (29%), a noncontrast CT covering the relevant location was available and negative for the sign. A prior CTM was available in 2 of 7 patients (29%), and in both cases the hyperdense paraspinal vein sign was also evident.CONCLUSION:The prevalence of the hyperdense paraspinal vein sign in SIH patients with dural CSF leak-negative standard CTM was 7%. As the sign was not seen in control groups, this sign is highly compatible with the presence of CSF-venous fistula. Since the CTMs were not specifically dedicated to identifying hyperdense paraspinal veins (i.e., they were not dynamic and were not preceded by digital subtraction myelography), the true prevalence of the sign may be higher. Radiologists should scrutinize conventional CTMs for this sign, especially in patients in whom a traditional dural CSF leak is not identified.

Abstract Background Poisoning is a major public health concern in sub-Saharan Africa, affecting patients of all age groups. Poisoned patients often present to the emergency department (ED) and prompt evaluation and appropriate management are imperative to ensure optimal outcomes. Unfortunately, little is known about the specific presentations of poisoned patients in East Africa. We describe the clinical and epidemiological features of patients presenting to the Muhimbili National Hospital (MNH) ED with suspected toxicological syndromes. Methods This prospective study enrolled a consecutive sample of ED patients who presented with a suspected toxicological syndrome from March 2013 to June 2013. Trained investigators completed a structured case report form (CRF) for each eligible patient, documenting the suspected poison, demographic information, the clinical presentation, and the ED outcome and disposition. The study data were analyzed and summarized with descriptive statistics. Results Of 8827 patients, who presented to ED-MNH, 106 (1.2%) met inclusion criteria, and all were enrolled. Among those enrolled, the median age was 28 years (interquartile range [IQR] 16 years), and 81 (76.4%) were male. Overall 55 (52%) were single, and 28 (26.4%) had professional jobs. 60 (56.6%) patients were referred from district hospitals, 86.8% of which were in Dar es Salaam. Only 13 (12.3%) of patients presented to the ED within 2 h of the toxic exposure. The etiology of poisoning included alcohol in 42 (50%), a mixture of different medications in 12 (14.3%), and snakebite in 6 (11.3%). Most exposures were intentional (63 [59.4%]) and were via the oral route (88 [83%]). The most common abnormal physical findings were altered mental status (66 [62.3%]) and tachypnoea (68 [64.2%]). One patient died in the ED and 98 (92.5%) required hospital admission. Conclusions Most patients presenting to the ED with a toxicological syndrome were adult males with intentional exposures. The most common toxic exposure was alcohol (ethanol) intoxication and the most common abnormal findings were altered mental status and tachypnoea. More than three-quarter of patients presented after 2 h of exposure. Almost all patients were admitted to the hospital.

We review the state of knowledge of moose (Alces alces shirasi) in the western US with respect to the species’ range, population monitoring and management, vegetative associations, licensed hunting opportunity and hunter harvest success, and hypothesized limiting factors. Most moose monitoring programs in this region rely on a mixture of aerial surveys of various formats and hunter harvest statistics. However, given the many challenges of funding and collecting rigorous aerial survey data for small and widespread moose populations, biologists in many western states are currently exploring other potential avenues for future population monitoring. In 2015, a total of 2,263 hunting permits were offered among 6 states, with 1,811 moose harvested and an average success rate per permit-holder of 80%. The spatial distribution of permits across the region shows an uneven gradient of hunting opportunity, with some local concentrations of opportunity appearing consistent across state boundaries. On average, hunting opportunity has decreased across 56% of the western US, remained stable across 17%, and increased across 27% during 2005–2015. Generally, declines in hunting opportunity for moose are evident across large portions (62–89%) of the “stronghold” states where moose have been hunted for the longest period of time (e.g., Idaho, Montana, Utah, and Wyoming). In contrast, increases in opportunity appear more common at peripheries of the range where populations have expanded, including most of Colorado, northeastern Washington, southern Idaho, and eastern Montana. There are many factors of potential importance to moose in this region, including parasites, predators, climate, forage quality, forage quantity, and humans. State wildlife agencies are currently conducting a variety of research focused on population vital rates, the development of monitoring techniques, forage quality, trace mineral levels, and evaluation of relative impacts among potential limiting factors.

A recent class of topological nodal-line semimetals with the general formula MSiX (M = Zr, Hf and X = S, Se, Te) has attracted much experimental and theoretical interest due to their properties, particularly their large magnetoresistances and high carrier mobilities. The plateletlike nature of the MSiX crystals and their extremely low residual resistivities make measurements of the resistivity along the [001] direction extremely challenging. To accomplish such measurements, microstructures of single crystals were prepared using focused ion beam techniques. Microstructures prepared in this manner have very well-defined geometries and maintain their high crystal quality, verified by the observations of quantum oscillations. We present magnetoresistance and quantum oscillation data for currents applied along both [001] and [100] in ZrSiS and ZrSiSe, which are consistent with the nontrivial topology of the Dirac line-node, as determined by a measured π Berry phase. Surprisingly, we find that, despite the three dimensional nature of both the Fermi surfaces of ZrSiS and ZrSiSe, both the resistivity anisotropy under applied magnetic fields and the in-plane angular dependent magnetoresistance differ considerably between the two compounds. Finally, we discuss the role microstructuring can play in the study of these materials and our ability to make these microstructures free-standing.

Background Automated individualized risk prediction tools linked to electronic health records (EHRs) are not available for management of patients with peripheral arterial disease. The goal of this study was to create a prognostic tool for patients with peripheral arterial disease using data elements automatically extracted from an EHR to enable real‐time and individualized risk prediction at the point of care. Methods and Results A previously validated phenotyping algorithm was deployed to an EHR linked to the Rochester Epidemiology Project to identify peripheral arterial disease cases from Olmsted County, MN, for the years 1998 to 2011. The study cohort was composed of 1676 patients: 593 patients died over 5‐year follow‐up. The c‐statistic for survival in the overall data set was 0.76 (95% confidence interval [CI], 0.74–0.78), and the c‐statistic across 10 cross‐validation data sets was 0.75 (95% CI, 0.73–0.77). Stratification of cases demonstrated increasing mortality risk by subgroup (low: hazard ratio, 0.35 [95% CI, 0.21–0.58]; intermediate‐high: hazard ratio, 2.98 [95% CI, 2.37–3.74]; high: hazard ratio, 8.44 [95% CI, 6.66–10.70], all P

BackgroundThiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change. Methods and ResultsGenome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P

BackgroundThe majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β‐blocker. Methods and ResultsA genome‐wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P

Mechanisms and interactions among intravascular cells contributing to development of subclinical atherosclerosis are poorly understood. In women, both menopausal status and pregnancy history influence progression of atherosclerosis. This study examined activation and interactions among blood elements with subclinical atherosclerosis in menopausal women with known pregnancy histories.Carotid intima-media thickness (CIMT), as a marker of subclinical atherosclerosis, was measured using B-mode ultrasound in age- and parity-matched women [40 with and 40 without a history of preeclampsia] 35 years after the index pregnancy. Interactions among intravascular cells (38 parameters) were measured by flow cytometry in venous blood. Data analysis was by principal component which retained 7 independent dimensions accounting for 63% of the variability among 38 parameters.CIMT was significantly greater in women with a history of preeclampsia (P = 0.004). Platelet aggregation and platelet interactions with granulocytes and monocytes positively associated with CIMT in postmenopausal women independent of their pregnancy history (ρ = 0.258, P< 0.05). However, the association of the number of platelets, platelet activation and monocyte-platelet interactions with CIMT differed significantly depending upon pregnancy history (test for interaction, P