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Background: Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. Methods: Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non‐case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non‐case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta‐analyzed using inverse‐variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)). Results: Meta‐analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75–0.79 in training set; AUC = 0.72, 95% CI = 0.69–0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma‐atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. Conclusion: This first large‐scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management. [ABSTRACT FROM AUTHOR]

We sought to identify genome‐wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome‐wide antihypertensive drug‐single nucleotide polymorphism (SNP) interaction tests for four drug classes (β‐blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide‐like diuretics, n = 3,516; ACE‐inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta‐analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome‐wide significance in the β‐blocker‐SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10−8). rs139945292 was validated through BP response to β‐blockers, with the T‐allele associated with less BP reduction (systolic BP response P = 6 × 10−4, Beta = 3.09, diastolic BP response P = 5 × 10−3, Beta = 1.53). The T‐allele was also associated with increased adverse cardiovascular risk within the β‐blocker treated patients' subgroup (P = 2.35 × 10−4, odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β‐blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome‐wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE‐inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β‐blocker treated patients. Further investigation into this region is warranted. [ABSTRACT FROM AUTHOR]

Objective: To evaluate which rapid blood administration technique causes the least iatrogenic hemolysis in canine packed red blood cells (pRBCs) as determined by plasma free hemoglobin (fHb) and percent hemolysis (% hemolysis). Design: Prospective in vitro randomized study. Setting: Private referral center. Animals: None. Interventions: Thirteen units of canine pRBCs were divided equally into 5 aliquots, resulting in 65 trials. The aliquots of each unit were subjected to the following administration techniques: gravity‐driven (control), an infusion pump at maximal rate, application of a pressure bag, manual compression, and syringe bolus. Plasma fHb and % hemolysis were recorded before and after each trial. Rate of administration (mL/s) was calculated for each method. Measurements and main results: Compared to the control, there were no significant increases in % hemolysis or plasma fHb noted among any of the trial methods. The manual compression and syringe bolus methods resulted in the fastest transfusion rates, whereas the infusion pump was not faster than the gravity‐driven method. Despite a storage time of ≤14 days, 15% of pRBC units had unsuitable (>0.8%) hemolysis before even being subjected to the trials. Conclusions: Commonly used rapid infusion techniques in small animal transfusion medicine do not cause significant iatrogenic hemolysis of canine pRBCs in vitro, although a significant risk is present in stored blood. This suggests that if an expedited transfusion is needed, any method described in this study could be considered, although stored pRBCs should be tested for unsuitable levels of hemolysis prior to transfusion. [ABSTRACT FROM AUTHOR]

Background: Non‐Hodgkin lymphoma in humans is associated with environmental chemical exposures, and risk is enhanced by genetic variants in glutathione S‐transferases (GST) enzymes. Objective: We hypothesized that boxer dogs, a breed at risk for lymphoma, would have a higher prevalence of GST variants with predicted low activity, and greater accumulated DNA damage, compared to other breeds. We also hypothesized that lymphoma in boxers would be associated with specific environmental exposures and a higher prevalence of canine GST variants. Animals Fifty‐four healthy boxers and 56 age‐matched nonboxer controls; 63 boxers with lymphoma and 89 unaffected boxers ≥10 years old. Methods: We resequenced variant loci in canine GSTT1, GSTT5, GSTM1, and GSTP1 and compared endogenous DNA damage in peripheral leukocytes of boxers and nonboxers using the comet assay. We also compared GST variants and questionnaire‐based environmental exposures in boxers with and without lymphoma. Results: Endogenous DNA damage did not differ between boxers and nonboxers. Boxers with lymphoma were more likely to live within 10 miles of a nuclear power plant and within 2 miles of a chemical supplier or crematorium. Lymphoma risk was not modulated by known canine GST variants. Conclusions and Clinical Importance: Proximity to nuclear power plants, chemical suppliers, and crematoria were significant risk factors for lymphoma in this population of boxers. These results support the hypothesis that aggregate exposures to environmental chemicals and industrial waste may contribute to lymphoma risk in dogs. [ABSTRACT FROM AUTHOR]

Objective: Determine the correlation between kaolin‐activated thromboelastography (TEG) variables (R, K, angle, and maximum amplitude [MA]) and PCV, fibrinogen concentration (FC), and total fibrinogen (TF) in an ex vivo model. Animals: Two healthy adult mixed‐breed dogs. Procedures: Citrated whole blood was obtained and separated into packed red cells, platelet rich plasma, and platelet poor plasma (PPP). An aliquot of PPP was heated to denature heat labile proteins (fibrinogen, factor V, factor VIII). Blood components were recombined for analyses of 6 physiological scenarios: anemia with low fibrinogen; anemia with moderate fibrinogen; anemia with normal fibrinogen; anemia with normal saline; normal PCV and normal fibrinogen; and normal PCV and low fibrinogen. A Kruskal–Wallis test, along with linear regressions on pairwise combinations of TEG variables, was used to determine the correlation between TEG variables and PCV, FC, and TF. Results: Maximum amplitude correlated with FC (R2 0.60, P < 0.001) and TF (R2 0.57, P < 0.001) but not PCV (R2 0.003, P = 0.7). Angle and K time were moderately correlated with FC ([angle: R2 0.53, P < 0.001]; [K: R2 0.55, P < 0.001]) and TF ([alpha angle: R2 0.52, P < 0.001]; [K: R2 0.51, P < 0.001]) but not PCV. The R time was weakly correlated with PCV (R2 0.15, P < 0.009) but not FC or TF. Conclusions and clinical relevance: In an ex vivo model, plasma proteins but not PCV impacted TEG variables. This suggests that TEG changes noted with anemia are imparted by changes in available fibrinogen in a fixed microenvironment rather than artifact of anemia. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic knowledge regarding noncardiovascular and all‐cause mortality in apparently healthy cats (AH) and cats with preclinical hypertrophic cardiomyopathy (pHCM) is limited, hindering development of evidence‐based healthcare guidelines. Objectives: To characterize/compare incidence rates, risk, and survival associated with noncardiovascular and all‐cause mortality in AH and pHCM cats. Animals: A total of 1730 client‐owned cats (722 AH, 1008 pHCM) from 21 countries. Methods: Retrospective, multicenter, longitudinal, cohort study. Long‐term health data were extracted by medical record review and owner/referring veterinarian interviews. Results: Noncardiovascular death occurred in 534 (30.9%) of 1730 cats observed up to 15.2 years. Proportion of noncardiovascular death did not differ significantly between cats that at study enrollment were AH or had pHCM (P = .48). Cancer, chronic kidney disease, and conditions characterized by chronic weight‐loss‐vomiting‐diarrhea‐anorexia were the most frequently recorded noncardiovascular causes of death. Incidence rates/risk of noncardiac death increased with age in AH and pHCM. All‐cause death proportions were greater in pHCM than AH (65% versus 40%, respectively; P < .001) because of higher cardiovascular mortality in pHCM cats. Comparing AH with pHCM, median survival (study entry to noncardiovascular death) did not differ (AH, 9.8 years; pHCM, 8.6 years; P = .10), but all‐cause survival was significantly shorter in pHCM (P =.0001). Conclusions and Clinical Importance: All‐cause mortality was significantly greater in pHCM cats due to disease burden contributed by increased cardiovascular death superimposed upon noncardiovascular death. [ABSTRACT FROM AUTHOR]

Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value = 0.001) and a phosphatidylcholine (q value = 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value = 0.040) and several high polyunsaturated fatty acid lipids (PUFAs). The half‐maximal inhibitory concentration (IC50) values of chenodeoxycholate and taurocholate were 13.55 and 19.51 μM, respectively, consistent with a physiological significance. In silico analysis suggested that bile acid inhibition of CES1 involved both binding to the active and superficial sites of the enzyme. We initiated identification of metabolites predicting PKs of drugs metabolized by CES1 and suggest lipids to regulate or be regulated by this enzyme. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. Hypothesis/Objectives: Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). Animals: One thousand seven hundred and thirty client-owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). Methods: Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long-term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. Results: During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean6standard deviation, 1.3±1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9-15 years. Conclusions and Clinical Importance: Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality. [ABSTRACT FROM AUTHOR]

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10‐6). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor‐beta (TGF‐β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D. [ABSTRACT FROM AUTHOR]

Abstract: Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV‐infected patients. Seventy‐four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging‐PGx‐PK association and interaction analyses were conducted using one‐way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P‐glycoprotein (P‐gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants. The clearance and cellular distribution of TFV were associated with P‐gp, MRP2, and concentrative nucleoside transporters (CNTs), and FTC parameters were associated with organic cation transporters (OCTs) and MRP2 genetic variants. Notably, p16INK4a expression, a cellular aging marker, predicted EFV and FTC PK when genetic factors were adjusted. Both age and p16INK4a expression interacted with PGx on ATV and TFV disposition, implying potential dose adjustment based on aging may depend on genetic background. [ABSTRACT FROM AUTHOR]

Introduction The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. Methods Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ 1–42 , tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. Discussion Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. [ABSTRACT FROM AUTHOR]

Objective To characterize the correlation between thromboelastography (TEG) variables using strong activators and anti-Xa (AXa) activity in healthy dogs administered subcutaneous unfractionated heparin (UFH). Design Prospective experimental study. Setting University research facility. Animals Eight adult random-source male dogs. Intervention Dogs were randomized to receive subcutaneous UFH at 200, 250, or 300 IU/kg every 8 hours for a total of 10 injections. Blood samples were collected at time 0 (preheparin) and 3, 6, and 8 hours after the 1st (Day 1) and 10th (Day 4) UFH injection. After the 8-hour blood sample was obtained on day 4, a 100 IU/kg IV bolus of UFH was administered and an additional blood sample was collected 1 hour later (hour 9). AXa activity, activated partial thromboplastin time (aPTT), and TEG (with up to 5 activators) were performed at each time point. Modes of activation for TEG included recalcified (Ca), Ca with heparinase (CaH), CaH and tissue factor 1:3600 (CTF3600H), Ca with tissue factor 1:100 (CTF100), and RapidTEG. Spearman rank correlations were calculated for each of the aforementioned parameters and the AXa activity. P-values were corrected for multiple comparisons with a Bonferroni correction. Measurements and Main Results Significant correlations were found between AXa activity and the TEG R values generated with CTF100 (R = 0.83, P ≤ 0.0001) and RapidTEG (R = 0.90, P < 0.0001), as well as both forms of aPTT measurement (R = 0.86 and 0.84, P < 0.0001). Conclusions This study demonstrates that TEG variables derived using robust activation correlate with AXa activity as well as aPTT and have the potential to be used for monitoring UFH therapy in healthy dogs. Future studies are warranted to evaluate its diagnostic utility in critically ill animals. [ABSTRACT FROM AUTHOR]

Canine immune thrombocytopenia ( ITP) is analogous to human ITP, with similar platelet counts and heterogeneity in bleeding phenotype among affected individuals. With a goal of ultimately investigating this bleeding heterogeneity, a canine model of antibody-mediated ITP was developed. Infusion of healthy dogs with 2 F9, a murine Ig G2a monoclonal antibody to the canine platelet glycoprotein GPIIb (a common target of autoantibodies in ITP) resulted in profound, dose-dependent thrombocytopenia. Model dogs developed variable bleeding phenotypes, e.g. petechiae and haematuria, despite similar degrees of thrombocytopenia. 2 F9 infusion was not associated with systemic inflammation, consumptive coagulopathy, or impairment of platelet function. Unexpectedly however, evaluation of cytokine profiles led to the identification of platelets as a potential source of serum interleukin-8 ( IL8) in dogs. This finding was confirmed in humans with ITP, suggesting that platelet IL8 may be a previously unrecognized modulator of platelet-neutrophil crosstalk. The utility of this model will allow future study of bleeding phenotypic heterogeneity including the role of neutrophils and endothelial cells in ITP. [ABSTRACT FROM AUTHOR]

The standard in genetic association studies of complex diseases is replication and validation of positive results, with an emphasis on assessing the predictive value of associations. In response to this need, a number of analytical approaches have been developed to identify predictive models that account for complex genetic etiologies. Multifactor Dimensionality Reduction (MDR) is a commonly used, highly successful method designed to evaluate potential gene-gene interactions. MDR relies on classification error in a cross-validation framework to rank and evaluate potentially predictive models. Previous work has demonstrated the high power of MDR, but has not considered the accuracy and variance of the MDR prediction error estimate. Currently, we evaluate the bias and variance of the MDR error estimate as both a retrospective and prospective estimator and show that MDR can both underestimate and overestimate error. We argue that a prospective error estimate is necessary if MDR models are used for prediction, and propose a bootstrap resampling estimate, integrating population prevalence, to accurately estimate prospective error. We demonstrate that this bootstrap estimate is preferable for prediction to the error estimate currently produced by MDR. While demonstrated with MDR, the proposed estimation is applicable to all data-mining methods that use similar estimates. [ABSTRACT FROM AUTHOR]