High-risk Phenotype Research Articles

0855 Primary Sleep Disorders And The Combined Outcome Of Poor Sleep Quality With Objective Short Sleep Duration In Older Persons

Abstract Introduction Poor sleep quality with short sleep duration (SSD) is a high-risk phenotype that is likely to be associated with primary sleep disorders (obstructive sleep apnea [OSA], periodic limb movements of sleep [PLMS], and restless legs syndrome [RLS]) in older persons. We evaluated the associations among primary sleep disorders and this high-risk phenotype in older persons. Methods Using data on 3,058 men from the Osteoporotic Fractures in Men Sleep Study and 3,127 women from the Study of Osteoporotic Fractures, mean ages 76 and 84 years, respectively, we evaluated cross-sectional associations between primary sleep disorders and the combined outcome of poor sleep quality with actigraphic SSD. In women, OSA and RLS were evaluated by self-report. In men, OSA and PLMS were evaluated by polysomnography and RLS by self-report. Poor sleep quality was defined by Pittsburgh Sleep Quality Index score >5 and SSD by average total sleep time ≤6 hours from wrist actigraphy (averaged over ~5 days). Men and women were evaluated separately. Multivariate logistic regression models also included demographics, self-reported chronic conditions, anxiety, depression, and medication use. Results Poor sleep quality with actigraphic SSD was more prevalent in men (475 [15.6%]) than women (400 [13.1%]). In unadjusted models in men, odds of poor sleep quality with actigraphic SSD were significantly higher with OSA, PLMS, and RLS (ORs [95% Cis] = 1.99 [1.57, 2.52], 2.11 [1.41, 3.18], and 5.58 [2.51, 12.43], respectively). In multivariable models in men, odds of poor sleep quality with actigraphic SSD were significantly higher with OSA (1.59 [1.18, 2.14]) but not with PLMS or RLS. In unadjusted models in women, odds of poor sleep quality with actigraphic SSD were significantly higher with OSA (3.57 [0.40, 31.88]) and RLS (5.60 [3.04, 10.32]), but results were not significant in multivariable models in women. Conclusion Older persons with primary sleep disorders have higher odds of poor sleep quality with actigraphic SSD. However, the predominant mechanisms underlying this high-risk phenotype may be driven more by medical and psychiatric comorbidity than by primary sleep disorders. Support The American Academy of Sleep Medicine Foundation and the Yale Claude D. Pepper Older Americans Independence Center

0852 Geriatric Health Conditions And The Combined Outcome Of Poor Sleep Quality With Objective Short Sleep Duration

Abstract Introduction Poor sleep quality with objective short sleep duration (≤6 hours) is a high-risk phenotype. The associations of geriatric health conditions with this sleep phenotype have not been described. Methods Using data on 3,127 older women from the Study of Osteoporotic Fractures (SOF), mean age 84 years, and 3,058 older men from the Osteoporotic Fractures in Men Sleep Study (MrOS), mean age 76 years, we evaluated cross-sectional associations between geriatric health conditions and the combined outcome of poor sleep quality with actigraphic short sleep duration. Geriatric health conditions included cognitive impairment (modified MMSE score 1.5SD below the cohort mean value), physical impairment (inability to do a chair stand), falls (≥2 in past year), and vision impairment (acuity ≤20/40). Poor sleep quality was defined by Pittsburgh Sleep Quality Index (PSQI) score >5 and short sleep duration by average total sleep time ≤6 hours from wrist actigraphy (averaged over ~5 days). Women (SOF) and men (MrOS) were evaluated separately and multivariate logistic regression models also included age, race, education, comorbidities (medical, psychiatric, and primary sleep disorders), and medication use. Results Poor sleep quality with actigraphic short sleep duration was present in 475 (15.6%) men and 400 (13.1%) women. In men, the unadjusted odds of having combined poor sleep quality with actigraphic short sleep duration were statistically higher with cognitive impairment (OR=1.45 [CI 1.05, 1.98]), physical impairment (2.90 [1.87, 4.51]), and falls (1.97 [1.48, 2.62]). In women, the unadjusted odds of having combined poor sleep quality with actigraphic short sleep duration were statistically higher with physical impairment (1.54 [1.16, 2.04]) and falls (1.63 [1.21, 2.20]). However, these associations were no longer statistically significant in adjusted models (men and women). Conclusion Older persons with geriatric health conditions are more likely to have the combined phenotype of poor sleep quality with actigraphic short sleep duration, but this association is likely explained by comorbidity and medication use. Support Dr. Miner is supported by the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342), the American Academy of Sleep Medicine Foundation, a foundation of the American Academy of Sleep Medicine, and the National Institute on Aging T32AG019134.

The Neuropsychological Profile of Attention Deficits of Patients with Obstructive Sleep Apnea: An Update on the Daytime Attentional Impairment.

Introduction: Patients with obstructive sleep apnea (OSA) suffer from several neurocognitive disturbances. One of the neuropsychological processes most investigated in OSA patients is attention, but the results have been controversial. Here, we update the attention profile of OSA patients with the final aim to improve attention assessment, with a possible impact on clinical and medical-legal practices, in terms of which attention subdomains and parameters need consideration and which one is a high-risk OSA phenotype for attention dysfunctions. Method: For this purpose, we assessed 32 previously untreated OSA patients (26 men and 6 women) under 65 years of age (mean age 53.2 ± 7.3; mean education level 10.4 ± 3.4 years) suffering from moderate to severe sleep apnea and hypopnea (mean apnea-hypopnea index (AHI) 45.3 ± 22.9, range 16.1–69.6). A control group of 34 healthy participants matched with OSA patients for age, education level, and general cognitive functioning were also enrolled. The OSA patients and healthy participants were tested through an extensive computerized battery (Test of Attentional Performance, TAP) that evaluated intensive (i.e., alertness and vigilance) and selective (i.e., divided and selective) dimensions of attention and returned different outcome parameters (i.e., reaction time, stability of performance, and various types of errors). Data analysis: The data were analyzed by ANCOVA which compared the speed and accuracy performance of the OSA and control participants (cognitive reserve was treated as a covariate). The possible mechanisms underlying attention deficits in OSA patients were examined through correlation analysis among AHI, oxygenation parameters, sleepiness scores, and TAP outcomes and by comparing the following three phenotypes of patients: severe OSA and severe nocturnal desaturators (AHI++D+), severe OSA nondesaturators (AHI++D−), and moderate OSA nondesaturators (AHI+D−). Results: The results suggest that the OSA patients manifest deficits in both intensive and selective attention processes and that reaction time (RT) alone is ineffective for detecting and characterizing their problems, for which error analysis and stability of performance also have to be considered. Patients with severe OSA and severe hypoxemia underperformed on alertness and vigilance attention subtests. Conclusions: The data suggest the importance of evaluating attention deficits among OSA patients through several parameters (including performance instability). Moreover, the data suggest a multifaceted mechanism underlying attention dysfunction in OSA patients.

Impaired orthostatic heart rate recovery is associated with smaller thalamic volume: Results from The Irish Longitudinal Study on Aging (TILDA).

The thalamus is a central hub of the autonomic network and thalamic volume has been associated with high‐risk phenotypes for sudden cardiac death. Heart rate response to physiological stressors (e.g., standing) and the associated recovery patterns provide reliable indicators of both autonomic function and cardiovascular risk. Here we examine if thalamic volume may be a risk marker for impaired heart rate recovery in response to orthostatic challenge. The Irish Longitudinal Study on Aging involves a nationally representative sample of older individuals aged ≥50 years. Multimodal brain magnetic resonance imaging and orthostatic heart rate recovery were available for a cross‐sectional sample of 430 participants. Multivariable regression and linear mixed‐effects models were adjusted for head size, age, sex, education, body mass index, blood pressure, history of cardiovascular diseases and events, cardiovascular medication, diabetes mellitus, smoking, alcohol intake, timed up‐and‐go (a measure of physical frailty), physical exercise and depression. Smaller thalamic volume was associated with slower heart rate recovery (−1.4 bpm per 1 cm3 thalamic volume, 95% CI −2.01 to −0.82; p < .001). In multivariable analysis, participants with smaller thalamic volumes had a mean heart rate recovery −2.7 bpm slower than participants with larger thalamic volumes (95% CI −3.89 to −1.61; p < .001). Covariates associated with smaller thalamic volume included age, history of diabetes, and heavy alcohol consumption. Thalamic volume may be an indicator of the structural integrity of the central autonomic network. It may be a clinical biomarker for stratification of individuals at risk of autonomic dysfunction, cardiovascular events, and sudden cardiac death.

Concise Review of the Clinical Approach to the Exclusion and Diagnosis of Pulmonary Embolism in 2020

Pulmonary embolism has extremely varied clinical presentations and can be difficult to diagnose. Clinical decision rules can help determine the probability of pulmonary embolism by assessment of the clinical presentation. After the diagnosis, several prognostic rules can be used to risk-stratify and facilitate outpatient treatment of pulmonary embolism. This review addresses the utility of clinical decision rules, biomarkers in the diagnosis of pulmonary emoblism, high-risk patient phenotypes, the use of this data to make disposition decisions for patients with a diagnosis of PE, and recent shifts in the management of pulmonary embolism in the clinical setting.

Association of Nonobstructive Chronic Bronchitis With Respiratory Health Outcomes in Adults

Chronic bronchitis has been associated with cigarette smoking as well as with e-cigarette use among young adults, but the association of chronic bronchitis in persons without airflow obstruction or clinical asthma, described as nonobstructive chronic bronchitis, with respiratory health outcomes remains uncertain. To assess whether nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes in adult ever smokers and never smokers. This prospective cohort study included 22 325 adults without initial airflow obstruction (defined as the ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity [FVC] of <0.70) or clinical asthma at baseline. The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 9 US general population-based cohorts. Thus present study is based on data from 5 of these cohorts. Participants were enrolled from August 1971 through May 2007 and were followed up through December 2018. Nonobstructive chronic bronchitis was defined by questionnaire at baseline as both cough and phlegm for at least 3 months for at least 2 consecutive years. Lung function was measured by prebronchodilator spirometry. Hospitalizations and deaths due to chronic lower respiratory disease and respiratory disease-related mortality were defined by events adjudication and administrative criteria. Models were stratified by smoking status and adjusted for anthropometric, sociodemographic, and smoking-related factors. The comparison group was participants without nonobstructive chronic bronchitis. Among 22 325 adults included in the analysis, mean (SD) age was 53.0 (16.3) years (range, 18.0-95.0 years), 58.2% were female, 65.9% were non-Hispanic white, and 49.6% were ever smokers. Among 11 082 ever smokers with 99 869 person-years of follow-up, participants with nonobstructive chronic bronchitis (300 [2.7%]) had accelerated decreases in FEV1 (4.1 mL/y; 95% CI, 2.1-6.1 mL/y) and FVC (4.7 mL/y; 95% CI, 2.2-7.2 mL/y), increased risks of chronic lower respiratory disease-related hospitalization or mortality (hazard ratio [HR], 2.2; 95% CI, 1.7-2.7), and greater respiratory disease-related (HR, 2.0; 95% CI, 1.1-3.8) and all-cause mortality (HR, 1.5; 95% CI, 1.3-1.8) compared with ever smokers without nonobstructive chronic bronchitis. Among 11 243 never smokers with 120 004 person-years of follow-up, participants with nonobstructive chronic bronchitis (151 [1.3%]) had greater rates of chronic lower respiratory disease-related hospitalization or mortality (HR, 3.1; 95% CI, 2.1-4.5) compared with never smokers without nonobstructive chronic bronchitis. Nonobstructive chronic bronchitis was not associated with FEV1:FVC decline or incident airflow obstruction. The presence of at least 1 of the component symptoms of nonobstructive chronic bronchitis (ie, chronic cough or phlegm), which was common in both ever smokers (11.0%) and never smokers (6.7%), was associated with adverse respiratory health outcomes. The findings suggest that nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes, particularly in ever smokers, and may be a high-risk phenotype suitable for risk stratification and targeted therapies.

Development and validation of autophagy-related-gene biomarker and nomogram for predicting the survival of cutaneous melanoma.

Autophagy plays a critical role in cutaneous melanoma, but the prognostic research of differentially expressed autophagy-related genes (DEARGs) in melanoma is lacking. Therefore, autophagy-related gene expression data of 630 melanoma patients were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas database. The DEARGs were identified by "limma" package in R software. Best survival analysis and the least absolute shrinkage and selection operator method were performed to identify a robust 7-DEARG signature as well as construct nomogram associated with the clinical characteristics and validation in internal and external sets. This 7-DEARG signature could be regarded as an independent prognostic signature in clinical setting, and nomogram may supply a more simple and accurate prediction for the prognosis of melanoma. Moreover, 5 cancer hallmarks and 18 potential compounds are commonly enriched in high-risk expression phenotype. Thus, our finding provides new clinical evidences for the accurate diagnosis and identifies a potential prognostic autophagy-related marker for the treatment of melanoma.

The presence of ectopic atrial rhythm predicts adverse cardiovascular outcomes in a large hospital-based population

Whether ectopic atrial rhythm (EAR) is a high-risk cardiovascular phenotype (eg, the manifestation of a diseased sinoatrial node) or just a benign accelerated ectopic pacemaker remains unclear. We aimed to analyze the cardiovascular outcomes and underlying mechanisms in patients with EAR. From a 12-lead electrocardiogram hospital-based electrocardiogram database, a total of 2896 adults with EAR were propensity score matched at 1:5 with 14,480 patients with sinus rhythm (SR). Patients were retrospectively followed up for cardiovascular mortality (the primary outcome) and permanent pacemaker implantation (the secondary outcome). Heart rate variability was analyzed to compare autonomic function between patients with EAR and those with SR. The prevalence of EAR was 1.13%, which increased with age. Compared with the matched patients, those with EAR had a higher risk of cardiovascular mortality (adjusted hazard ratio 1.93; 95% confidence interval 1.52-2.44; P < .0001) and permanent pacemaker implantation (adjusted hazard ratio 5.94; 95% confidence interval 3.89-9.09; P < .0001) according to the Cox proportional hazards regression model. The risk of cardiovascular mortality was similar across the subgroups on the basis of age, sex, hypertension, type 2 diabetes mellitus, congestive heart failure, myocardial infarction, stroke, and chronic kidney diseases. In patients with EAR, the low frequency/high frequency and standard deviation of the mean normal-to-normal intervals/root mean square of successive RR interval differences ratios for heart rate variability were both lower than those in patients with SR. This implied autonomic imbalance in patients with EAR. Patients with EAR have a higher risk of cardiovascular mortality and permanent pacemaker implantation, which was associated with autonomic imbalance.

Identification of High-Risk Left Ventricular Hypertrophy on Calcium Scoring Cardiac Computed Tomography Scans: Validation in the DHS.

Coronary artery calcium scoring only represents a small fraction of all information available in noncontrast cardiac computed tomography (CAC-CT). We hypothesized that an automated pipeline using radiomics and machine learning could identify phenotypic information about high-risk left ventricular hypertrophy (LVH) embedded in CAC-CT. This was a retrospective analysis of 1982 participants from the DHS (Dallas Heart Study) who underwent CAC-CT and cardiac magnetic resonance. Two hundred twenty-four participants with high-risk LVH were identified by cardiac magnetic resonance. We developed an automated adaptive atlas algorithm to segment the left ventricle on CAC-CT, extracting 107 radiomics features from the volume of interest. Four logistic regression models using different feature selection methods were built to predict high-risk LVH based on CAC-CT radiomics, sex, height, and body surface area in a random training subset of 1587 participants. The respective areas under the receiver operating characteristics curves for the cluster-based model, the logistic regression model after exclusion of highly correlated features, and the penalized logistic regression models using least absolute shrinkage and selection operators with minimum or one SE λ values were 0.74 (95% CI, 0.67-0.82), 0.74 (95% CI, 0.67-0.81), 0.76 (95% CI, 0.69-0.83), and 0.73 (95% CI, 0.66-0.80) for detecting high-risk LVH in a distinct validation subset of 395 participants. Ventricular segmentation, radiomics features extraction, and machine learning can be used in a pipeline to automatically detect high-risk phenotypes of LVH in participants undergoing CAC-CT, without the need for additional imaging or radiation exposure. Registration: URL http://www.clinicaltrials.gov. Unique identifier: NCT00344903.

Clinical factors associated with acute exacerbations of chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is complicated by frequent acute exacerbations leading to significant health care burden and impaired quality of life. The objective of this study was to identify clinical factors associated with frequent acute exacerbation of CRS (AECRS). This is a retrospective cohort study of patients with CRS from January 1, 2014, to May 31, 2016. Frequent AECRS was defined as at least 4 episodes over a 12-month period in which an antibiotic was prescribed for worsening sinus symptoms, and infrequent AECRS was defined as 0 to 3 episodes. Clinical factors, including asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease, were evaluated for associations between the 2 groups. Of the 3109 patients with CRS who were identified, 600 (19.3%) were classified as having frequent exacerbation. Asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease were associated with frequent AECRS with statistically significant adjusted odds ratios (aORs) after controlling for age, race, and sex in multivariate analysis (asthma aOR= 2.61 [95% CI= 2.14-3.18]; allergic rhinitis aOR= 1.96 [95% CI= 1.58-2.42]; eosinophil count of at least 150 cells per microliter aOR= 1.54 [95% CI= 1.21-1.97]; and autoimmune disease aOR= 1.68 [95% CI= 1.36-2.07]). Antibody deficiency, antibiotic allergy, lower FEV1, radiographic sinus disease severity, nasal polyposis, and systemic corticosteroid use were also associated with frequent AECRS. Patients with frequent episodes of AECRS were characterized by a higher prevalence of asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, autoimmune disease, and other allergic and immunologic diseases. These findings identify a high-risk phenotype of patients with CRS for preventive interventions to reduce exacerbation frequency.

Lymphoma in Sjögren’s Syndrome: Predictors and Therapeutic Options

Sjogren’s syndrome (SS) is a chronic systemic disorder of autoimmune origin characterized by impaired secretory function of the exocrine glands and a high susceptibility for non-Hodgkin’s lymphoma development. The aim of the present review is to summarize the main clinical and molecular contributors of lymphoma development in the setting of SS and discuss current therapeutic options. Male sex, earlier SS onset, systemic features including salivary gland enlargement, purpura, lymphadenopathy, Raynaud’s phenomenon, tongue atrophy, autoantibody production, depressed C4 complement levels, monoclonal gammopathy, and cryoglobulinemia are the main features denoting a high-risk SS phenotype for the practicing clinician. Additional molecular markers involving innate immune pathways, B cell activation, and epigenetic alterations have been recently revealed. For the treatment of SS-related lymphoma, the basic principles for treatment of lymphomas in general are applied. Identification of predictors for lymphoma development in the setting of SS is of crucial importance for a prompt diagnosis and early therapeutic intervention. Moreover, discovery of novel genetic and epigenetic contributors through international collaborative efforts will allow a better understanding of underlying molecular pathways and establishment of tailored treatment approaches for these patients.

Effects of Family-Focused Therapy vs Enhanced Usual Care for Symptomatic Youths at High Risk for Bipolar Disorder

Behavioral high-risk phenotypes predict the onset of bipolar disorder among youths who have parents with bipolar disorder. Few studies have examined whether early intervention delays new mood episodes in high-risk youths. To determine whether family-focused therapy (FFT) for high-risk youths is more effective than standard psychoeducation in hastening recovery and delaying emergence of mood episodes during the 1 to 4 years after an active period of mood symptoms. This multisite randomized clinical trial included referred youths (aged 9-17 years) with major depressive disorder or unspecified (subthreshold) bipolar disorder, active mood symptoms, and at least 1 first- or second-degree relative with bipolar disorder I or II. Recruitment started from October 6, 2011, and ended on September 15, 2016. Independent evaluators interviewed participants every 4 to 6 months to measure symptoms for up to 4 years. Data analysis was performed from March 13 to November 3, 2019. High-risk youths and parents were randomly allocated to FFT (12 sessions in 4 months of psychoeducation, communication training, and problem-solving skills training; n = 61) or enhanced care (6 sessions in 4 months of family and individual psychoeducation; n = 66). Youths could receive medication management in either condition. The coprimary outcomes, derived using weekly psychiatric status ratings, were time to recovery from prerandomization symptoms and time to a prospectively observed mood (depressive, manic, or hypomanic) episode after recovery. Secondary outcomes were time to conversion to bipolar disorder I or II and longitudinal symptom trajectories. All 127 participants (82 [64.6%] female; mean [SD] age, 13.2 [2.6] years) were followed up for a median of 98 weeks (range, 0-255 weeks). No differences were detected between treatments in time to recovery from pretreatment symptoms. High-risk youths in the FFT group had longer intervals from recovery to the emergence of the next mood episode (χ2 = 5.44; P = .02; hazard ratio, 0.55; 95% CI, 0.48-0.92;), and from randomization to the next mood episode (χ2 = 4.44; P = .03; hazard ratio, 0.59; 95% CI, 0.35-0.97) than youths in enhanced care. Specifically, FFT was associated with longer intervals to depressive episodes (log-rank χ2 = 6.24; P = .01; hazard ratio, 0.53; 95% CI, 0.31-0.88) but did not differ from enhanced care in time to manic or hypomanic episodes, conversions to bipolar disorder, or symptom trajectories. Family skills-training for youths at high risk for bipolar disorder is associated with longer times between mood episodes. Clarifying the relationship between changes in family functioning and changes in the course of high-risk syndromes merits future investigation. ClinicalTrials.gov identifier: NCT01483391.

In silico analysis and high-risk pathogenic phenotype predictions of non-synonymous single nucleotide polymorphisms in human Crystallin beta A4 gene associated with congenital cataract.

In order to provide a cost-effective method to narrow down the number of pathogenic Crystallin beta A4 (CRYBA4) non-synonymous single nucleotide polymorphisms (nsSNPs), we collected nsSNP information of the CRYBA4 gene from SNP databases and literature, predicting the pathogenicity and possible changes of protein properties and structures using multiple bioinformatics tools. The nsSNP data of the CRYBA4 gene were collected from 4 databases and published literature. According to 12 criteria, six bioinformatics tools were chosen to predict the pathogenicity. I-Mutant 2.0, Mupro and INPS online tools were used to analyze the effects of amino acid substitution on protein stability by calculating the value of ΔΔG. ConSurf, SOPMA, GETAREA and HOPE online tools were used to predict the evolutionary conservation of amino acids, solvent accessible surface areas, and the physical and chemical properties and changes of protein structure. All 157 CRYBA4 nsSNPs were analyzed. Forty-four CRYBA4 high-risk pathogenic nsSNPs (predicted to be pathogenic by all six software tools) were detected out of the 157 CRYBA4 nsSNPs, four of which (c.283C>T, p.R95W; c.449T>A, p.V150D; c.475G>A, p.G159R; c.575G>C, p.R192P) should be focused on because of their high potential pathogenicity and possibility of changing protein properties. Thirty high-risk nsSNPs were predicted to cause a decrease of protein stability. Twenty-nine high-risk nsSNPs occurred in evolutionary conserved positions. Twenty-two high-risk nsSNPs occurred in the core of the protein. It is predicted that these high-risk pathogenic nsSNPs can cause changes in the physical and chemical properties of amino acids, resulting in structural changes of proteins and changes in the interactions between domains and other molecules, thus affecting the function of proteins. This study provides important reference value when narrowing down the number of pathogenic CRYBA4 nsSNPs and studying the pathogenesis of congenital cataracts. By using this method, we can easily find 44 high-risk pathogenic nsSNPs out of 157 CRYBA4 nsSNPs.

Risk Factors Associated with Development of Pulmonary Arterial Hypertension and Corpulmonale in Patients with Chronic Obstructive Pulmonary Disease

Background: Chronic Obstructive Pulmonary Disease is an important cause of morbidity and mortality globally. The onset of pulmonary hypertension and corpulmonale is associated with decreased survival in patients with COPD. Objective: To assess risk factors associated with the development of pulmonary hypertension and corpulmonale and to identify high-risk phenotypes who may need early evaluation and intervention. Methods: Consecutive adult patients with COPD were evaluated for factors influencing the development of pulmonary hypertension and corpulmonale which included symptomatology, hospitalization in the previous year, MMRC dyspnea grade, SGRQ score, 6 minute walk test, ABG, CRP, spirometry and echocardiography. Results: We found Pulmonary Hypertension in 36(30%) patients and 27(22.5%) had corpulmonale. On multivariate analysis, we found PaO2 ≤75 mm Hg and six minute walk test &lt;80% predicted to be significantly associated with the development of Pulmonary hypertension and we found hospitalization in the previous year to be significantly and independently associated with the development of corpulmonale. Conclusion: We observed hospitalization in the previous year was an independent risk factor for the development of corpulmonale and six-minute walk test &lt;80% predicted, PaO2 &lt;75 mm Hg were independent risk factors for the development of pulmonary hypertension.

Renal Dysfunction in Heart Failure With Preserved Ejection Fraction: Insights From the RELAX Trial

Patients with heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) represent a high-risk phenotype. The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial enrolled a high proportion of CKD participants, allowing investigation into differences in HFpEF by CKD status. Among 212 participants, we investigated the associations of CKD with biomarkers, cardiac structure, and exercise capacity, and identified predictors of change in estimated glomerular filtration rate (eGFR) over trial follow-up. CKD participants (eGFR ≤60 mL/min/1.73m2) were older, had more comorbidities, and had worse diastolic function. Lower eGFR was associated with higher levels of endothelin-1, N-terminal pro-B-type natriuretic peptide, aldosterone, uric acid, and biomarkers of fibrosis (P < .05 for all). Whereas lower eGFR was associated with worse peak oxygen consumption (VO2) after adjustment for demographics, clinical comorbidities, exercise modality, ejection fraction, and chronotropic index (β coefficient per 1 SD decrease in eGFR: -0.61, 95% CI: -1.01, -0.22, P = .002), this association was attenuated after further adjustment for hemoglobin (β coefficient: -0.26, 95% CI: -0.68, 0.16, P = .22). Hemoglobin mediated 35% of the association between eGFR and peak VO2. Sildenafil therapy was independently associated with worsening eGFR over the trial (β coefficient: -2.79, 95% CI: -5.34, -0.24, P = .03). Renal dysfunction in HFpEF is characterized by echocardiographic and biomarker profiles indicative of more advanced disease, and reduced hemoglobin is a strong mediator of the association between renal dysfunction and low exercise capacity. Sildenafil therapy was associated with worsening of renal function in RELAX.

Global Distribution of CYP2C19 Risk Phenotypes Affecting Safety and Effectiveness of Medications

Background: Genetic variability of CYP2C19 may affect safety or effectiveness of many drugs as outlined in the CPIC dosing guidelines. Aim was to determine the predictive prevalence of high-risk phenotypes due to CYP2C19 variants collectively in the world population. It was also aimed to establish a correlation how the identified high-risk phenotypes may affect safety or effectiveness of drugs. Methods: Frequency of CYP2C19*2, *3 and *17 alleles were obtained from 1000 Genomes project Phase III in line with Fort Lauderdale principles. Phenotypes were assigned using international standardized consensus terms based on the carrier of characteristics alleles. The CYP2C19 pharmacogenomics information of drugs were obtained from international pharmacogenomics working groups. Association of predicted high-risk phenotypes with the safety or effectiveness of medications were gained from CPIC dosing guidelines. Findings: Following CPIC dosing guidelines, ultrarapid metabolizers and poor metabolizers were considered as being as high-risk phenotypes for at least ten clinically important medications. Meta-analysis of the prevalence of high-risk phenotypes showed that it was statistically significant ( P <0.0001) in different ethnic groups with pooled prevalence of 27.4% (95% CI 18%-37%). The present study suggests that African (37.2%; 95% CI 34%-41%) and European (35.4%; 95% CI 31%-40%) population are being at particularly higher risk of either sub therapeutic drug responses or toxicities. Interpretation: Approximately one third of the world population were predictively identified as being as high-risk phenotypes affecting safety or effectiveness of certain number of medications. Large scale clinical studies are warranted to assess clinical outcomes of these medications considering CYP2C19 pharmacogenomics effects. Funding Statement: The author stated there was no funding. Declaration of Interests: The author declares no conflict of interest. Ethics Approval Statement: Not required.

160 Reduced NT-proBNP Threshold for Risk Prediction in High-Risk Elderly With Subclinical Heart Failure: Support From Cardiopulmonary Exercise Testing

Risk of heart failure (HF) progression in subclinical HF may not soley depend on echocardiographic abnormalities. Oxygen utilisation (VO2) provides prognostic information in symptomatic HF but data on VO2 and other prognostic cardiopulmonary test (CPET) measures in subclinical HF, especially in the elderly is lacking. VO2 may refine risk prediction in subclinical HF. 91 asymptomatic individuals ≥65 years (mean age 71±4 years, 53% female) with ≥1 non-ischaemic risk factor for HF underwent NT-proBNP measurement and treadmill CPET (modified Bruce protocol) to determine peak VO2. Low VO2 was defined as ≤20thpercentile in age and sex matched healthy populations. SBHF was defined as global longitudinal strain≤16%, diastolic dysfunction or LV hypertrophy (LVMI>95 g/m2[women], >115 g/m2[men]). 46 (51%) had SBHF and NT-proBNP did not differ by HF stage (59 [26-85]pg/ml vs 60 [30-99]pg/ml, SAHF vs SBHF, p=0.94). Average peak VO2 was 19.96±4.6ml/kg/min and was low in 71(78%). VO2 did not differ by HF stage 20.34±4.9ml/kg/min vs 19.55±4.4ml/kg/min for SAHF vs SBHF, p=0.62). NT-proBNP was significantly higher in those with abnormal VO2 (66 [34-110]pg/ml vs 31[20-70]pg/ml, p=0.016). Within each HF stage, low VO2 was associated with higher NT-proBNP (Figure). Of those with NT-proBNP >100pg/ml 95%had low VO2 compared with 72% of those ≤100pg/ml, p=0.02. In logistic regression analysis NT-proBNP independently associated with low VO2 (p=0.036). Low VO2 identifies a high-risk cardiac phenotype within subclinical HF. Levels of NT-proBNP beneath the cut-off used for HF exclusion may assist risk stratification in this population.

Prognostic significance of lymph node count in high-risk node-negative colon carcinoma.

the prognostic value of the number of lymph nodes isolated (< 12 versus ≥ 12) in the surgical specimen continues to be controversial. In this study, the impact of isolating fewer or more than 12 lymph nodes in stage II colon cancer with a high-risk biologic phenotype was analyzed, such as the presence of perineural invasion. all cases of stage II disease (T3-4N0M0) with perineural invasion (PNI+) were retrospectively identified from a prospective database of patients undergoing surgery for colon cancer. The cohort was divided into two groups depending on the number of lymph nodes isolated (< 12 vs ≥ 12). Apart from clinical and surgical data, the patterns of recurrence, overall (OS) and disease-free survival (DFS) at five and ten years were analyzed. sixty patients met the inclusion criteria, 31.7 % had < 12 lymph nodes isolated and 68.3 % had more than 12 isolated. There were no clinical or surgical differences between the two groups. OS at five and ten years was significantly lower in the patients with < 12 lymph nodes isolated (84.2 %, 62.7 % vs 94.6 % and 91.6 %, p = 0.01). DFS at five and ten years was 51 % vs 86.5 %, respectively (p = 0.005). the number of lymph nodes isolated (with a cutoff of 12) in stage II colon cancer with PNI+ has prognostic value and should therefore be borne in mind when planning adjuvant chemotherapy.

Biopsychosocial Influences on Shoulder Pain: Analyzing the Temporal Ordering of Postoperative Recovery

Shoulder surgery is a primary intervention for shoulder pain, yet many individuals experience persistent postoperative pain. Previously, we found individuals categorized as having a high-risk phenotype (comprised of COMT variation and pain catastrophizing) had approximately double the chance of not reaching a 12-month pain recovery criterion. As a means to better understand the development of persistent postoperative shoulder pain, this study advanced our previous work by examining temporal ordering of postoperative shoulder recovery based on potential mediating factors, and expansion of outcomes to include movement-evoked pain and shoulder active range of motion. Before surgery, individuals were categorized as either high-risk (high pain catastrophizing, COMT-genotype linked to low enzyme activity [n = 41]) or low-risk (low pain catastrophizing, COMT-genotype linked to normal enzyme activity [n = 107]). We then compared potential mediating variables at 3, 6, and 12 months postoperatively 1) endogenous pain modulation defined by a conditioned pain modulation paradigm; and 2) and emotion factors such as anxiety, fear of movement, and depressive symptoms. At 3 months, the high-risk subgroup had higher fear and movement-evoked pain, and causal mediation analysis confirmed the direct effect of risk subgroup on 12-month movement evoked pain. However, baseline to 12-month change in depressive symptoms were found to mediate 53% of the total effect of risk subgroup on 12-month movement-evoked pain. This study introduces potential temporal components and relationships to the development of persistent postoperative shoulder pain, which future studies will confirm and assess for potential therapeutic targets. PerspectiveThis study expands upon postoperative shoulder recovery measures to include movement-evoked pain and depressive symptoms, and provides preliminary indication of temporal ordering to postoperative shoulder recovery for a preidentified high-risk subgroup. Future studies will distinguish temporal components of shoulder surgery that may optimize treatment targets of postoperative recovery.

Genomic Analysis of R2CHOP-Treated DLBCL Reveals a High-Risk Population Driven By Inflammatory Pathways

Genomic Analysis of R2CHOP-Treated DLBCL Reveals a High-Risk Population Driven By Inflammatory Pathways