Premature Ventricular Complexes on Screening Electrocardiogram and Risk of Ischemic Stroke

Background and Purpose— Premature ventricular complexes (PVCs) detected from long-term ECG recordings have been associated with an increased risk of ischemic stroke. Whether PVCs seen on routine ECG, commonly used in clinical practice, are associated with an increased risk of ischemic stroke remains unstudied. Methods— This analysis included 24 460 participants (aged, 64.5+9.3 years; 55.1% women; 40.0% blacks) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who were free of stroke at the time of enrollment. PVCs were ascertained from baseline ECG (2003–2007), and incident stroke cases through 2011 were confirmed by an adjudication committee. Results— A total of 1415 (5.8%) participants had at least 1 PVC at baseline, and 591 developed incident ischemic stroke during an average (SD) follow-up of 6.0 (2.0) years. In a cox proportional hazards model adjusted for age, sex, race, geographic region, education, previous heart disease, systolic blood pressure, blood pressure–lowering medications, current smoking, diabetes mellitus, left ventricular hypertrophy by ECG, and aspirin use and warfarin use, the presence of PVCs was associated with 38% increased risk of ischemic stroke (hazard ratio [95% confidence interval], 1.38 [1.05–1.81]). Conclusions— PVCs are common on routine screening ECGs and are associated with an increased risk of ischemic stroke.

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Left ventricular geometry and risk of incident hypertension

Heart ◽

10.1136/heartjnl-2018-314657 ◽

2019 ◽

Vol 105 (18) ◽

pp. 1402-1407 ◽

Cited By ~ 2

Author(s):

Sung Keun Park ◽

Ju Young Jung ◽

Jeong Gyu Kang ◽

Pil-Wook Chung ◽

Chang-Mo Oh

Keyword(s):

Wall Thickness ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Left Ventricular ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Left Ventricular Geometry ◽

Incident Hypertension ◽

Increased Risk ◽

Echocardiographic Parameters

ObjectiveLeft ventricular (LV) geometry change is an independent predictor for cardiovascular disease. However, data are equivocal on the association of echocardiographic parameters of LV geometry with incident hypertension. Thus, we were to investigate the risk of hypertension according to the baseline echocardiographic parameters of LV geometry.MethodsStudy participants were 12 562 Koreans without hypertension who received echocardiography as an item of health check-up. They were divided into normotensive or prehypertensive group according to baseline blood pressure. In each group, study subjects were classified by quintiles of baseline echocardiographic parameters including left ventricular mass index (LVMI), relative wall thickness (RWT), interventricular septal thickness (IVST), posterior wall thickness (PWT) and IVST plus PWT and followed up for 5 years. Cox proportional hazards model was used in calculating adjusted HRs and their 95% CI for hypertension according to each quintile group. Area under the curve (AUC) analysis (AUC [95% CI]) was performed to compare the predictability of LVMI, RWT, IVST, PWT, IVST plus PWT for hypertension.ResultsPrehypertensive group had the worse clinical and echocardiographic parameters in baseline analysis than normotensive group. The risk of hypertension significantly increased proportionally to baseline LVMI, RWT, IVST, PWI and IVST plus PWT above specific quintile levels, which was identified in both normotensive and prehypertensive group. In AUC analysis, IVST, PWT and IVST plus PWT showed a significantly increased AUC, compared with LVMI.ConclusionLV geometry change was significantly associated with the increased risk for hypertension in non-hypertensive individuals.

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Blood pressure levels and risk of haemorrhagic stroke in patients with atrial fibrillation and anticoagulants: results from a primary care cohort with hypertension

European Heart Journal ◽

10.1093/ehjci/ehaa946.2725 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J.-E Bager ◽

L Schioler ◽

K Manhem ◽

P Hjerpe ◽

H Odesjo ◽

...

Keyword(s):

Atrial Fibrillation ◽

Blood Pressure ◽

Primary Care ◽

Proportional Hazards Model ◽

Haemorrhagic Stroke ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Funding Source ◽

Spline Curve ◽

Increased Risk

Abstract Background Haemorrhagic stroke (HS) is a serious condition that kills and debilitates many of those afflicted by it. Hypertension and oral anticoagulation (OAC) are independent risk factors for HS. Many patients with atrial fibrillation (AF) have hypertension and OAC. The concomitance of hypertension and OAC confers an even higher risk of haemorrhagic stroke, but less is known about the association between specific blood pressure levels and the risk of HS in patients with AF and OAC. Purpose To assess the risk of haemorrhagic stroke at different systolic blood pressure (SBP) levels in a primary care population with hypertension, AF and OAC. Methods We identified 3972 patients with hypertension, AF and OAC in a primary care database in southern Sweden. We followed patients from Jan 1, 2006 until a first event of HS, death, cessation of OAC or Dec 31, 2016. HS was defined as ICD-10 diagnosis codes: I60, I61, and I62. We analysed the association between SBP levels and HS by dividing SBP into five categories: <130, 130–139, 140–159, 160–179 and ≥180 mmHg. We also fitted a spline curve to visualise the relationship between SBP and HS. Hazard ratios (HR) were calculated for the SBP categories with a Cox proportional hazards model. The 130–139 group was used as a reference in the model. We identified age, sex, previous stroke, platelet inhibitor treatment, alcohol abuse and smoking as possible confounders with a directed acyclic graph and included them as co-variates in the model. Results We identified 51 cases of HS during follow-up. In the categorical analysis of SBP, point estimates of HRs for HS increased gradually from the lowest SBP category to the 160–179 category. Only the 160–179 category had a significantly different HR (3.76, CI 1.56–9.04) than the reference 130–139 category, however. See Table 1. No other co-variates were significantly associated with HS. The spline curve, Figure 1, illustrates a significantly increased HR for HS in the 140–175 SBP range. Conclusions In this real-world primary care cohort with hypertension, AF and OAC, we found that SBP in the 160–179 mmHg range was significantly associated with an increased risk of haemorrhagic stroke. Our findings emphasise the importance of blood pressure control in this patient category. Figure 1. Continuous and categorical SBP & HS risk Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The study was financed by grants from the Swedish state under the agreement between the Swedish government and the country councils, the ALF-agreement.

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Abstract P291: Anger Expression and Risk of Stroke Subtypes: The Circulatory Risk in Communities Study (CIRCS)

Circulation ◽

10.1161/circ.125.suppl_10.ap291 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Tetsuya Ohira ◽

Takeshi Tanigawa ◽

Hironori Imano ◽

Akihiko Kitamura ◽

Masahiko Kiyama ◽

...

Keyword(s):

Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Proportional Hazards Model ◽

Statistical Significance ◽

Anger Expression ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Adjusted Relative Risk ◽

Stroke Subtypes ◽

Increased Risk

Background: Previous studies have reported that anger expression style is associated with cardiovascular disease and its risk factors. Epidemiologic data regarding the association between anger expression and risk of stroke have been inconsistent, and few studies have reported the association of anger expression with stroke subtypes. Hypothesis: We assessed the hypothesis that suppressed anger is associated with increased risk of stroke, and the associations vary by stroke subtype. Methods: A prospective study of Japanese subjects aged 30–74 years was undertaken using data collected from 6,276 participants (2,285 men and 3,991 women) in cardiovascular risk surveys conducted in four communities between 1995 and 1998. We used the Spielberger Anger Expression Scale to measure self-reported levels of anger expression style; anger expressed outwardly is regarded as “anger-out” and anger held in or suppressed is classified as “anger-in.” The incidence of stroke was ascertained by systematic surveillance. The hazard ratios (HRs) of incidence of stroke and its subtypes and 95% confidence intervals (CI) relative to the lowest tertile of anger expression were calculated with adjustment for age and other potential confounding factors using the Cox proportional hazards model. Results: During an average follow up of 9.1-years, 129 incident strokes (50 hemorrhagic, 77 ischemic, and 2 unclassified strokes) occurred. Men with “anger-in” scores in the highest tertile had a 1.7-fold multivariable-adjusted relative risk of stroke as compared with those in the lowest tertile, but it did not reach statistical significance (HR; 1.73, 95% CI; 0.94–3.19, p=0.08). When stratifying for stroke subtypes, the associations between “anger-in” and stroke tended to be stronger for hemorrhagic stroke than ischemic stroke; HRs (95% CI) were 3.82 (1.03–14.1) for hemorrhagic stroke and 1.32 (0.64–2.71) for ischemic stroke. Anger-in score was not associated with incidence of either hemorrhagic or ischemic stroke in women. In men and women, there were no significant associations between “anger-out” and incidence of stroke. As compared with the lowest tertile of “anger-out” scores, the multivariable-adjusted HRs of stroke for the highest tertile of “anger-out” scores were 1.39 (0.74–2.59) for men and 1.48 (0.78–2.78) for women, respectively. Conclusions: Suppressed anger may be associated with increased risk of hemorrhagic stroke among middle-aged Japanese men, but not women.

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Glucocorticoid use is associated with an increased risk of hypertension

Rheumatology ◽

10.1093/rheumatology/keaa209 ◽

2020 ◽

Vol 60 (1) ◽

pp. 132-139

Author(s):

Ruth E Costello ◽

Belay B Yimer ◽

Polly Roads ◽

Meghna Jani ◽

William G Dixon

Keyword(s):

Blood Pressure ◽

Cumulative Dose ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Incident Hypertension ◽

Increased Risk

Abstract Objectives Patients with RA are frequently treated with glucocorticoids (GCs), but evidence is conflicting about whether GCs are associated with hypertension. The aim of this study was to determine whether GCs are associated with incident hypertension in patients with RA. Methods A retrospective cohort of patients with incident RA and without hypertension was identified from UK primary care electronic medical records (Clinical Practice Research Datalink). GC prescriptions were used to determine time-varying GC use, dose and cumulative dose, with a 3 month attribution window. Hypertension was identified through either: blood pressure measurements >140/90 mmHg, or antihypertensive prescriptions and a Read code for hypertension. Unadjusted and adjusted Cox proportional hazards regression models were fitted to determine whether there was an association between GC use and incident hypertension. Results There were 17 760 patients in the cohort. A total of 7421 (42%) were prescribed GCs during follow-up. The incident rate of hypertension was 64.1 per 1000 person years (95% CI: 62.5, 65.7). The Cox proportional hazards model indicated that recent GC use was associated with a 17% increased hazard of hypertension (hazard ratio 1.17; 95% CI: 1.10, 1.24). When categorized by dose, only doses above 7.5 mg were significantly associated with hypertension. Cumulative dose did not indicate a clear pattern. Conclusion Recent GC use was associated with incident hypertension in patients with RA, in particular doses ≥7.5 mg were associated with hypertension. Clinicians need to consider cardiovascular risk when prescribing GCs, and ensure blood pressure is regularly monitored and treated where necessary.

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Risk Factors Associated with Time to First Infection and Time to Failure on CAPD

Peritoneal Dialysis International ◽

10.1177/089686088300303s04 ◽

1983 ◽

Vol 3 (3_suppl) ◽

pp. 14-17 ◽

Cited By ~ 10

Author(s):

Paul N. Corey ◽

Cathy Steele

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Serum Creatinine ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Time To Failure ◽

Continuous Variables ◽

Risk Of Failure ◽

Increased Risk

The Cox proportional hazards model was used to identify prognostic risk factors for time to first infection and time to failure among 183 patients on chronic ambulatory peritoneal dialysis (CAPD). This methodology permits continuous variables such as albumin and blood pressure to be used in the predictive equation avoiding arbitrary categorization. Initial serum creatinine and albumin were found to be related to the risk of first infection. Serum creatinine increases the risk whereas albumin is protective. Age and blood pressure are related to an increased risk of failure on CAPD whereas albumin is associated with a lower risk. The occurrence of the first infection almost doubles the risk of failure. Patients who have “high” albumin and “low” blood pressure have a 75th percentile for time to failure on CAPD which is more than 1000 days longer than those who have both “low” albumin and “high” blood pressure.

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Migraine and incidence of ischemic stroke: A nationwide population-based study

Cephalalgia ◽

10.1177/0333102416642602 ◽

2016 ◽

Vol 37 (4) ◽

pp. 327-335 ◽

Cited By ~ 25

Author(s):

Kuan-Po Peng ◽

Yung-Tai Chen ◽

Jong-Ling Fuh ◽

Chao-Hsiun Tang ◽

Shuu-Jiun Wang

Keyword(s):

Ischemic Stroke ◽

Migraine With Aura ◽

Proportional Hazards Model ◽

Population Based ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Research Database ◽

Increased Risk ◽

Comparison Cohort ◽

Matched Comparison

Background The association between migraine and the incidence of ischemic stroke varies in different subgroups of patients. We aimed to clarify this association using a population-based database. Method A nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Two cohorts were extracted: a neurologist-diagnosed migraine cohort, and a non-headache, propensity score-matched comparison cohort. All participants were enrolled in this study between 2005 and 2009, and were followed through the end of 2010, death, or the occurrence of ischemic stroke. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated with a Cox proportional hazards model to compare the between-group risks. Results Both cohorts ( n = 119,017 each) were followed for a mean period of 3.6 ± 1.3 years. A total of 744 migraine patients (429,741 person-years) and 617 matched comparison individuals (436,141 person-years) developed ischemic stroke during the research period. Compared to the comparison cohort, patients with migraine were at an increased risk of ischemic stroke (aHR: 1.24, 95% CI: 1.12–1.38, p < 0.001). Subgroup analysis by age and sex revealed the highest risk in women aged ≤ 45 years (aHR: 3.44, 95% CI: 2.20–5.39, p < 0.001), especially among those with migraine with aura (aHR: 4.58, 95% CI: 2.45 – 8.56, p < 0.001). A trend for increased stroke risk was observed in men aged ≤ 45 years (aHR: 1.54, 95% CI: 0.96–2.48, p = 0.075). Conclusion Migraine is associated with an increased risk of ischemic stroke, especially in younger (age ≤ 45 years) women with migraine with aura. The trend toward ischemic stroke in younger men merits further exploration.

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Elevated plasma growth and differentiation factor 15 predicts incident anemia in older adults aged 60 years and older

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa324 ◽

2020 ◽

Author(s):

Yuko Yamaguchi ◽

Marta Zampino ◽

Toshiko Tanaka ◽

Stefania Bandinelli ◽

Yusuke Osawa ◽

...

Keyword(s):

Older Adults ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Differentiation Factor ◽

Hazards Model ◽

Increased Risk ◽

The Relationship

Abstract Background Anemia is common in older adults and associated with greater morbidity and mortality. The causes of anemia in older adults have not been completely characterized. Although elevated circulating growth and differentiation factor 15 (GDF-15) has been associated with anemia in older adults, it is not known whether elevated GDF-15 predicts the development of anemia. Methods We examined the relationship between plasma GDF-15 concentrations at baseline in 708 non-anemic adults, aged 60 years and older, with incident anemia during 15 years of follow-up among participants in the Invecchiare in Chianti (InCHIANTI) Study. Results During follow-up, 179 (25.3%) participants developed anemia. The proportion of participants who developed anemia from the lowest to highest quartile of plasma GDF-15 was 12.9%, 20.1%, 21.2%, and 45.8%, respectively. Adults in the highest quartile of plasma GDF-15 had an increased risk of developing anemia (Hazards Ratio 1.15, 95% Confidence Interval 1.09, 1.21, P<.0001) compared to those in the lower three quartiles in a multivariable Cox proportional hazards model adjusting for age, sex, serum iron, soluble transferrin receptor, ferritin, vitamin B12, congestive heart failure, diabetes mellitus, and cancer. Conclusions Circulating GDF-15 is an independent predictor for the development of anemia in older adults.

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Abstract 187: Electrocardiographic Heart Rate-corrected Qt Interval And Risk Of Stroke In The REasons For Geographic And Racial Differences In Stroke (REGARDS) Study

Stroke ◽

10.1161/str.43.suppl_1.a187 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Elsayed Z Soliman ◽

George Howard ◽

Mary Cushman ◽

Brett Kissela ◽

...

Keyword(s):

Heart Rate ◽

Racial Differences ◽

Qt Interval ◽

Proportional Hazards ◽

Left Ventricular ◽

Cox Proportional Hazards ◽

Corrected Qt Interval ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk ◽

Regards Study

Background: Prolongation of heart rate-corrected QT interval (QTc) is a well established predictor of cardiovascular morbidity and mortality. Little is known, however, about the relationship between this simple electrocardiographic (ECG) marker and risk of stroke. Methods: A total of 27,411 participants aged > 45 years without prior stroke from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were included in this analysis. QTc was calculated using Framingham formula (QTcFram). Stroke cases were identified and adjudicated during an up to 7 years of follow-up (median 2.7 years). Cox proportional hazards analysis was used to estimate the hazard ratios for incident stroke associated with prolonged QTcFram interval (vs. normal) and per 1 standard deviation (SD) increase, separately, in a series of incremental models. Results: The risk of incident stroke in the study participants with baseline prolonged QTcFram was almost 3 times the risk in those with normal QTcFram [HR (95% CI): 2.88 (2.12, 3.92), p<0.0001]. After adjustment for age, race, sex, antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, prior cardiovascular disease, QRS duration, warfarin use, and QT-prolonging drugs (full model), the risk of stroke remained significantly high [HR (95% CI): 1.67 (1.16, 2.41), p=0.0060)], and was consistent across several subgroups of REGARDS participants. When the risk of stroke was estimated per 1 SD increase in QTcFram, a 24% increased risk was observed [HR (95% CI): 1.24 (1.16, 1.33), p<0.0001)]. This risk remained significant in the fully adjusted model [HR (95% CI): 1.12 (1.03, 1.21), p=0.0055]. Similar results were obtained when other QTc correction formulas including Hodge’s, Bazett’s and Fridericia’s were used. Conclusions: QTc prolongation is associated with a significantly increased risk of incident stroke independently from known stroke risk factors. In light of our results, examining the risk of stroke associated with QT-prolonging drugs may be warranted.

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Abstract P670: Obesity and Mortality After the First Ischemic Stroke: Is Obesity Paradox Real?

Stroke ◽

10.1161/str.52.suppl_1.p670 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Durgesh Chaudhary ◽

Ayesha Khan ◽

Mudit Gupta ◽

Yirui Hu ◽

Jiang Li ◽

...

Keyword(s):

Ischemic Stroke ◽

Proportional Hazards Model ◽

Obesity Paradox ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Obese Patients ◽

Stroke Patients ◽

Stroke Event ◽

One Year ◽

First Time

Introduction: Obesity is an established risk factor for ischemic stroke but the association of increased body mass index (BMI) with survival after ischemic stroke remains controversial. Many studies have shown that increased BMI has a “protective” effect on survival after stroke while other studies have debunked the obesity paradox. This study aimed at examining the relationship between BMI and all-cause mortality at one year in first-time ischemic stroke patients using data extracted from different resources including electronic health records. Methods: We analyzed consecutive ischemic stroke patients captured in the Geisinger NeuroScience Ischemic Stroke (GNSIS) database. Survival in first-time ischemic stroke patients was analyzed using Kaplan-Meier estimator, stratified by different BMI categories. The predictors of mortality at one-year were assessed using a multivariate Cox proportional hazards model. Results: Among 6,703 first-time adult ischemic stroke patients, mean age was 70.2 ±13.5 years and 52% were men. Of these patients, 24% patients were non-overweight (BMI < 25), 34% were overweight (BMI 25-29.9) and 41% were obese (BMI ≥ 30). One-year survival probability was significantly higher in overweight patients (87%, 95% CI: [85.6 - 88.4], p<0.001) and obese patients (89.5%, 95% CI: [88.4 - 90.7], p<0.001) compared to non-overweight patients (78.1%, 95% CI: [76.0 - 80.1]). In multivariate analysis, one-year mortality was significantly lower in overweight and obese patients (overweight patients- HR = 0.61 [95% CI, 0.52 - 0.72]; obese patients- HR = 0.56 [95% CI, 0.48 - 0.67]). Other significant predictors of one-year mortality were age at the ischemic stroke event (HR = 1.04 [95% CI, 1.03 - 1.04]), history of neoplasm (HR = 1.59 [95% CI, 1.38 - 1.85]), atrial fibrillation or flutter (HR = 1.26 [95% CI, 1.09 - 1.46]), heart failure (HR = 1.68 [95% CI, 1.42 - 1.98]), diabetes mellitus (HR = 1.27 [95% CI, 1.1 - 1.47]), rheumatic disease (HR = 1.37 [95% CI, 1.05 - 1.78]) and myocardial infarction ((HR = 1.23 [95% CI, 1.02 - 1.48]). Conclusion: Our results support the obesity paradox in ischemic stroke patients as shown by a significantly decreased hazard ratio for one-year mortality among overweight and obese patients in comparison to non-overweight patients.

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Blood eosinophils on hospital admission for COPD exacerbation do not predict the recurrence of moderate and severe relapses

ERJ Open Research ◽

10.1183/23120541.00543-2020 ◽

2021 ◽

Vol 7 (1) ◽

pp. 00543-2020

Author(s):

Balázs Csoma ◽

András Bikov ◽

Ferenc Tóth ◽

György Losonczy ◽

Veronika Müller ◽

...

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Forced Expiratory Volume ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Full Blood Count ◽

Rank Test ◽

Severe Exacerbation ◽

Increased Risk ◽

Exacerbation Of Copd

Background and objectiveThe relationship between hospitalisation with an eosinophilic acute exacerbation of COPD (AE-COPD) and future relapses is unclear. We aimed to explore this association by following 152 patients for 12 months after hospital discharge or until their first moderate or severe flare-up.MethodsPatients hospitalised with AE-COPD were divided into eosinophilic and non-eosinophilic groups based on full blood count results on admission. All patients were treated with a course of systemic corticosteroid. The Cox proportional hazards model was used to study the association with the time to first re-exacerbation; a generalised linear regression model was applied to identify clinical variables related to the recurrence of relapses.ResultsWe did not find a difference in the time to the next moderate or severe exacerbation between the eosinophilic (≥2% of total leukocytes and/or ≥200 eosinophils·µL−1, n=51, median (interquartile range): 21 (10–36) weeks) and non-eosinophilic groups (n=101, 17 (9–36) weeks, log-rank test: p=0.63). No association was found when other cut-off values (≥3% of total leukocytes and/or ≥300 eosinophils·µL−1) were used for the eosinophilic phenotype. However, the higher number of past severe exacerbations, a lower forced expiratory volume in 1 s (FEV1) at discharge and higher pack-years were related to shorter exacerbation-free time. According to a subgroup analysis (n=73), 48.1% of patients with initial eosinophilic exacerbations had non-eosinophilic relapses on readmission.ConclusionsOur data do not support an increased risk of earlier recurring moderate or severe relapses in patients hospitalised with eosinophilic exacerbations of COPD. Eosinophilic severe exacerbations present a variable phenotype.

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