Alcohol and stroke: the splitters win again.

Study of the relationships of alcohol drinking and risk of stroke can readily become mired in the labyrinthine interactions of drinking categorizations, non-linear associations, disparate cardiovascular conditions, and the heterogeneous types of stroke. This Commentary discusses the recent article by Larsson et al. (BMC Medicine 14:178, 2016). The authors split their material into separate meta-analyses of subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke, finding disparate alcohol-stroke relationships. Our Commentary pursues the disparity theme, using the lumpers versus splitters paradigm to explore several aspects of this complex area.Please see related article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0721-4 .

Risk of cancer in Asian Americans: a Kaiser Permanente cohort study.

PURPOSE: To supplement published cohort data about incident cancer in Asian Americans (Asians) including risk of specific Asian ethnic groups. METHODS: A cohort study in 124,193 persons (13,344 Asians) with baseline examination data in 1978-1985 used Cox proportional hazards models with seven covariates to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: Through 2012 cancer was diagnosed in 18,687 persons including 1,522 Asians. Compared to Whites, the HR (CIs) for any cancer in Asians was 0.8 (0.7-0.9, p < 0.001). Lower Asian risk was stronger for men (HR = 0.7, p < 0.001) than for women (HR = 0.9, p = 0.003). Lower Asian vs. White risks with p < 0.05 were found for cancers of the upper airway digestive area, hematologic malignancies, melanoma, and cancers of the prostate, bladder, and brain. Melanoma contributed substantially to lower Asian risk, especially in women. HRs for specific Asian groups versus Whites follow: Chinese = 0.9 (p < 0.001), Japanese = 0.9 (p = 0.01), Filipinos = 0.8 (p < 0.001), South Asians = 0.5 (p < 0.001), and Other Asians = 0.7 (p = 0.006). Both South Asian men and women had lower risk than Whites, and South Asians had lower risk than any other racial/ethnic group. CONCLUSIONS: Asians had lower cancer risk than Whites, due to lower risk of several cancer types. Each Asian ethnic group had lower risk than Whites with South Asians at the lowest risk.

Moderate alcohol intake and cancer: the role of underreporting.

PURPOSE: There is compelling evidence that heavy alcohol drinking is related to increased risk of several cancer types, but the relationship of light-moderate drinking is less clear. We explored the role of inferred underreporting among light-moderate drinkers on the association between alcohol intake and cancer risk. METHODS: In a cohort of 127,176 persons, we studied risk of any cancer, a composite of five alcohol-associated cancer types, and female breast cancer. Alcohol intake was reported at baseline health examinations, and 14,880 persons were subsequently diagnosed with cancer. Cox proportional hazard models were controlled for seven covariates. Based on other computer-stored information about alcohol habits, we stratified subjects into 18.4 % (23,363) suspected of underreporting, 46.5 % (59,173) not suspected of underreporting, and 35.1 % (44,640) of unsure underreporting status. RESULTS: Persons reporting light-moderate drinking had increased cancer risk in this cohort. For example, the hazard ratios (95 % confidence intervals) for risk of any cancer were 1.10 (1.04-1.17) at <1 drink per day and 1.15 (1.08-1.23) at 1-2 drinks per day. Increased risk of cancer was concentrated in the stratum suspected of underreporting. For example, among persons reporting 1-2 drinks per day risk of any cancer was 1.33 (1.21-1.45) among those suspected of underreporting, 0.98 (0.87-1.09) among those not suspected, and 1.20 (1.10-1.31) among those of unsure status. These disparities were similar for the alcohol-related composite and for breast cancer. CONCLUSIONS: We conclude that the apparent increased risk of cancer among light-moderate drinkers may be substantially due to underreporting of intake.

Short QT in a cohort of 1.7 million persons: prevalence, correlates, and prognosis.

BACKGROUND: Short QT syndrome (QTc ≤ 300 ms) is a novel hereditary channelopathy linked to syncope, paroxysmal atrial fibrillation, and sudden cardiac death. However, its epidemiological features remain unsettled. OBJECTIVES: (1) To assess the prevalence of short QT in a large population-based sample; (2) to evaluate its demographic and clinical correlates and; (3) to determine its prognosis. METHODS: A database of 6.4 million electrocardiograms (ECGs) obtained between 1995 and 2008 among 1.7 million persons was used. An internal, population-based method for heart rate correction (QTcreg ) was used and all ECGs with QTcreg ≤300 ms were manually validated. Linked health plan databases were used for covariate and survival ascertainment. RESULTS: Of 6,387,070 ECGs, 1086 had an ECG with machine-read QTcreg ≤300 ms. Only 4% (45/1086) were validated yielding a prevalence of 0.7 per 100,000 or 1 of 141,935 ECGs. At the person level, the overall prevalence of QTcreg ≤300 ms was 2.7 per 100,000 or 1 of 37,335. The factors independently and significantly associated with validated QTcreg ≤300 ms were age over 65 years, Black race, prior history of ventricular dysrhythmias, chronic obstructive pulmonary disease, ST-T abnormalities, ischemia, bigeminy pattern, and digitalis effect. After 8.3 years of median follow-up and relative to normal QTcreg , validated QTcreg ≤300 ms was associated after multivariate adjustment with a 2.6-fold (95% confidence interval [CI] = 1.9-3.7) increased risk of death. CONCLUSION: QTcreg ≤300 ms was extraordinarily rare and was associated with significant ECG abnormalities and reduced survival.

The South Asian Paradox.

For several decades we have studied health outcomes in identified Asian American (ASAM) ethnic groups, comparing ASAM subgroups to whites and to each other. The most striking disparities we found involved South Asians (SAs). The SA individuals had higher coronary artery disease (CAD) risk and lower cancer risk than whites or any other ASAM group. The SA individuals also did not share the lower venous thromboembolism risk of all other ASAM groups. The relatively low prevalence of CAD risk traits in SAs with high CAD incidence defines a paradox. Exploration of these data might help the search for therapeutic and preventive medical benefits.

Lower risk of venous thromboembolism in multiple Asian ethnic groups.

Lower risk of venous thromboembolism in Asians compared to Whites has been suggested. Despite the biological and cultural diversity of Asian Americans, data are sparse for specific ethnic groups. In our prior study of lower Asian American risk, the small number of subjects (337 in all races) precluded accurate study of specific Asian American groups. We present here a new study with 4674 venous thromboembolism subjects diagnosed between 1996 and 2015. Our study population was derived from 61,459 voluntary health examinees in a comprehensive northern California health plan with self-classified ethnicity: 53.0% Whites, 28.4% Blacks, 11.6% ASAMs, 6.8% Others. Of Asian Americans, 44.7% were Chinese, 32.8% Filipinos, 12.9% Japanese, 4.5% South Asians, and 5.0% Other Asians. Chinese, Japanese, Filipinos, and Other Asians each had lower venous thromboembolism risk than both Whites and South Asians, who had risk similar to each other. These data indirectly support a genetic explanation.

Invited commentary: never, or hardly ever? It could make a difference.

A paper showing that about one half of persons stating lifelong alcohol abstinence had previously reported drinking (Am J Epidemiol 2008;168(8):866-871) reopens debate about the validity of this frequently used referent group in alcohol-health studies. Misclassification of lifelong abstainers could result in underestimation of harmful effects of heavy drinking and overestimation of benefits of lighter drinking. Imprecise and unreliable ascertainment of alcohol intake is the rule in the area of alcohol epidemiology research. However, inaccurate ascertainment of past infrequent drinking may have less effect upon outcome estimates than the consequences of other measurement errors such as underreporting of intake. Communication about alcohol-health relations would be improved if all research reports explicitly described queries and methods by which alcohol intake was categorized and if limitations were always frankly acknowledged.

The confounded relation of coffee drinking to coronary artery disease.

After decades of conflicting studies, the relation of coffee drinking to coronary artery disease (CAD) risk remains unresolved. Using Cox proportional-hazards models with 5 covariates, 127,212 subjects who supplied baseline data at voluntary health examinations from 1978 to 1985 were studied. Subsequently, 8,357 subjects were hospitalized for CAD. Coffee drinking was unrelated to CAD risk in 58,888 never smokers, but in ex-smokers and current baseline smokers, daily coffee intake was associated with higher CAD risk. This disparity was generally consistent in stratified subgroups. In conclusion, this relation of coffee consumption to increased CAD risk only in smokers could be explained by incomplete control for smoking, by other traits of smokers, or by an adverse biologic interaction of a coffee ingredient with smoking effect on CAD.

Low Cancer Risk of South Asians: A Brief Report.

CONTEXT: South Asians (ancestry in India, Pakistan, Bangladesh, or Sri Lanka) may have lower cancer risk than other racial-ethnic groups. OBJECTIVE: To supplement published cohort data suggesting low cancer risk in South Asians. DESIGN: Logistic regression models with 7 covariates to study cancer mortality through 2012 in 273,843 persons (1117 South Asians) with baseline examination data from 1964 to 1985. MAIN OUTCOME MEASURE: Cancer mortality. RESULTS: Through 2012, death was attributed to cancer in 28,031 persons, of which 1555 were Asians, including 32 South Asians. The all-Asian vs white adjusted odds ratio was 1.0, and the South Asian vs white odds ratio was 0.5 (p < 0.001). In separate regressions, South Asians were at lower risk than blacks, Chinese, Filipinos, Japanese, or other Asians. The South Asian-white disparity was concentrated in men but was generally similar when strata of smoking, body mass index, baseline age, and date of death were compared. CONCLUSION: These data support the observation that compared with whites and other Asian groups, South Asians, especially men, have a lower risk of cancer.

Coffee, cirrhosis, and transaminase enzymes.

BACKGROUND: A minority of persons at risk develop liver cirrhosis, but knowledge of risk modulators is sparse. Several reports suggest that coffee drinking is associated with lower cirrhosis risk. METHODS: We studied 125,580 multiethnic members of a comprehensive prepaid health care plan without known liver disease who supplied baseline data at voluntary health examinations from 1978 to 1985. Subsequently, through 2001, 330 of them were diagnosed with liver cirrhosis. Review of medical records confirmed the diagnosis of cirrhosis and ascertained probable etiology. The association of coffee drinking with cirrhosis was estimated by Cox proportional hazards models with 7 covariates. We also did a cross-sectional analysis of baseline aspartate aminotransferase and alanine aminotransferase levels, studied by logistic regression. RESULTS: In the cohort study, relative risks of alcoholic cirrhosis (199 subjects) for coffee drinking (vs none) were less than 1 cup per day, 0.7 (95% confidence interval [CI], 0.4-1.1); 1 to 3 cups, 0.6 (95% CI, 0.4-0.8; P<.001); and 4 or more cups, 0.2 (95% CI, 0.1-0.4; P<.001). For 131 subjects with nonalcoholic cirrhosis, relative risks were less than 1 cup, 1.2 (95% CI, 0.6-2.2); 1 to 3 cups, 1.3 (95% CI, 0.8-2.1); and 4 or more cups, 0.7 (95% CI, 0.4-1.3). These relative risks for coffee drinking were consistent in subsets. Tea drinking was unrelated to alcoholic or nonalcoholic cirrhosis. In the cross-sectional analyses, coffee drinking was related to lower prevalence of high aspartate aminotransferase and alanine aminotransferase levels; for example, the odds ratio of 4 or more cups per day (vs none) for a high aspartate aminotransferase level was 0.5 (95% CI, 0.4-0.6; P<.001) and for a high alanine aminotransferase level, 0.6 (95% CI, 0.6-0.7; P<.001), with stronger inverse relations in those who drink large quantities of alcohol. CONCLUSION: These data support the hypothesis that there is an ingredient in coffee that protects against cirrhosis, especially alcoholic cirrhosis.

Body Mass Index and Mortality in a Very Large Cohort: Is It Really Healthier to Be Overweight?

CONTEXT: Controversy persists about optimal body weight. Many experts define "normal" (healthy) body mass index (BMI) as 18.5 to 24.9 kg/m2, 25 to 29.9 kg/m2 as overweight, and 30 kg/m2 or greater as obese. Obesity is subdivided into 30 to 34.9 kg/m2 (Grade 1), 35 to 39.9 kg/m2 (Grade 2), and 40 kg/m2 and above (Grade 3). Studies consistently show higher mortality for underweight and Grade 2 or 3 obesity, but results conflict for the overweight category and Grade 1 obesity. OBJECTIVE: To study 30-year risk of death related to baseline BMI. DESIGN: Retrospective cohort study in a multiracial population of 273,843 persons using logistic regression with 7 covariates (sex, age, race-ethnicity, education, marital status, smoking, alcohol intake). MAIN OUTCOME MEASURES: Mortality risk by baseline BMI. RESULTS: With average follow-up exceeding 30 years, there were 103,218 deaths: 41,215 attributed to cardiovascular causes and 62,003 to noncardiovascular causes. Odds ratios (and 95% confidence intervals) for all deaths in BMI categories, with a BMI of 18.5 to 24.9 kg/m2 as the referent, were BMI below 18.5 kg/m2 = 1.1 (1.0-2.0), BMI 25 to 29 kg/m2 = 1.1 (1.1-1.2), BMI 30 to 34 kg/m2 = 1.5 (1.4-1.5), BMI 35 to 39 kg/m2 = 2.1 (1.9-2.3), and BMI 40 kg/m2 or higher = 2.7 (2.4-3.0). Disparities existed regarding age, race/ethnicity, cause of death, and interval to death. CONCLUSION: Compared with persons with BMI defined as normal, persons who were underweight, overweight, and obese were at increased risk of death over 30 years.

Sequelae of systemic hypertension in alcohol abstainers, light drinkers, and heavy drinkers.

A link exists between alcohol intake and increased blood pressure (BP), with many studies showing increased hypertension prevalence in heavy drinkers. The harmful and beneficial effects of alcohol can confound the study of the long-term risks of alcohol-related hypertension. We therefore studied cardiovascular sequelae separately in heavy drinkers, light drinkers, and abstainers among 127,212 subjects with BP and alcohol intake ascertained at 1978 to 1985 health examinations. Subsequent cardiovascular end points included mortality risk, hospitalization risk, and outpatient diagnosis of hypertension. Analyses were performed for all subjects and stratified by 5 alcohol-drinking categories (from never drinkers to >or=3 drinks/day). With <120/80 mm Hg as the referent, Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for 3 higher BP categories (120 to 129/80 to 84, 130 to 139/85 to 89, and >or=140/90 mm Hg). The covariates were age, gender, race, body mass index, education, and smoking. The risk of all outcomes was progressively higher for increasing BP categories, with a similarly increased risk for abstainers, light drinkers, and heavy drinkers. The interaction tests for alcohol and BP were not statistically significant for the mortality and hospitalization outcomes. Interpretation was limited by an inability to separate subjects with increased BP from alcohol consumption from those with other etiologies. In conclusion, the data indicate that the risks of hypertension are similar regardless of the amount of alcohol consumption.

Higher prevalence of systemic hypertension among moderate alcohol drinkers: an exploration of the role of underreporting.

OBJECTIVE: Heavy alcohol drinking is associated with increased prevalence of systemic hypertension (HTN), but the relationship between moderate drinking and HTN remains unclear. We explored the possible role of underreporting among moderate drinkers. METHOD: In a cross-sectional analysis of 105,378 persons, we defined a subset among persons reporting three or fewer drinks per day that was likely to include a disproportionate number of underreporters. This subset included persons who, on another occasion, indicated intake of three or more drinks per day or who ever had a diagnosis of an alcohol-related condition; these persons are called "positive." Persons who never reported three or more drinks per day and who had no alcohol-related diagnosis were called "negative." Logistic regression models estimated the odds ratios (ORs) for prevalent HTN (140/90 mm Hg or greater) in the positive and negative subgroups, compared with lifelong abstainers as referent. All persons and four race-gender groups were studied, and they were controlled for age, education, smoking, and body mass index. We also studied the relationship of blood liver transaminase enzyme levels in the positive and negative subgroups at specific alcohol intake strata. RESULTS: For persons reporting one to two drinks per day, the OR (95% confidence interval) of HTN was 1.32 (1.21-1.43) for positive persons and 1.16 (1.09-1.25) for negative persons. For those reporting less than one drink per day, the ORs were 0.97 (0.89-1.06) for positives and 0.92 (0.87-0.98) for negatives. For those reporting one to two drinks per day, positive/negative comparisons showed approximately a 75% increased prevalence of high liver transaminase enzymes. For those reporting less than one drink per day, the positive/negative difference was approximately 30%. CONCLUSION: In these data, increased prevalence of HTN among persons reporting one to two drinks per day appears to be partially due to underreporting of alcohol intake.

Alcohol drinking and risk of hospitalization for heart failure with and without associated coronary artery disease.

Myocardial damage from heavy alcohol intake can cause the heart failure (HF) syndrome, but the relation of lighter alcohol intake to HF has rarely been studied. We examined the risk of HF hospitalization among 126,236 subjects who supplied data about alcohol during health examinations from 1978 to 1985. Among 2,594 subjects who were subsequently hospitalized for HF, record review established an association between coronary artery disease (CAD) and HF (CAD-HF) in 1,559 patients. Among the remaining 1,035 subjects who had HF (non-CAD-HF), we attempted determination of preponderant etiologic and contributory factors. Analyses used Cox models that were controlled for 7 covariates, with usual alcohol intake studied categorically compared with that in subjects who did not drink alcohol. Heavier drinkers (> or =3 drinks/day) but not light to moderate drinkers had increased risk of non-CAD-HF; e.g., relative risk for subjects who reported > or =6 drinks/day was 1.7 (95% confidence interval 1.1 to 2.6). This association of non-CAD-HF with heavy drinking was limited to subsets with cardiomyopathy or of unclear preponderant etiology. Alcohol drinking was inversely related to risk of CAD-HF (e.g., at 1 to 2 drinks/day, relative risk 0.6, 95% confidence interval 0.5 to 0.7), with consistency across subgroups of age, gender, ethnicity, education, smoking status, interval to diagnosis, and presence or absence of baseline heart disease or systemic hypertension. Moderate drinking was inversely related to non-CAD-HF only in subjects who had diabetes mellitus (n = 252). In conclusion, heavy, but not light, alcohol drinking is associated with increased risk of non-CAD-HF and that apparent protection by alcohol drinking against CAD-HF risk provides confirmation of a protective effect of alcohol against CAD.

Health problems and hospitalizations among Asian-American ethnic groups.

OBJECTIVES: To study health status and hospitalization risk among Asian Americans. DESIGN: Cross-sectional analyses and cohort study. SETTING: Comprehensive prepaid health care program in Northern California. PATIENTS: Adult Asian Americans (N=13,592), self-classified at health examinations as 6050 (44.5%) Chinese, 1707 (12.6%) Japanese, 4232 (31.1%) Filipinos, 714 (5.3%) South Asians, and 889 (6.5%) Other Asians. INTERVENTIONS: None except data analysis. OUTCOME MEASURES: With Chinese and Whites (n=72,019) as referents, comparison of symptom composites by logistic regression and hospitalization risk by Cox proportional hazards models. RESULTS: Compared to Chinese, Filipinos, South Asians, and other Asians more frequently reported coronary, respiratory, gastrointestinal, and emotional problems. Chinese and Japanese generally had the lowest hospitalization risk. Compared to Chinese, hospitalization risk was higher (P<.05) among Filipinos for circulatory (men or women), respiratory (men), and digestive (women) conditions (relative risks [RR] range from 1.5 to 1.7) and among South Asian men for cardiovascular conditions (RR=2.2). While Asian groups generally had similar or lower hospitalization risk than Whites, risks were higher for asthma (Filipino and South Asian men, RRs >3.0), peptic ulcer (Chinese men, Filipino men and women, other Asian women [RRs 1.9-5.6]), and coronary disease (South Asian men (RR=2.3) and Filipino women (RR=1.5). CONCLUSIONS: Variations in risk of hospitalization and frequency of reported health problems point out differences in health problems and health needs among subgroups of Asian Americans. This diversity shows the need to study Asian ethnic groups separately.

Alcohol intake, beverage choice, and cancer: a cohort study in a large kaiser permanente population.

The authors studied incident cancer risk from 1978 to 1985 and through follow-up in 2012 relative to light-to-moderate and heavy drinking and to the choice of alcoholic beverage in a cohort of 124,193 persons. With lifelong abstainers as referent, heavy drinking (≥ 3 drinks per day) was associated with increased risk of 5 cancer types: upper airway/digestive tract, lung, female breast, colorectal, and melanoma, with light-to-moderate drinking related to all but lung cancer.

The early repolarization normal variant electrocardiogram: correlates and consequences.

PURPOSE: We compared the characteristics and outcomes of patients with "early repolarization" electrocardiograms (ECGs) with those who had normal ECGs. METHODS: In 1983 to 1985, we collected photocopies of 2234 selected ECGs from 73088 patients undergoing health examinations. Excluding 153 ECGs with missing data or that were judged to be abnormal, the remaining ECGs were reinterpreted in 2000 by cardiologists as showing early repolarization (n = 670), or being borderline (n = 330) or normal (n = 1081). Characteristics and outcomes of persons with early repolarization ECGs were compared with those who had normal ECGs using analysis of variance, logistic regression, or proportional hazards models. Information on exercise was available in 325 patients. RESULTS: Patients with early repolarization were more likely to be male (81% [n = 583] vs. 33% [n = 360]), <40 years old (60% [n = 441] vs. 37% [n = 403]), black (48% [n = 384] vs. 26% [n = 280]), and more athletically active (mean [+/- SD], 10.4 +/- 1.3 hours per week of activity vs. 6.4 +/- 1.2 hours per week of activity) than those with normal ECGs. Patients with early repolarization were not more likely to be hospitalized (hazard ratio [HR] = 1.0; 95% confidence interval [CI]: 0.9 to 1.2) or to die (HR = 0.8; 95% CI: 0.6 to 1.2) during follow-up than those with normal ECGs. Outpatient diagnoses were not more common in those with early repolarization; arrhythmias were actually less common (P <0.01). CONCLUSION: Although especially prevalent in young, athletic, black men, early repolarization is not rare in other patients. The long-term prognosis of early repolarization is benign.

Analysis of late risk of systemic blood pressures <120/80 mm Hg.

We studied categories of blood pressure (BP) <120/80 mm Hg as predictors of hypertension 10 to 22 years later by logistic regression analyses with 6 covariates. There was progressively increased risk for subjects with systolic BP 100 to 109 and 110 to 119 mm Hg (vs <100 mm Hg) or diastolic BP 70 to 74 and 75 to 79 mm Hg (vs <70 mm Hg). These relations were similar in men, women, and several ethnic groups but stronger in subjects <40 years old. These data suggest a definition of optimal BP of <100/70 mm Hg, similar to usual BP levels in children <10 years old.

Traits of persons who drink decaffeinated coffee.

PURPOSE: Little is known about the traits of decaffeinated coffee drinkers, who are sometimes used to ascertain whether the health effects of coffee intake are due to caffeine or some other coffee ingredient. METHODS: We studied these traits in 12,467 persons who reported type of coffee consumed at health examinations; 36% drank caffeinated only, 13% drank decaffeinated only, 27% drank both types and 24% drank no coffee. RESULTS: Odds ratios estimated from logistic regression analyses revealed that compared with regular (caffeinated) coffee drinkers or abstainers, decaffeinated coffee drinkers were less likely to be heavy coffee drinkers, smokers, alcohol drinkers, users of caffeinated soft drinks and medication and to be free of illness. Increased decaffeinated coffee drinking was associated with older age, female sex, African American ethnicity, use of special diets and cardiovascular, gastrointestinal, or neuropsychiatric symptoms. Persons on special diets were more likely to drink decaffeinated coffee whether they had heart disease or were free of any illness. CONCLUSION: These data suggest that decaffeinated coffee use is related to illness in some persons but to a healthy lifestyle in others. These potential and possibly conflicting confounding factors need to be considered when studying the health effects of coffee or caffeine.

Alcohol and cardiovascular diseases: a historical overview.

Studying its history generally provides insights relevant to current understanding of a subject: the health effects of alcohol consumption is no exception to this rule. Perceiving past errors in the hopes of avoiding their repetition is crucial. Because there are clear disparities in the relationships of alcohol drinking to various cardiovascular conditions, attempts to simplify the subject of alcohol and cardiovascular diseases have delayed understanding this area. Thus, the following are considered separately: cardiomyopathy, arsenic and cobalt beer-drinkers' disease, cardiovascular beri-beri, systemic hypertension, cardiac arrhythmias, stroke, atherosclerotic coronary heart disease (CHD), total mortality, and definitions of safe drinking limits. The basic disparity underlying all alcohol-health relations is between effects of lighter and heavier drinking.