Background: This study used multi-level analysis to estimate which type of factor explains most of the variance in alcohol consumption of Vietnamese students. Methods: Data were collected among 6011 students attending 12 universities/faculties in four provinces in Vietnam. The three most recent drinking occasions were investigated per student, resulting in 12,795 drinking occasions among 4265 drinkers. Students reported on 10 aspects of the drinking context per drinking occasion. A multi-level mixed-effects linear regression model was constructed in which aspects of drinking context composed the first level; the age of students and four drinking motives comprised the second level. The dependent variable was the number of drinks. Results: Of the aspects of context, drinking duration had the strongest association with alcohol consumption while, at the individual level, coping motive had the strongest association. The drinking context characteristics explained more variance than the individual characteristics in alcohol intake per occasion. Conclusions: These findings suggest that, among students in Vietnam, the drinking context explains a larger proportion of the variance in alcohol consumption than the drinking motives. Therefore, measures that reduce the availability of alcohol in specific drinking situations are an essential part of an effective prevention policy. Heavy drinking among students in developed countries is well documented. In 2011, a study including 36 European countries showed a prevalence of drinking five or more drinks on one occasion in the last 30 days of 27%–61% among male students and 12%–53% among female students ,5. FactoConceptually, environmental factors are important for etiological explanations of drinking behavior . IndividDrinking context is very rarely studied in Vietnam. Only one study among young people aged over 15 years in three provinces in Vietnam showed that most people drink in the late afternoon (87% for wines/spirits and 31% for beer). In terms of the drinking place, the most frequently reported location was at home (55.5% when drinking wine and 22.2% when drinking beer), followed by parties/weddings (39.6% for wine and 16.4% for beer) and street bars (11.6% when drinking wine and 12.5% for beer) .While the study of contextual aspects is based on the assumption that the individual adjusts their drinking to the situation, most theories  assume that individual characteristics have the strongest influence on drinking. The assumption of this model is that motives are the most proximate determinant of an individual’s drinking and that other factors, like biochemical factors, personality characteristics, situational and other cognitive factors should be considered as antecedent factors, which are reflected in the motives of drinking ,20,21. IThe present study is based on the assumption that both drinking motives and drinking context characteristics are explanatory variables for alcohol consumption. Individuals might seek to participate in drinking environments that are consistent with their motivations. On the other hand, individuals interact with each other and the drinking environment that they are participating in. Therefore, the same individual may drink differently on different occasions ,16. DrinA few multilevel studies included context and individual levels in order to examine the association with alcohol consumption. Kypri et al.  studied This study involved 6011 students from the first to the last academic years of total 10 universities from four provinces: Hanoi (HN) in the north; HoChiMinh (HCM) in the south; Hue in the middle and BuonMeThuat (BMT) in a remote region of Vietnam. In three of the cities  the three largest universities focusing on Economics, Technology and Medicine were selected for this study. BMT has only one university; therefore, in that university the three faculties focusing on Economics, Technology and Medicine were selected. A multi-stage sampling strategy was used with the city as the first stratum, the university/faculty as the second stratum, and the academic year (from the first to the last academic year) the third stratum. Since medical undergraduate education takes six years to complete, while the technological and economics/nature, and the technology science/agriculture & forestry undergraduate education takes only five and four years, respectively, the numbers of students in each academic year in those universities/faculties were 85 for medical, 100 for technological, and 125 for economic studies. Within each academic year, one or two classes  were randomly selected for this study, ensuring that the sample size per academic year was sufficient. As a result, 6011 students who were in the classes at the data collection time all agreed to participate in the research. The structured questionnaire contained pictures of the most common beverages in Vietnam  per container ). In this way students were supported to correctly report the number of drinks. Standard drink (SD) = 1 can beer (330 mL at 5%) = 1 glass wine (140 mL at 12%) = 1 shot spirit (40 mL at 40%) = 12.6 g of pure alcohol. Investigators instructed students on how to fill out the questionnaire. The students were assured of their right to withdraw from the study. If a student had any queries related to the questions, the investigators provided clarification. This study was approved by the Biomedical Research Ethics Committee of School of Public Health in Hanoi, Vietnam (Code: 136/2012/YTCC-HD3). General information concerned the city; the university/faculty; gender and age.Outcome variable: Number of glasses reported for each of the three drinking occasions is the outcome variable in our analysis. Since students will considerably differ in the time span over which these three occasions were distributed, this measure is not indicative of level of consumption understood in the more common way as for example number of glasses per week or month. It appears that the correlation of number of glasses per occasion with consequences due to drinking (measured with the Alcohol Use Disorders Identification Test (AUDIT) questionnaire) is about the same as the correlation of the correlation of level of consumption (defined by AUDIT questions on frequency of drinking and number of glasses per drinking day and consequences. For men these correlations were 0.43 (number of glasses per occasion) and 0.49 (AUDIT measure of volume), respectively and the correlations for women were 0.36 and 0.41, respectively. Therefore the informative value of our outcome variable for experiencing negative consequences due to drinking is about as good as an outcome defined in terms of level of consumption.Drinking behavior and context: Each student was asked: “How often did you drink in the last 12 months” with the five answers of categories: never/maximum of 1 time a month/2–4 times a month/2–3 times a week, and at least 4 times a week. Students who answered “never” in the last year (n = 1021) and who answered “no” to the question “Did you drink at least three times in the last year” (n = 725) were excluded from the analysis. As a result, 4265 individuals who drank on at least three occasions remained in the analysis.Drinking context characteristics: Students were asked to name and describe the last three occasions at which they drank; there were 12,795 drinking occasions in the analysis. For each drinking occasion, students described how many SDs they consumed; the drinking day ; the time of day , duration of drinking ; main purpose of drinking occasion , and no specific purpose); drinking with food, even a snack ; drinking location ; number of people that they drank with ; the gender of the people they drank with ; and the relationship with the people they drank with .Drinking motives: For this study we used the Drinking Motive Questionnaire Revised, as developed by Cooper [y Cooper .This wasThe missing observations are reported in p < 0.01), (Pearson correlation was used and the significance level was tested using a two-tailed test).The inter-correlations between the situational variables and motives were relatively low  and the individual variables . Studies have suggested that students from different disciplines may differ in their frequency and quantity of alcohol consumption . Since tSince the time span over which the three drinking occasions were distributed varies between the students, another model including a variable indicating the time interval over which the three drinking occasions took place  was tested. Due to the fact that a substantial number of students could not recollect at which time one or more of the three most recent drinking occasions took place, this analysis includes a far less large number of students . The purpose of testing this model was to exploring whether the frequency of drinking occasions influences the effect of contextual variables and motives on drinking. Data of this model was not shown.Of the total number of 12,795 drinking occasions during the previous 12 months, 13.9% occurred within the previous week; 20.6% occurred between 2 weeks and 1 month ago, 18.8% occurred more than 1 month ago, and of the remaining 46.7% of the drinking occasions the students did not remember when they had happened. Comparison of the three most recent drinking occasions revealed that there was no significant difference in the standard drinking intake between the first, the second and the third most recent occasion. However, comparing occasions for which a date was reported with those the date was not reported, we found significant difference indicating a higher consumption in occasions with date was reported  vs. with no date reported was 2.6 (SD = 2.7)). At the individual level, all drinking motives were significantly associated with drinking among male students. Conformity motives were not significantly associated with drinking among women, while a higher score on conformity motives was associated with a significantly lower consumption among male students.Individual characteristics explained 7% and 10% of the variance in alcohol intake per occasion among female and male students, respectively. Situational characteristics explained 11% and 23% of the variance in alcohol intake per occasion among female and male students, respectively. Together, the individual and contextual characteristics explained 16% and 27% of the variance in alcohol intake per occasion among female and male students, respectively. In a combined model, the contextual characteristics explained more variance (women 11% and men 23%) than individual characteristics  in alcohol intake per occasion. Controlling for the time span over which the three drinking occasions took place did not change anything in the effect of the contextual and individual variables on the outcome (number of glasses per occasion). Additionally, it confirmed our conclusion that drinking context variables explain more variance than individual ones (data not shown).Vietnamese students seem to consume less alcohol per drinking occasion than, for example, Canadian students (3.0 SDs vs. 4.4–4.5 SDs) ,10 and pThe results of the present study indicate that, at the contextual level, drinking sessions lasting more than 3 h, drinking in large groups, and drinking with casual acquaintances rather than with family members, are associated with a significantly higher level of alcohol consumption. Drinking without food and drinking in a tavern/pavement/an outside location are likely to increase alcohol consumption per occasion among male students only. Findings at the contextual level are similar to those from studies among students in other countries such as in the U.S., Canada and the Netherlands, showing that students drink less when in the presence of a family member , that stAt the individual level, coping, social and enhancement motives are associated with a higher level of alcohol consumption among both genders, while conformity motives are associated with less alcohol consumption among male students. In this study, coping motives were most strongly positively associated with alcohol consumption of male and female students. Studies among adolescents in Switzerland, Canada, and the U.S.  similarlBoth individual and contextual characteristics are important in explaining alcohol consumption per occasion. However, the variance explained by situational level variables is higher than that explained by individual level factors. A study among U.S. college students examined the relationship between individual and environmental variables and heavy alcohol use at the most recent drinking occasion; that study showed that environmental level characteristics explained more variance than the individual level predictors . On the p < 0.01). The low inter-correlations indicate little influence of motives on the selection of drinking situations. Beside that, as Cooper et al. suggest [Our finding that contextual variables explain more of the variance might be an underestimation of the importance of motives. The correlation between contextual variables and motives was rather low . This is different from most previously reported findings on motives from 13 other European countries ,45, U.S.In Vietnam, with the development of the economy, alcohol use has become a normal way to develop contacts, stimulate social interaction, and business discussions. In many regions in Vietnam, a frequently reported reason for drinking among Vietnamese people is peer pressure. People can only start to negotiate or work after drinking at least three “cups” of alcohol . Of courThese findings have implications for alcohol prevention policies in Vietnam. Importantly, prevention should focus on detecting and discouraging Vietnamese students that score high on coping motives to help them reduce their alcohol consumption level. However, considering the relatively large influence of contextual variables on drinking, the main focus should be on prevention measures discouraging drinking for a long period per occasion, in taverns, at special events, in large groups, or with casual acquaintances. This implies an alcohol policy with general measures aiming to reduce both the frequency of certain drinking context and of alcohol consumption per occasion. Policies should aim to reduce the drinking duration per occasion by restricting the daily opening hours of alcohol outlets ,48. AddiThe present study required students to recall the three most recent drinking occasions, which is likely to lead to recall bias. The finding that, for those drinking occasions for which students could not specify how long ago they had occurred, the consumption was significantly lower than for those occasions that students could (still) remember how long ago they occurred, is an indication that there is some recall bias. Additionally, the study tested the model with only 2 individual variables (drinking motives and age) and 10 situational variables. The situational variables focused upon aspects of the direct drinking context. A limitation was not only unable to include other aspects of drinking context which may possibly influence drinking such as loudness of music and crowdedness ,16,17 buFurthermore, in our study, motives and context were measured on a different level. When motives are measured within a situation, this might change the amount of variance explained by both context and motives. Longitudinal studies with many more than three drinking occasions are required to further elucidate the interaction between motives and contextual variables. In addition, the generalizability of the results is limited since the study included Vietnam only.The results of this study contribute to the empirical evidence on alcohol intake among students, suggesting that drinking context more strongly predict alcohol consumption than drinking motives. Prevention programs should incorporate these findings within a Vietnamese cultural context by looking at both the individual level variables (people in whom coping motives are dominant) and contextual level factors .


Several imaging-based indices were constructed quantitatively using the emphysema index (EI) and fibrosis score (FS) on high-resolution computed tomography (HRCT). We evaluated the ability of these indices to predict mortality compared to physiologic results. Additionally, prognostic predictive factors were compared among subgroups with biopsy-proven fibrotic idiopathic interstitial pneumonia (IIP) (biopsy-proven CPFE) and in a separate cohort with subclinical CPFE.Three chest radiologists independently determined FS. EI was automatically quantified. PFTs, smoking history, and composite physiologic index (CPI) were reviewed. Predictors of time to death were determined based on clinico-physiologic factors and CT-based CPFE indices.p = 0.013). However, the extent of fibrosis did not differ significantly between the two cohorts. In subclinical CPFE, prevalence was 0.04% , EI was 11.3±10.4, and FS was 9.1±7.1. FVC and a fibrosis-weighted CT index were independent predictors of survival in the biopsy-proven CPFE cohort, whereas only the fibrosis-weighted CT index was a significant prognostic factor in the subclinical CPFE cohort.The prevalence of biopsy-proven CPFE was 26% (66/254), with an EI of 9.1±7.1 and a FS of 19.3±14.2. In patients with CPFE, median survival and 5-year survival rates were 6.0 years and 34.8%, respectively, whereas those in fibrotic IIP without emphysema were 10.0 years and 60.9% (Recognition and stratification using CT quantification can be utilized as a prognostic predictor. Prognostic factors vary according to fibrosis severity and among cohorts of patients with biopsy-proven and subclinical CPFE. We evaluated the ability of these indices to predict mortality and compared their performance with those of previous physiologic factors. Additionally, prognostic predictive factors were compared among subgroups with biopsy-proven fibrotic idiopathic interstitial pneumonia (IIP) and in a separate earlier cohort.Our institutional review board ) approved this retrospective study and the requirement for informed consent was waived.Details on study population, pulmonary function test, and imaging are provided in the For the biopsy-proven CPFE cohort, we included a total of 254 consecutive patients seen from 1996 to 2008 at Samsung Medical Center who had pathologically confirmed fibrotic IIP on surgical lung biopsy. Cases of combined fibrotic IIP and emphysema were selected by two radiologists. The remaining 188 fibrotic IIP patients without emphysema were categorized into the fibrosis only cohort .A separate CPFE cohort at the subclinical level was enrolled from the screening sample. At first, we acquired our patient data from 20,372 individuals who underwent chest CT for lung cancer screening or metastasis work-up and were found to have extrathoracic malignancy between June 2008 and May 2010. The same two radiologists reviewed all CT images, and 93 CPFE patients were identified. Seven of the 93 patients were excluded from this study due to difficulties interpreting CT images due to concurrent acute illness (n = 4) and poor imaging resolution (n = 3).Another three independent chest radiologists analyzed the CT images The three observers reached the most likely diagnosis based on radiographic classification of the screening cohort To assess EI, we used in-house computerized software We derived five CT indices as follows: Fibrosis score (FS), emphysema index (EI), CPFE score, which combined FS and EI (FS+EI), fibrosis-weighted CPFE score, which combined doubled FS and EI (FS X 2+ EI), and emphysema-weighted CPFE score, which combined FS and doubled EI (FS+EI X 2).t-test for continuous variables, the Fisher’s exact test for categorical variables, and the log-rank test for survival curves. A p-value <0.05 was considered significant in all cases. Predictors of time to death were determined for patients using Cox proportional hazards analysis. Variables associated with time to death based on unadjusted analysis were considered for inclusion in the multivariate model. Statistical analyses were conducted using SPSS for Windows, version 15.0.Inter-reviewer agreement among the three radiologists was reported using an intra-class correlation coefficient for total fibrosis score. Patient demographics, as well as clinical and radiographic data, were compared across cohorts using the unpaired p<0.01). DLco results were available for 60 of 66 patients (91%) among the biopsy-proven CPFE cohort, and 42 of 86 patients (49%) in the subclinical CPFE cohort. DLco was lower in the subclinical CPFE cohort than in the biopsy-proven CPFE cohort. On CT, the subclinical CPFE cohort had less severe fibrosis (p<0.01). As for the subtypes of interstitial lung disease identified in the subclinical CPFE cohort, respiratory bronchiolitis (RB), RB-ILD, or desquamative interstitial pneumonia (DIP) patterns were identified in 12% of patients (p<0.01). No significant differences were noted in FEV1, emphysema distribution or EI between the biopsy-proven and subclinical CPFE cohorts.Criteria for the biopsy-proven CPFE cohort were met in 66 of 254 fibrotic IIP patients, representing 26.0% of the overall cohort. In the subclinical setting, CPFE prevalence was 0.04%  . Baselinp = 0.013). However, the severity of fibrosis did not differ significantly between the two cohorts  (p = 0.007), but those difference were not seen in the subgroup with FS ≥20% (p = 0.512)  . When Ka= 0.512) . The thr= 0.512) .The intra-class correlation coefficient for FS among three radiologists was 0.81 .In patients with biopsy-proven CPFE, on univariate analysis, FVC and CPI were associated with greater risk of mortality as compared to similar degrees of dysfunction in FEV1 and DLco. Regarding CT features, the diagnosis of usual interstitial pneumonia (UIP) and fibrosis-weighted CT index were associated with higher mortality risk as compared to other CT-driven indices. On multivariate analysis, only FVC and fibrosis-weighted CT index were associated with a greater risk of mortality .In patients with subclinical CPFE, a positive smoking history and fibrosis-weighted CT index were associated with greater mortality on univariate analysis. Of these factors, only fibrosis-weighted CT index was associated with mortality on multivariate analysis .CO and FEV1/FVC, as well as altering changes in these values over time. Ultimately, this influences the assessment of disease severity at baseline and over time Patients with IPF and emphysema are usually males with heavy cigarette-smoking histories who experience severe dyspnea on exertion with relatively conserved lung volumes despite disproportionate impairment of gas exchange p = 0.69). These results seem to contradict the results of the present study and those of several other related studies p = 0.013), even though the severity of fibrosis did not differ significantly between the two groups (p = 0.925).Ryerson et al. compared CPFE and IPF without emphysema We additionally compared two groups stratified by a FS of 20% on CT, and found that the difference in mortality was relevant only for FSs <20%. We also found that individual PFT measures varied in terms of predicting patient survival in both cohorts. The interaction between emphysema and fibrosis was very complicated. Effects on survival may differ according to degrees of fibrosis or emphysema, making the clinical relevance of these results all the more difficult to interpret. Recently, Schmidt We found that a fibrosis-weighted CT index was a significant predictor of prognosis among a variety of predictive variables in patients with both biopsy-proven and subclinical CPFE. These findings may be partially explained by the effect of emphysema in a subgroup with less severe fibrosis (<20%). We believe that our study is the first trial to quantitatively measure EI and FS together in CPFE patients, and to assess and evaluate the prognostic significance of these two CT-based indices/scores. Over the years, there have been significant advancements in HRCT technology, and HRCT has become the standard approach to radiographic evaluations of pulmonary fibrosis et al.Our data highlight that the use of a fibrosis-weighted CT index is a better surrogate for PFTs or CPI in predicting subsequent mortality in patients with both biopsy-proven and subclinical CPFE. Of course, our DLco data may not be conclusive, given that data were not available for all patients. However, our results were similar to those reported in a recent study conducted by Schmidt via CT.Our patients with fibrotic IIPs had milder radiologic fibrosis than previously reported IPF patients, a finding that may help explain the higher survival rates among this cohort than in previous studies. We selectively included patients who were scheduled to undergo surgical lung biopsy for IIP diagnosis. Patients with typical UIP on imaging and who were not candidates for biopsy were excluded. However, we focused more on subclinical or early manifestations of IIP since clinical and research settings indicate that HRCT facilitates the detection of ILD in asymptomatic and undiagnosed individuals The current study had several limitations. First, our study was retrospectively designed at a single tertiary center. Therefore, some selection bias may have affected our findings. Second, the results of physiologic tests were unavailable, especially for the subclinical cohort. Third, we did not consider other prognostic factors such as pulmonary hypertension; we evaluated only physiologic and CT features as predictors of patient survival.In conclusion, recognition and stratification of CPFE using quantitative CT analysis may be an important prognostic tool. In univariate and multivariate analyses, prognostic predictive factors for survival may vary according to the severity of fibrosis and patient characteristics, including whether the study cohort consists of patients with biopsy-proven or a subclinical CPFE.Figure S1Kaplan-Meier survival curves of fibrotic IIP patients in each 5%-class of FS, stratified by CPFE vs. fibrosis only (online only).(TIF)Click here for additional data file.File S1(DOCX)Click here for additional data file.


Background: light-to-moderate drinking is apparently associated with a decreased risk of physical limitations in middle-aged and older adults.Objective: to investigate the association between alcohol consumption and physical limitations in Eastern European populations.Study design: a cross-sectional survey of 28,783 randomly selected residents (45–69 years) in Novosibirsk (Russia), Krakow (Poland) and seven towns of Czech Republic.Methods: physical limitations were defined as <75% of optimal physical functioning using the Physical Functioning (PF-10) Subscale of the Short-Form-36 questionnaire. Alcohol consumption was assessed by a graduated frequency questionnaire, and problem drinking was defined as ≥2 positive responses on the CAGE questionnaire. In the Russian sample, past drinking was also assessed.Results: the odds of physical limitations were highest among non-drinkers, decreased with increasing drinking frequency, annual consumption and average drinking quantity and were not associated with problem drinking. The adjusted odds ratio (OR) of physical limitations in non-drinkers versus regular moderate drinkers was 1.61 . In the Russian sample with past drinking available, the adjusted OR in those who stopped drinking for health reasons versus continuing drinkers was 3.19 (2.58–3.95); ORs in lifetime abstainers, former drinkers for non-health reasons and reduced drinkers for health reasons were 1.27 (1.02–1.57), 1.48 (1.18–1.85) and 2.40 (2.05–2.81), respectively.Conclusion: this study found an inverse association between alcohol consumption and physical limitations. The high odds of physical limitations in non-drinkers can be largely explained by poor health of former drinkers. The apparently protective effect of heavier drinking was partly due to less healthy former heavy drinkers who moved to lower drinking categories. Physical functioning, an essential component of health for older adults, is influenced by biological, lifestyle and environmental factors. Numerous studies have investigated the relationship between alcohol consumption and physical functioning –8. A sysThe prevalence of physical limitations appears to be higher in Central and Eastern Europe (CEE) than in the west , 11. GivBesides potential harmful effects of heavy drinking, the literature suggests that abstainers have lower physical functioning –5, 7, 9.In this paper, we investigated the role of alcohol consumption on physical functioning in three ageing populations of CEE: whether heavy drinking is associated with lower functioning, and whether the apparently protective effect of moderate drinking (if found) can be explained by past drinking behaviour.We used data from the baseline survey (2002–2005) of Health, Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study in Novosibirsk (Russia), Krakow (Poland) and seven middle-sized towns in Czech Republic . Random samples of urban residents aged 45–69 years, stratified by sex and 5-year age groups, were selected from population registers (Czech towns and Krakow) and electoral lists (Novosibirsk) using a computerised procedure. A total of 28,783 participants were recruited. Participants completed a structured questionnaire either at home (Czech towns and Krakow) or in a clinic (Novosibirsk) and attended a short examination in a clinic . The quewww.sf-36.com). The PF-10 assesses limitations on light, moderate and vigorous activities, mobility and self-care tasks. A score (0–100) was calculated, and the higher score indicates better physical functioning. The PF-10 was associated with objective physical performance in the expected direction . Participants with a score <75 were classified as having physical limitations.Physical functioning was measured by the Physical Functioning Subscale (PF-10) of the Short-Form-36 (SF-36) questionnaire , which hAlcohol consumption in the last 12 months was evaluated by the graduated frequency (GF) questionnaire , with siAge and Ageing online, Table S2Supplementary data available in ).The drinking pattern combined drinking quantity and corresponding frequency in the GF. Light-to-moderate drinking was defined as ≤4 drinks during 1 day in men (≤2 drinks in women); higher intakes were considered as heavy drinking. Regular drinking was defined as ≥1/month; less than that was considered as irregular drinking. Problem drinking was classified as answering two or more positive responses to the CAGE questionnaire , in lineIn Russia, past drinking behaviour was assessed by additional questions. Current non-drinkers were further categorised into lifetime abstainers and former drinkers. Similarly, current drinkers were also grouped into those who had reduced their consumption versus ‘continuing’ drinkers. Former drinkers and reduced drinkers were further categorised based on why they stopped/reduced drinking: health reasons versus other reasons.2). Smoking status was classified into current, past and never smokers.Socioeconomic position (SEP) was evaluated by highest educational attainment, current economic activity and number of household amenities in childhood and adulthood, selected to be comparable across countries. Marital status was categorised into married/cohabiting, single, divorced and widowed. Body mass index (BMI) was calculated by objectively measured height and weight  had complete information on all variables. Multiple imputations by chained equations (MICE) were used to handle missing data , and 20 The association between alcohol consumption and physical limitations in the multiply imputed data sets was analysed by multivariate logistic regression. Two models were estimated: (i) adjusted for age and sex  and (ii) additionally adjusted for SEP, marital status, BMI and smoking. All the data analyses were performed in Stata 12 using commands appropriate for imputed data .Table Age and Ageing online, Tables S3–S5Supplementary data available in ); therefore, the data were pooled. The results of pooled analyses are shown in Table Associations between alcohol consumption characteristics and physical limitations were similar across populations and sexes .Table In this large population-based study in CEE, we found that physical limitations were inversely associated with alcohol consumption, with the highest ORs among non-drinkers. However, much of the increased risk of physical limitations in non-drinkers was due to sick quitters. Similarly, some of the apparently protective effect of alcohol among drinkers appeared to be due to less healthy former heavy drinkers who reduced their intake and moved to lower drinking categories. There was no association between problem drinking and physical limitations.Our study has several limitations. First, the cross-sectional nature of the data complicates the assessment of temporality, and we had to rely on self-reported past drinking behaviour. However, the history of alcohol-related health damage is likely to be under-reported due to social stigma, and one would expect under-reported stopping/reducing drinking for health reasons. In this case, the importance of past drinking behaviour in explaining the inverse association between alcohol consumption and physical limitations would also be under-estimated.Second, the overall response rate was 60% , and we Third, participants may have under-reported their alcohol consumption and over-reported their physical functioning because of the social stigma attached to drinking and being unhealthy. However, physical limitations and alcohol consumption were associated with separately taken self-reports and objective makers, supporting the validity of the measurements. This bias is difficult to quantify; it would tend to under-estimate the role of past drinking behaviour and therefore not change the direction of our findings. Participants may have also over-reported their reduction of alcohol intake, and some of the ‘reduced drinkers’ are actually continuing drinkers. As in Russia the social stigma associated with alcohol affects women much more than men, the similarity of results in men and women points against the presence of a major bias.Fourth, data on past drinking behaviour was only available in Russians. However, the pattern of associations between current drinking indices and physical limitations was very similar among the three populations, and it is reasonable to assume that if data on past drinking were available in Czechs and Poles, the results would be similar to those found in Novosibirsk.Finally, we dealt with missing data by the MICE statistical technique to avoid loss of statistical power in complete-case analyses . AdditioThis study also has a number of strengths. It has large statistical power, collected extensive data on different aspects of alcohol consumption, adopted a widely used measure of physical functioning and examined rarely studied ageing populations in CEE. In particular, the availability of data on abstinence/reduction of drinking in studies in CEE is not common and, to our knowledge, valuable data on the reasons for stopping/reducing drinking have not been used in the region.At the time these data were collected, the Czechs and Poles preferred beer and had similar per capita consumption  ; the RusGiven the relatively high levels of alcohol intake in these populations, we were surprised that the heaviest drinking groups and problem drinkers did not have increased odds of physical limitations. Instead, we found an inverse association between alcohol consumption and physical limitations, consistent with other studies –5, 7, 8,Most of previous studies, including the Russian report, did not consider former drinking. We are aware of only two studies, which examined former drinkers separately; one study found an increased risk of mobility limitations among male former drinkers ; the othIn our data, abstinence for health reasons was associated with an increased risk of physical limitations in both sexes, consistent with the hypothesis that non-drinkers include sick quitters . HoweverWith increasing age, decrease of alcohol consumption for health reasons might occur across all drinking groups . In our We conclude that the inverse association between alcohol consumption and physical limitations in these ageing populations was partly explained by drinkers who reduced or quitted drinking due to health reasons. After excluding former drinkers, the results are consistent with a small (or no) protective effect for physical limitations. However, longitudinal studies that can directly address the issue of temporality are required to disentangle the effect of quitting or reducing drinking on physical functioning.Alcohol consumption was inversely associated with physical limitations in ageing populations in CEE.Non-drinkers had the highest odds of physical limitations, but no increased odds were found in the heaviest drinking group.The excess risk of physical limitations in non-drinkers was largely explained by poor health of former drinkers.The lower risk in heavy drinkers was partly due to former heavy drinkers who reduced drinking and moved to lower drinking groups.Age and Ageing online.Supplementary data mentioned in the text are available to subscribers in Wellcome Trust ‘Determinants of Cardiovascular Diseases in Eastern Europe: A Multi-centre Cohort Study’ (grant numbers 064947 and 081081), the US National Institute on Aging‘Health Disparities and Aging in Societies in Transition (the HAPIEE study)’ (grant number 1R01 AG23522) and MacArthur Foundation Research Network ‘Health and Social Upheaval’ (grant number 712058).The HAPIEE study was supported by the None declared.


The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex  and (3) PF4 monomer/RTO-Fab complex . Fondaparinux binds to the ‘closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open' end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation  Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disease with limited treatment options. Here the authors present crystallographic data on the disease-causing immune complex, providing the structural basis for the development of new diagnostic and therapeutic approaches to HIT. Heparin-induced thrombocytopenia/thrombosis (HIT) is a potentially fatal immune complex mediated thrombotic disorder that develops in ∼1% of patients exposed to unfractionated heparin or, less commonly, to low-molecular-weight heparins23In prior studies, we identified a murine monoclonal antibody (KKO) to PF4/heparin complexes that causes heparin-induced thrombosis and thrombocytopenia in a murine model, thus sharing salient features with the clinical disorderin vitro and has potent inhibitory effects on thrombus progression in vivo.Here we describe and compare the crystal structures of PF4 in complex with Fabs derived from KKO and RTO and the structure of PF4 in complex with a heparin-mimic pentasaccharide, fondaparinux. These results suggest that by stabilizing the structure of the asymmetric PF4 tetramer, fondaparinux might foster the binding of HIT antibody and formation of the pathogenic ternary complex. Surprisingly, the non-HIT antibody RTO binds to an epitope expressed on the surface of the PF4 monomer that partly overlaps with the KKO epitope in the tetramer. Binding of RTO prevents tetramerization of PF4 and inhibits KKO-induced platelet activation and aggregation These crystallographic data lead to a model to help understand the structural basis of the pathogenic immune complex that causes HIT at the atomic level and provide a structural basis for the development of new diagnostics and non-anticoagulant therapeutics for HIT. Our data also provide insights into the process through which a normal human protein becomes ‘antigenic' to the mammalian immune system after complexing with endogenous or exogenous GAGs.Based on previously reported crystal structures, human PF4 can assume an asymmetric tetrameric configuration. Each monomer contains three-stranded antiparallel β-sheets on which an aperiodic N-terminal domain and an amphipathic C-terminal α-helix are foldedBinding of pathogenic HIT antibodies to PF4 is markedly enhanced by heparin or various glycosaminoglycans (GAGs), which are themselves highly heterogeneous in size and composition and unsuitable for crystallization. To investigate how the GAGs might induce or augment neoantigen formation, we crystallized PF4 in complex with fondaparinux, a homogenous synthetic pentasaccharide heparin that forms complexes with PF4 as assessed by atomic force microscopy and photon correlation spectroscopy161719202122We solved the crystal structure of PF4 in complex with fondaparinux as a model GAG. The PF4/fondaparinux complex is a pseudo-222 tetramer formed by a pseudo two-fold non-crystallographic symmetry and a perpendicular two-fold crystallographic symmetry . Superpo24The PF4 tetramer displays a pseudosymmetry characterized by an ‘open' end and a ‘closed' end that can be defined by the intra-chain distances between amino acids E28 and K50. E28 and K50 are ∼3 Å apart and form stable salt bridge pairs between chain A and chain C. However, the same interchain salt bridge pairs do not form between E28 and K50 in chains B and D, which are ∼8 Å apart . This asPF4 tetramers can be formed between the AB and CD dimers, or between the AC and BD dimersAnalysis of the crystal lattice further reveals that fondaparinux not only makes contact with a single PF4 tetramer within the groove formed by three monomers (ABC or ACD), but also at a second site involving the C-terminal helix of the third monomer (B or D). It has been proposed that the HIT antigen develops when charge neutralization by polyanions allows positively charged PF4 tetramers to undergo close approximation14Based on what is observed in the crystal, we propose the following pathway for the formation of the heparin/PF4 complex. Heparin first binds to the groove in one PF4 tetramer. Binding of the first PF4 tetramer imparts a local linearized structure on heparin. This enhances the binding of a second tetramer. Progression of this process eventuates in the formation of the large antigenic complex in which PF4 tetramers cluster around a semi-rigid linear heparin chain . Cluster28142530in vivo and competes with human platelet activating anti-PF4/heparin antibodies in vitro8To understand the structural basis for the formation of pathogenic immune complexes, we next solved the crystal structure of human PF4 complexed with the Fab fragment of the monoclonal antibody KKO (KKO does not bind to murine PF4 (mPF4) complexed with heparin. Therefore, we compared the sequence of human PF4 (hPF4) with mPF4, and made structure-based mutants based on the proposed contact sites identified in the co-crystal . MutatioFurther analysis revealed that PF4 within the PF4/KKO-Fab complex adopts a symmetric tetrameric structure, which is an ‘open'-‘open', possibly intermediate, conformation . This reThese structures provide the first atomic level description of the pathological complex that might occur in HIT. The model might also help to explain why fondaparinux, a short fragment of heparin, which is antigenic, only rarely causes HIT. Although the protein–GAG interactions can in theory be propagated to additional PF4 tetramers and fondaparinux molecules, we propose that covalent bonding between pentasaccharide units in longer heparins markedly increases the stability of the holo-complex. Consequently, the more ‘stable' complex becomes more antigenic by enhancing antibody avidity.in vivo6RTO is an anti-PF4 antibody that possesses the same isotype as KKO, but does not cause HIT To help understand the difference between the impacts of these two antibodies, we next solved the crystal structure of the RTO-Fab in complex with hPF4 .Also unexpectedly, the RTO epitope on PF4 overlapped considerably with the KKO epitope compare . In the Based on the knowledge that PF4 tetramers exist in equilibrium with monomers and dimers, and with even higher ordered complexes when heparin is present, we predicted that RTO might prevent or disrupt tetramer formation and thereby prevent KKO-induced platelet activation in the presence of heparin. Indeed, RTO inhibited the activation of platelets by KKO and human HIT IgG in the presence of heparin in a dose-dependent manner, as assessed by expression of P-selectin on flow cytometry . Pre-inc−/−/human PF4+/+/human FcRγIIA+ miceMoreover, RTO completely inhibited KKO-induced progression of thrombosis in a laser microvascular injury model in mouse PF4It is uncertain how heparin or an endogenous GAG converts a normal host protein, PF4, into an ‘autoantigen'. Our crystallographic data provide insight into the multistep process of neoantigen formation at the atomic level. We report the first crystal structure of the PF4 monomer, here in complex with the Fab fragment of an anti-PF4 antibody RTO, which affirms that PF4 exists in solution as an equilibrium among monomers, dimers and tetramersOur data also indicate that the asymmetry of the fondaparinux-bound PF4 tetramer, which has an ‘open' end and a ‘closed' end, plays an important role in forming the pathogenic antigenic complex. Based on our findings, we propose that heparin or a GAG fragment stabilizes the PF4 tetramer by clamping the monomers together through the ‘closed' end, orienting the ‘open' end in the asymmetric PF4 tetramer that comprises the binding site for KKO. Thus, in the absence of heparin, the KKO binding site on the tetramer is nonexistent or incompletely expressed on the PF4 monomer and dimer and is only transiently expressed and unstable on tetramers that form at high concentrations of PF4. Thus, stabilization of the tetramer by heparin leading to a more stable orientation of an epitope on each PF4 tetramer, compared with the transient and more random orientation of the epitope in the absence of heparin, is a second defining step in the process of generating the HIT neoantigen. Heparins or GAGs of sufficient lengths can then cluster several PF4 tetramers further enhancing stability, which helps to explain why PF4, among heparin binding proteins, is especially antigenic7Our studies were performed with fondaparinux because the heterogeneity of clinical heparins and GAGs preclude obtaining structural detail. Therefore, we do not exclude the possibility that low molecular weight or unfractionated heparin might induce additional changes within and between PF4 tetramers24The A32-A39 loop on the PF4 monomer appears to be highly immunogenic. However, our data suggest that pathogenic and non-pathogenic antibodies that bind to this region differ in how they affect the monomer–dimer–tetramer equilibrium. Pathogenic antibodies that act like KKO and preferentially recognize the tetrameric species display greater avidity in the presence of heparin, which approximates epitopes, and in turn the bound antibody fosters oligomerization26Our studies might have implications for the diagnosis of HIT. The two prototypic antibodies we studied, RTO and KKO, bind comparably to PF4/heparin on ELISA plates at equilibrium and do not compete with each other for binding in this format7in vitro and, importantly, progression of antibody-induced thrombosis in vivo. It is likely release of PF4 and formation of antigenic complexes extend beyond diagnosis and introduction of a direct thrombin inhibitor, as does the risk of recurrent thromboembolic complications. The inhibitory effects of RTO indicate that tetramerization of PF4 is targetable and that this antibody may provide a structural basis for developing rational non-anticoagulant HIT-specific intervention for this serious and common iatrogenic disorder.Our studies might also have implications for therapy. Anticoagulants are the standard treatment for HIT, but their efficacy is incomplete and dosing is limited by the risk of bleeding5It has been difficult to differentiate between the impact of changes within the secondary structure of individual PF4 tetramers that affect antibody affinity and effects on tetramer oligomerization that enhance avidity, because both contribute to antibody binding measured in ELISA wells that likely contain various conformations of PF4. Our use of Fab fragments that are unable (or show little ability) to oligomerize PF4 tetramers, and fondaparinux, which is antigenic but rarely pathogenic because it has a low capacity to form higher ordered structures, provided an opportunity to delineate the evolution of the antigenic site within the PF4 tetramer itself.in vivo following exposure to KKO.Nevertheless, we wish to emphasize that our studies also have potential limitations. First, the necessity of using fondaparinux as the GAG precluded possible additional relevant changes within PF4 induced by longer heparin molecules that are more likely to induce HIT. Nor can we assess the intra-molecular and intermolecular effects on PF4 imparted by the complex array of cellular GAGs. Second, although most HIT antibodies compete with KKO for binding, our data do not preclude additional contact sites between polyspecific human antibodies and PF4/heparin. Third, crystallography and other biophysical approaches using purified proteins inherently explore atomic interactions in a single stable structure favored by the experimental conditions. Thus, the full range of dynamic changes in (super)oligomerization that occur during the evolution of the disease may not be captured. Thus, our study only provides a model that may help to explain sentinel events through which GAGs may induce binding of autoantibodies to a normal host protein. Fourth, in our experiments, RTO was added before KKO. The dynamics of RTO binding to PF4 might well be different when heparin and a pathogenic HIT antibody are already present. We are currently investigating the effect of RTO on thrombus growth Wild-type hPF4 and hPF4 mutants in plasmid pMT/BiP/V5-His , were expressed using the Drosophila Expression System (Invitrogen), purified and characterizedThe murine anti-human PF4 IgG2bκ monoclonal antibodies KKO and RTO have previously been described−1. The plates were incubated for 30 min with either PBS (control) or with 0.5% glutaraldehyde at room temperature, extensively washed and blocked with 1% bovine serum albumin (BSA) in PBS. The plates were incubated with human patient IgG samples at experimentally selected concentration of 20 μg ml–1 for 30 min at 37 °C. IgG binding was measured as absorbance at 405 nm (A405) after incubation for 30 min at 37 °C with horseradish peroxidase-conjugated ImmunoPure Goat Anti-Human IgG (H+L), HRP Conjugated Product No. 31412  diluted 1:10,000 in 1% BSA/PBS. Horseradish peroxidase substrate ABTS was from Roche Applied Science, Penzberg, Germany. Absorbance was measured with a SpectraCount plate reader .Binding of human IgG was measured essentially as previously described for KKO and RTO antibodiesin vitro studies (platelet activation and light transmission aggregometry) was collected after informed consent from healthy, aspirin-free volunteers using a 19-gauge butterfly needle in 129 mM sodium citrate  under protocols approved by the Institutional Review Board of the University of Pennsylvania and the Children's Hospital of Philadelphia. Whole blood samples were incubated in Ca++/Hepes buffer  1/100 v/v in the presence of allophycocyanin (APC) labelled anti-hCD41 and PE labelled anti-P-selectin, PF4 (10 μg ml−1) and the concentrations of RTO MOAb indicated in the figure for 15 min at room temperature. KKO (20 μg ml−1) or human HIT IgG (500 μg ml−1) was added for 20 min at room temperature, samples were then diluted by adding 400 μl of HBSA/BSA/EDTA buffer and immediately measured by flow cytometry (BD LSRFortessa). Platelets were gated based on the forward-scatter and CD41 fluorescence parameters, and binding of anti-P-selectin antibodies was quantified as geometric mean fluorescent intensity.Blood for g at 25 °C to generate platelet-rich plasma (PRP) and at 900g for 10 min at 25 °C to produce platelet-poor plasma. Platelet aggregation was measured in PRP using a dual-channel lumi-aggregometer  per the manufacturer's instructions. All experiments were completed within 4 h of blood collection. PRP (500 μl) was pre-warmed for 2 min at 37 °C, heparin  was added  for 30 s followed by wild type or mutant rPF4  for 30 s followed by KKO or RTO (100 μg ml−1) for up to 10 min. The final volume of added reagents did not exceed 5% of the starting volume of PRP. To examine inhibition of KKO-induced platelet aggregation, 100 μg RTO was preincubated with 5 μg PF4 for 15 min at 25 °C. Heparin  was added to pre-warmed PRP. After 30 s PF4 or PF4/RTO complex was added . KKO  was added 30 s later and aggregation was assessed as above.Blood was centrifuged for 12 min at 210in vivo thrombus formation. After surgical preparation, Alexa 647 (BD Biosciences) labelled mouse CD41-F(ab')2 fragments were infused intravenously to label circulating platelets. Each mouse then received 50 μg g−1 of either RTO or the IgGκ2B isotype control TRA intravenously followed by 7–8-focal arterial injuries. A brightfield and fluorescence snapshot of each injury was taken 15 min after the initial injury. KKO was then injected intravenously at a dose of 2.5 μg g−1. Fifteen minutes after injection of KKO, a second brightfield and fluorescence snapshot of the same injuries was taken to compare platelet deposition before and after KKO. Image analysis was performed using the Slidebook 6 . The size of the thrombus was determined by having the software automatically segment the image using Otsu thresholding to remove background and then calculate and export the size of the platelet fluorescence in micronsTransgenic male C57BL mice, lacking mouse PF4 but expressing human PF4 and human FcγRIIA33in vivo injuries was performed using the Prism 6 . A two-tailed Student's t-test under non-parametric conditions with Mann–Whitney correction was performed to assess statistical significance. P values<0.05 were considered significant. There was no randomization of mice. The mice used were selected based on availability. There was no exclusion criteria established before experimentation, available healthy mice were selected for use. No tests of normality or power analyses were conducted.Statistical analysis of −1) and RTO-Fab (5 mg ml−1) were mixed with hPF4 at different ratios and incubated on ice overnight before setting up crystallization trials. The hPF4/fondaparinux complex was prepared by adding six-fold molar excess fondaparinux  into purified hPF4 (7 mg ml−1); the mixture was incubated on ice in a buffer containing PBS and 0.3 M NaCl.Purified KKO-Fab . Diffraction-quality KKO-Fab crystals were obtained in the well solution containing 14% PEG2000, 0.06 M zinc acetate and 0.1 M sodium cacodylate, pH 6.8. KKO-Fab crystals were transferred into the well solution supplemented with 25% glycerol, soaked for one second, and then flash-cooled in liquid nitrogen. Diffraction-quality hPF4/KKO-Fab crystals were obtained in the well solution containing 7% PEG6000, 0.1 M Tris-HCl, pH 7.8. hPF4/KKO-Fab complex crystals were flash-cooled in liquid nitrogen similarly as KKO-Fab crystals. hPF4/RTO-Fab complex crystals were obtained in the well solution containing 0.2 M ammonium sulfate, 0.1 M BIS-TRIS, pH 6.5, 25% w/v polyethylene glycol 3350. The diffraction-quality hPF4/RTO-Fab crystals were optimized by macro-seeding. hPF4/RTO-Fab complex crystals were transferred into the well solution supplemented with 20% glycerol, soaked for one second, and then flash-cooled in liquid nitrogen.All crystallographic data sets were collected at 100 K with ADSC CCD detectors. The long-wavelength (λ=2.07 Å) sulfur anomalous diffraction data sets for hPF4/fondaparinux complex and hPF4/RTO-Fab complex were collected at beamline X4A at National Synchrotron Light Source at Brookhaven National Laboratory . Other data sets were collected at National Synchrotron Light Source beamlines X6A and X4C at Brookhaven National Laboratory. All diffraction data were processed by using the HKL-2000 packageAll structures were solved by molecular replacement. The structure of the hPF4/fondaparinux complex was solved by the CCP4 program MOLREP42http://www.delanoscientific.com/). The electrostatics potentials were calculated by program APBS, an adaptive Poisson–Boltzmann solver53All models were iteratively built in COOT46Accession codes: Atomic coordinates and structure factor files have been deposited in the Protein Data Bank (PDB) under the accession codes 4R9W for hPF4/fondaparinux complex, 4R97 for KKO-Fab, 4R9Y for hPF4/KKO-Fab complex, 4RAU for hPF4/RTO-Fab complex.How to cite this article: Cai, Z. et al. Atomic Description of the Immune Complex involved in heparin-induced thrombocytopenia. Nat. Commun. 6:8277 doi: 10.1038/ncomms9277 (2015).Supplementary Figures 1-7 and Supplementary Table 1A three dimensional view of the Heparin/PF4 antigenic complex modelA three dimensional view of the Heparin/PF4/KKOFab ternary immune complex model


Background. It has been widely documented that males were more likely to drinking alcohol and have alcohol use disorders (AUD). The degrees of the male-female differences in drinking and AUD have varied across countries. The reasons behind these variations have not been fully understood. The current study compared the estimated male-female differences across US-born and foreign-born Latino and Asian Americans with respect to alcohol drinking behavior and AUD. Method. Data come from the National Latino and Asian American Study (NLAAS), a national household survey of adults with Latinos and Asian decent in the United States. Male-female differences were estimated for drinking behavior and AUD among drinkers for US-born and foreign-born individuals, respectively. Zero-inflated Poisson regressions were utilized to estimate male-female differences in the number of AUD clinical features once it occurs. Results. Larger male-female differences were found for foreign-born individuals as compared to US-born individuals, especially the occurrence of AUD among drinkers. Once AUD clinical feature occurs, there was no male-female difference for foreign-born individuals, while there was a males excess in the number of clinical features for US-born individuals. Conclusion. Results from this study supports the importance of sociocultural influence in drinking and AUD. Implications for prevention and intervention programs were discussed. Worldwide, it has been extensively documented that alcohol consumption and alcohol use disorders (AUD) are more common in males as compared to females –6. The rPrevious studies have shown that the male-female difference in AUD is considerably smaller in the United States as compared to Latin American and Asian countries, suggesting female drinking is tolerated more in the USA when compared to Latin American and Asian countries , 18–22. Reviewing previous literature, some exploration may aid further understanding of drinking and AUD. As suggested by previously studies, male-female difference may vary across various stages of alcohol involvement , 29. ThuLatinos and Asians are two of the fastest growing ethnic groups within the USA. The US census bureau projects that by 2050, each group will nearly triple in size , accounting for more than one-third (37.9%) of the total US population jointly . HoweverThe study utilized a version of the World Health Organization's (WHO) World Mental Health Composite International Diagnostic Interview (WMH-CIDI) . The WMHIn this study, key response variables are lifetime history of AUD including DSM-IV alcohol abuse and alcohol dependence. The endorsement of any of the four clinical features of socially maladaptive drinking qualifies the individual of lifetime history of DSM-IV alcohol abuse. To ease discussion and presentation, they were labeled as “responsibility interference,” “drink despite social problems”, “hazardous use”, and “legal problems.” Lifetime DSM-IV alcohol dependence was defined as the occurrence of at least three of the seven clinical features of alcohol dependence during the same 12 months. Lifetime occurrence of clinical features of alcohol dependence is defined as the occurrence of at least one of the seven DSM-IV clinical features and “irresistible desire to drink.” Opportunity to drink alcohol is defined as ever having opportunity to drink alcohol; more than minimum (MTM) drinking is defined as having at least 12 drinks in a given year; heavier drinking is defined as at least 5 drinks per day for males and 4 for females. This latter definition is consistent with the definition of “binge drinking” used by the US National Institute of Alcohol Abuse and Alcoholism (NIAAA) and the most commonly used definitions for “binge drinking” and “heavy episodic drinking” in previous studies .Gender and place of birth were the main covariates in this analysis. Other covariates include age (in years), ethnicity (Latino or Asian), and number of parents born in the USA. All of these variables were based upon the respondent's self-report. During the first steps, we provided a description of the sample and lifetime estimates of AUD, as well as stratified estimates by male-female and place of birth. In subsequent steps, a series of logistic regressions were conducted to estimate the variation in male-female differences in alcohol involvement and the occurrence of AUD among drinkers. The male-female gap in drinking and AUD is estimated in the form of odds ratios (ORs). Statistical comparisons are made to investigate the variation of OR in US-born and foreign-born LAA by the inclusion of a product term. First, bivariate logistic regression was conducted to produce the unadjusted OR. Second, age, ethnicity, and number of parents born in the US, was introduced to the regression model.  In these steps, since the occurrence of outcomes, especially early alcohol involvement  was quite high, the odds ratio (OR) is not a good simulation for relative risk (RR). In order to be able to attach a more substantive meanings to estimates, we used the formula suggested by Zhang and Yu  to transThe final steps consisted of using the zero-inflated Poisson (ZIP) regressions to estimate male-female differences for foreign-born and US-born LAA with respect to both the occurrence of AUD and the increment in numbers of clinical features of AUD among drinkers. Due to the fact that a vast majority of individuals did not have any clinical feature of AUD (a count of zero) there was an “over-dispersion” of zeros in the outcome, the number of AUD clinical features. The ZIP model can account for this “inflation” of zeros . The ZIPThe complex survey sampling strategy and selection probabilities were accounted for by applying proper sampling weights and post stratification adjustments. In this work, the precision of estimates was expressed by 95% confidence intervals. Stata software was used for all analyses . The sample included 1378 US-born LAA (924 Latinos and 454 Asians) and 3268 foreign-born LAA (1629 Latinos and 1659 Asians). With respect to alcohol use and related problems, males were more likely to drink and were more likely to have drinking-related problems than females in both US-born and foreign-born LAA see . US-born Individuals were more likely to drink when compared to foreign-born individuals . The same pattern was found for the lifetime occurrence of AUD. Smaller male-female ratios were found for US-born LAA in the occurrence of AUD as compared to foreign-born LAA: the male-female ratio was above 20  for foreign-born LAA and approximately three in US-born LAA. P < 0.05). Larger RR were found for the foreign-born LAA. Nonetheless, point estimates indicate that the male excessive risk is rather small in earlier alcohol involvement  in both groups. In contrast, as alcohol drinking progresses, much larger male-female gaps were found for foreign-born LAA , while moderately larger male-female gaps were found for US-born LAA . In foreign-born LAA, as one female drinker developed any socially maladaptive drinking, there were almost 10 male drinkers did so; in US-born LAA, this ratio was two. Similar pattern was found in the occurrence of alcohol dependence. Interestingly, the male excessive risk of heavy drinking, which is an indicator of problematic drinking, was much smaller, especially in foreign-born LAA. Variations across Latinos and Asians were tested, but the results were not statistically significant (P > 0.05).As presented in The main findings of this study maybe summarized succinctly. First, substantially larger male-female differences in drinking and AUD were found for foreign-born LAA compared to their US-born counterparts. Second, the male-female difference in foreign-born LAA occurs mainly in later stages that involve the occurrence of AUD. In contrast, the male-female difference is much more homogeneous across all stages of alcohol involvement among US-born LAA. Third, in foreign-born LAA, once AUD clinical feature occurs, there was no male-female in the increment in number of clinical features; for US-born LAA, males were more likely to have a larger number of AUD clinical features once it occurs.The current study found male-female ratios in foreign-born LAA were close to those from Latin and Asian countries , 18–21, This study provided some empirical evidence on the male-female differences for US-born and foreign-born LAAs in relation to stages of alcohol involvement and what happen after the occurrence of the first clinical feature of AUD. The results signal that the differential social expectation may impact drinking behavior more in the later stages when maladaptive drinking pattern is manifested rather than early stages of alcohol involvement. It is interesting that the male-female difference in heavy drinking is not as large as that for AUD after MTM drinking has occurred. This suggests that occasional heavy episodic drinking in female may not be socially discouraged behavior as long as it does not evolve into a pattern of maladaptive drinking. However, heavy episodic drinking is associated with substantial disease burden through various routes . The resn = 11 as presented in Several study limitations merit attention while interpreting findings. Of central concern is the cross-sectional nature of the study. Possible recall bias and survival bias cannot be ruled out . Thus, tCounterbalancing strengths include that NLAAS is a nationally representative study. With statistical adjustments, such as sample weights and poststratification adjustment, the selection bias was minimized and thus results were generalizable to the LAA population as a whole. Based on findings like these, it is of interest to probe the role of acculturation in order to shed some light on the mechanism of the observed male-female differences among foreign-born LAAs. Also, studies on the male-female differences stratified by fine-grained grouping of ethnicity  may yield more relevant results for each subgroups of LAA.


Introduction. Restorative surgery for ulcerative colitis with ileal pouch anal anastomosis (IPAA) is frequently accompanied by complications. Volvulus of the ileal pouch is one of the most rarely reported late complications and to our knowledge no report exists on reoperative surgery for this condition. Case Report. A 58-year-old woman who previously had undergone restorative proctocolectomy due to ulcerative colitis with an IPAA presented with volvulus of the pouch. She was operated with a single row pouchopexy to the presacral fascia. Two months later she returned with a recurrent volvulus. At reoperation, the pouch was found to have become completely detached from the fascia. A new pexy was made by firmly anchoring the pouch with two rows of sutures to the presacral fascia as well as with sutures to the lateral pelvic walls. At follow-up after five months she was free of symptoms. Conclusion. This first report ever on reoperative surgery for volvulus of a pelvic pouch indicates that a single row pouchopexy might be insufficient for preventing retwisting. Several rows seem to be needed. Ileal pouch anal anastomosis for ulcerative colitis is a complex surgical procedure frequently accompanied by short- and long-term complications . The mosA 58-year-old woman operated with proctocolectomy and an ileal J-pouch 11 years earlier due to ulcerative colitis complicated by colonic cancer presented at a local hospital because of abdominal pain and failure of faecal evacuation. There was a previous history of similar but short and self-resolving episodes of obstruction without clear explanation. A CT-scan aroused suspicion of twisting of the pouch along its longitudinal axis causing an obstruction at the ileoanal anastomosis. An intestinal tube was passed into the pouch for decompression which resulted in relief of symptoms lasting also the day after removal of the tube. She was therefore discharged and referred to our hospital for follow-up with pouchoscopy. However, on the same day as she had been discharged, she presented as an emergency case at our hospital with identical symptoms of obstruction and was admitted to a surgical ward after the application of a tube into the pouch for deflating. Repeated CT-scans at presentation and after application of the tube showed again volvulus of the pouch, which resolved after tube insertion as did the symptoms . EndoscoTwo months later the patient presented with identical symptoms and a CT-scan showed again volvulus of the pouch. Insertion of a tube on this occasion did not fully relieve symptoms, so this led to a decision to proceed to laparotomy. A volvulus of the pouch along its longitudinal axis was found intraoperatively as well as an accompanying volvulus of the small bowel behind the afferent loop similar to the previous laparotomy . No new Volvulus of a pelvic pouch is a very rare condition. Presumably our patient had been suffering from intermittent partial twisting of the pouch for several years, but making a correct diagnosis of this condition had been almost impossible. To the best of our knowledge, only three cases of true pelvic pouch volvulus have been described in the literature –11. In tThe case in our opinion is of general interest due to the fact that intermittent volvulus should be borne in mind as a possible, if rare, cause of episodic obstruction in patients with a pelvic pouch. Furthermore, if a volvulus of a pelvic pouch is found at emergency laparotomy, a single row pouchopexy presumably is not sufficient to prevent retwisting. Therefore, we advocate firm anchoring to the sacral fascia using at least two rows of nonabsorbable sutures.


Malnutrition can be defined as a state of nutrition where the weight for age, height for age and weight for height indices are below -2 Z-score of the NCHS reference. It has posed a great economic burden to the developing world.The objective of this study is to assess the prevalence of malnutrition among pre-school children in abakiliki in Ebonyi state of Nigeria.This is a cross-sectional studies that assess the prevalence of malnutrition and associated factors among children aged 1-5 years attending nursery and primary schools. Nutritional assessment was done using anthropometry and clinical examination.A total of 616 children aged one to 5 years were enrolled into this study. Three hundred and sixty-seven (59.6%) were males while 249 (40.4%) were females. Sixty of the 616 children (9.7%) had acute malnutrition based on WHZ-score. Moderate acute malnutrition (MAM) was present in 33 children (5.3%) while 27 (4.4%) had severe acute malnutrition.The prevalence of global and severe acute malnutrition using z-score is 9.7% and 4.4% respectively while that of stunting is 9.9% with a male preponderance. Malnutrition is an unbearable burden not only on the health systems, but the entire socio-cultural and economic status of the society . MalnutrThe worldwide malnutrition estimation rates indicate that 35.8% of preschool children in developing countries are underweight, 42.7% are stunted, and 9.2% are wasted [None of these classifications address all the three indices of undernutrition - Stunting, Wasting and Underweight. Stunting (Low height-for-Age) is an indicator of chronic undernutrition due to prolonged food deprivation and/or illness; Wasting (Low weight for height) is an indicator of acute undernutrition, the result of more recent food deprivation and/or illness; Underweight (Low weight-for-age) is used as a composite measure to reflect both acute and chronic undernutrition .Currently, the WHO recommended the use Z-Score or SD system to grade undernutrition. This method measures all the three indices and expresses the results in terms of Z scores or standard deviation units. Children who are more than 2 SD below the reference median (i.e. a Z-Score of less than -2) are considered to be undernourished i.e. to be stunted, wasted or to be underweight. Children with measurements below 3 SD (a Z-Score of less than-3) are considered to be severely undernourished [Evaluation of prevalence of malnutrition among pre-school children using z-score is a very vital issue often under reported in pediatrics practice and in this part of the world, its importance therefore cannot be downplayed especially its impact on health which had been mentioned above.This study therefore is aimed at determining the prevalence and pattern of malnutrition among pre-school children using z-score. The results will help us to know the burden of this disease. This will enable us to establish a baseline data where other related issue will hinge on.We are not aware of any study of this nature from this environment. It is hoped that this will add to the body of knowledge available on these disorders and the findings of this study could form the template for intervention strategies in helping reduce this social malaise and managing such cases.This is a cross-sectional studies that assess the prevalence of malnutrition and associated factors among children aged 1-5 years.The study was conducted from selected two nursery and two primary schools in Abakiliki, Ebonyi state. Abakiliki is the capital of Ebonyi state, south-east Nigeria and has a population of 134102 according to the GeoNames geographical database [Source populations were all children aged 1-5 years attending nursery and primary schools in Abakiliki. Written Consent and approval were given by the school authorities where this study was carried out while verbal consent was obtained from parents of the pupils.Confidentiality of responses was also conveyed. Pupils were chosen by systemic sampling from nursery one to primary one. The study population are made up of people from mainly middle and lower class. Nutritional assessment was done using anthropometry. Children were weighed and measured as per the WHO guidelines on Anthropometry ,12.Stadiometer (Floor type model with sensitivity of 0.1 cm and 0.1 kg): was used to measure the height and weight of the children. It typically consists of a vertical ruler with a sliding horizontal rod or paddle which is adjusted to rest on top of the head. The mid arm circumference was measure with a measuring tape on two consecutive times. The sensitivity is 0.1 cm.Children aged 1-5 years who live and attend schools in nursery and primary schools in Abakiliki whose teachers gave consent were included in this study while children who were seriously ill and those whose parents did not give consents were excluded.The objective of this study is to assess the prevalence of malnutrition among children aged 1-5 years attending nursery and primary schools in Abakiliki in Ebonyi state of Nigeria.Moderate acute malnutrition was defined as weight for height of ≥ -3 and < -2 z-score and mid arm circumference (MAC) of 11 - <12.5 cm. Severe acute malnutrition was defined as weight for height z-score of < -3 and MAC of <11 cm. Stunting was defined as height for age z-score of < -2.Data analysis was with Statistical Package for Social Sciences (SPSS) version 19 (Chicago IL). Chi-square test was used to test for significant association of the proportion. A p-value of < 0.5 was regarded as significant. All reported p-values were 2-sided.A total of 616 children aged one to 5 years were enrolled into this study. Three hundred and sixty-seven (59.6%) were males while 249 (40.4%) were females. The distribution of the children according to age and gender is shown in Table Sixty of the 616 children (9.7%) had acute malnutrition based on WHZ-score. Moderate acute malnutrition (MAM) was present in 33 children (5.4%) while 27 (4.4%) had severe acute malnutrition. However, MAM and SAM based on MAC criteria was present in only 10 (1.6%) and 1 (0.2%) of the 616 children respectively. Thirty-seven of the 330 males (10.1%) compared to 23 of the 226 females (9.2%) had acute malnutrition (p = 0.78). Prevalence of acute malnutrition was highest among the one (12.4%) and two year olds (12.8%) and least among the four year old (4.7%) (p = 0.14). A higher proportion of the males (6%) than females (4.4%) had MAM. Conversely, a slightly higher proportion of the females (4.8%) than males (4.1%) had SAM. Nine of the 47 one year old females (19.1%) compared to 6 of 74 males (8.1%) had acute malnutrition. This difference showed a trend that failed to attain significance (p = 0.09). Conversely, 18 of 106 two- year old males (17.0%) compared to 5 of 74 females of same age had acute malnutrition. This difference also showed a trend that failed to attain statistical significance (p = 0.07). Detailed comparison of acute malnutrition between the genders according to their ages is shown in Table Sixty-one of the 616 children (9.9%) were stunted. Thirty nine of the 367 males (10.6%) were stunted compared to 22 of the 249 females (8.8%) although this difference was not statistically significant (p = 0.47). Across the age groups, a higher proportion of the two (19.4%) and three year olds (10.5%) compared to one (3.3%), four (2.8%) and five (2.7%) year olds were stunted (p < 0.001). However, 23 of 106 two-year old males compared to 12 of 74 females of same age were stunted (p = 0.45). Additionally, 13 of 112 males (11.6%) compared to 5 of 59 females aged 3 years were stunted (p = 0.61). Detailed comparison of stunting between the genders according to their ages is shown in Table The results of this study show acute malnutrition in this metropolis do exit, though there is lack of cultural and social recognition of this hidden malaise. The prevalence of stunting from our study is 9.9%. The result of this study revealed that, the prevalence of stunting is low when compared with a community cross-sectional study conducted in rural kebeles of Haramaya and NorthShewa district all in Ethiopia where a prevalence of 32.4% and 47.7% respectively were obtained ,14. The Possible reasons for the observed sex differences in these studies mainly centres on behavioural patterns . For insWe noted from this study that the prevalence of severe acute malnutrition and global malnutrition is 4.4% and 9.7% respectively. This is at variance with the global prevalence of 16.1 obtained by Casie et al.  who obtaThe prevalence of moderate acute malnutrition was 5.4% with a slight male preponderance. This is lower than the 16% reported by WHO with a female preponderance . A studyUsing MAC alone, a prevalence of severe malnutrition of 1.6% was obtained in this study. This is very low when compared with the 9% obtained by WHO . AlthougThe prevalence of global and severe acute malnutrition using z-score is 9.7% and 4.4% respectively while that of stunting is 9.9% with a male preponderance.Study of the prevalence of malnutrition in a larger community setting will make the impact and attendant problems to be appreciated better.