Cost effectiveness of ribavirin/interferon alfa-2b after interferon relapse in chronic hepatitis C

PURPOSE: Many patients with chronic hepatitis C who are treated with interferon suffer a relapse after an initial response. About half of these patients have a sustained virological response to retreatment with the combination of ribavirin and interferon alfa-2b. The aim of this study was to estimate the cost effectiveness of retreatment with combination therapy versus interferon alone for patients who have previously relapsed after interferon. SUBJECTS AND METHODS: Data from a randomized trial among 345 relapsed patients that compared combination therapy with interferon alone were used to project lifelong clinical and economic outcomes. Natural history and economic estimates (discounted at 3% per year) were based upon published literature, expert panel estimates, and cost and reimbursement data. RESULTS: Compared with retreatment with interferon alone, combination therapy should prolong life expectancy by about 2 discounted quality-adjusted life years (3 life years, undiscounted) while increasing costs modestly. The results were robust, maintaining an advantage to combination therapy in sensitivity analysis for all subgroups and with reasonable variations in all model parameters. CONCLUSION: For patients with chronic hepatitis C who relapse after an initial response to interferon alone, retreatment with the combination of ribavirin and interferon alfa-2b should prolong life and be cost effective.     

College students lack knowledge of standard drink volumes: implications for definitions of risky drinking based on survey data

BACKGROUND: College students tend to pour single servings of beer and liquor that are larger than commonly used standards. The reasons for this are unknown. Students might overpour because they lack knowledge of standard serving sizes. Alternatively, they might know how much alcohol to pour but simply have difficulty pouring the correct amounts. Misperceptions of standard serving sizes could lead to inaccuracies in self-reported consumption. If this is the case, then the validity of students' responses on alcohol surveys and the definitions of risky drinking that are based on them would be called into question. This study examined how college students define standard drinks, whether their definitions are similar to the definitions commonly used by alcohol researchers and government agencies, and whether their definitions of standard drinks are related to the sizes of the drinks that they pour. The study also examined whether feedback regarding the accuracy of their definitions of standard drinks leads students to alter their self-reported levels of consumption. METHODS: Students (N = 133) completed an alcohol survey and performed tasks that required them to free-pour a single beer, glass of wine, shot of liquor, or the amount of liquor in a mixed drink. Roughly half of the students received feedback regarding their definitions of standard drinks. All students then were resurveyed about their recent levels of consumption. RESULTS: With the exception of beer, students incorrectly defined the volumes of standard servings of alcohol, overestimating the appropriate volumes. They also overestimated appropriate volumes when asked to free-pour drinks. Positive relationships existed between students' definitions of standard drinks and the sizes of the drinks that they free-poured. Feedback regarding misperceptions of standard drink volumes led to an increase in levels of self-reported consumption, suggesting that students' original estimates of their alcohol consumption were too low. CONCLUSIONS: Despite the recent focus on alcohol education and prevention at the college level, college students have not been taught how to define standard drinks accurately. They tend to overstate the appropriate volumes, leading them to overpour drinks and underreport levels of consumption. Self-reported consumption levels are altered by feedback regarding the accuracy of students' definitions of standard drinks. The findings raise important questions about the validity of students' responses on alcohol surveys and the definitions of risky drinking that are based them.     

Subjective response to alcohol challenge: a quantitative review

Background: Individual differences in subjective response to alcohol, as measured by laboratory‐based alcohol challenge, have been identified as a candidate phenotypic risk factor for the development of alcohol‐use disorders (AUDs). Two models have been developed to explain the role of subjective response to alcohol, but predictions from the 2 models are contradictory, and theoretical consensus is lacking. Methods: This investigation used a meta‐analytic approach to review the accumulated evidence from alcohol‐challenge studies of subjective response as a risk factor. Data from 32 independent samples (total N = 1,314) were aggregated to produce quantitative estimates of the effects of risk‐group status (i.e., positive family history of AUDs or heavier alcohol consumption) on subjective response. Results: As predicted by the Low Level of Response Model (LLRM), family history–positive groups experienced reduced overall subjective response relative to family history–negative groups. This effect was most evident among men, with family history–positive men responding more than half a standard deviation less than family history–negative men. In contrast, consistent with the Differentiator Model (DM), heavier drinkers of both genders responded 0.4 standard deviations less on measures of sedation than did the lighter drinkers but nearly half a standard deviation more on measures of stimulation, with the stimulation difference appearing most prominent on the ascending limb of the blood alcohol concentration curve. Conclusions: The accumulated results from 3 decades of family history comparisons provide considerable support for the LLRM. In contrast, results from typical consumption comparisons were largely consistent with predictions of the DM. The LLRM and DM may describe 2 distinct sets of phenotypic risk, with importantly different etiologies and predictions for the development of AUDs.     

Turning off the tap: the real solution to cigarette smuggling.

The tobacco industry has argued that tobacco smuggling is caused by market forces, i.e., by the price differences between countries, which create an incentive to smuggle cigarettes from 'cheaper' to 'more expensive' countries, and so urged governments to solve the problem by reducing taxes to remove this differential, which will also, they say, restore revenue. Although such market forces have some effect, smuggling is in fact more prevalent in 'cheaper' countries, and reducing tax is not the solution. Where taxes have been reduced tobacco consumption has risen and revenue has fallen, with disastrous consequences for public health. The key to understanding cigarette smuggling is understanding the role of the tobacco industry. At the heart of cigarette smuggling is large scale fraud: container loads of cigarettes are exported, legally and duty unpaid, to countries where they have no market, and where they disappear into the contraband market. They are often smuggled back into the country of origin, where they are sold at a third to half price. It is therefore profitable because duty has been illegally evaded. The key to controlling cigarette smuggling is not lowering taxes, it is controlling the tobacco manufacturing industry and its exporting practices.     

Idiopathic mesenteric phlebosclerosis associated with long-term use of medical liquor:Two case reports and literature review

A 62-year-old woman was admitted to our hospital in2011 because of recurrent abdominal pain,nausea and constipation for six months.Computed tomography enterography(CTE)showed tortuous thread-like calcifications in the ileocolic vein and right colic vein,while colonoscopy revealed purple-blue mucosa extending from the cecum to the splenic flexure.Based on the results of these tests,the patient was diagnosed with idiopathic mesenteric phlebosclerosis(IMP).She had a history of Chinese medical liquor intake for one and a half years and her symptoms subsided after conservative treatment.In 2013,a 63-year-old male patient who presented with recurrent lower right abdominal pain,bloating,melena and diarrhea for fifteen months was admitted to our institution.Colonoscopy and CTE led to the diagnosis of IMP.He also used Chinese medical liquor for approximately 12 years.The patient underwent total colectomy and the postoperative course was uneventful.We searched for previously published reports on similar cases and analyzed the clinical data of 50 cases identified in PubMed.As some of these patients admitted use of Chinese medicines,we hypothesize that Chinese medicines may play a role in the pathogenesis of IMP.     

A longitudinal analysis of alcohol outlet density and domestic violence

Aims A small number of studies have identified a positive relationship between alcohol outlet density and domestic violence. These studies have all been based on cross‐sectional data and have been limited to the assessment of ecological correlations between outlet density and domestic violence rates. This study provides the first longitudinal examination of this relationship. Design Cross‐sectional time‐series using aggregated data from small areas. The relationships between alcohol outlet density and domestic violence were assessed over time using a fixed‐effects model. Controls for the spatial autocorrelation of the data were included in the model. Setting The study uses data for 186 postcodes from within the metropolitan area of Melbourne, Australia for the years 1996 to 2005. Measures Alcohol outlet density measures for three different types of outlets (hotel/pub, packaged liquor, on‐premise) were derived from liquor licensing records and domestic violence rates were calculated from police‐recorded crime data, based on the victim's postcode. Findings Alcohol outlet density was associated significantly with rates of domestic violence, over time. All three licence categories were positively associated with domestic violence rates, with small effects for general (pub) and on‐premise licences and a large effect for packaged liquor licences. Conclusions: In Melbourne, the density of liquor licences is positively associated with rates of domestic violence over time. The effects were particularly large for packaged liquor outlets, suggesting a need for licensing policies that pay more attention to o off‐premise alcohol availability.     

An unusual case of self-induced electrolyte depletion

A case of anorexia nervosa, presenting with unexplained hypokalaemia, is described. The patient was also secretly addicted to purgatives and diuretics. During an attempted metabolic balance study she secretly disposed of food and excreta, which were smuggled from the hospital by her sister. The patient induced her husband to bring his own stools into the ward, these then being substituted for her own.The interrelationships of the electrolyte disturbances, elevation of plasma renin, renin substrate, and hyperaldosteronism are discussed, particularly in connexion with the pathogenesis of peripheral oedema in anorexia nervosa.     

Type of alcoholic beverage and risk of myocardial infarction

We examined the relation of alcoholic beverage type and risk of myocardial infarction (MI) in a case-control study among 340 cases of MI and an equal number of age-, sex-, and community-matched controls. Alcohol consumption was estimated using a food frequency questionnaire, with alcohol drinkers defined as those consuming > or = 1/2 drink/day on average of any alcoholic beverage. Beer, wine, and liquor drinkers had at least half of their consumption from 1 beverage type. Fasting venous blood samples were obtained and analyzed for lipid profiles. Compared with nondrinkers, after adjustment for age and sex, reductions in risk of MI were similar for regular drinkers of any type of alcoholic beverage (relative risk [RR] 0.54; 95% confidence interval [CI] 0.37 to 0.79; p = 0.001), beer (RR 0.55; 95% CI 0.31 to 0.97; p <0.05), wine (RR 0.48; 95% CI 0.27 to 0.87; p <0.05), and liquor (RR 0.59; 95% CI 0.38 to 0.91; p <0.05) drinkers. Comparable benefits remained apparent even after multivariate adjustment for a wide range of nonlipid coronary risk factors. High-density lipoprotein (HDL) levels were significantly higher in all 4 beverage categories when compared with levels in nondrinkers, and as expected, adjustment for total HDL, a major direct effect of alcohol, substantially attenuated the protective effect in all 4 beverage categories. Relative risks were 0.94 for any beverage, 1.09 for beer, 0.97 for wine, and 0.83 for liquor after further adjustment. This strongly suggests that the protective effect of each beverage type is, in large part, mediated by increased HDL. These data indicate that regular consumption of small to moderate amounts of alcoholic beverages, regardless of the type, reduces the risk of MI, and further suggest that there is benefit, in large part, from increases in HDL levels.     

Perceived vs Actual Knowledge and Risk of Heart Disease in Women: Findings From a Canadian Survey on Heart Health Awareness,Attitudes, and Lifestyle

Background

Heart disease is a leading cause of morbidity and mortality in men and women. Our understanding of heart disease stems chiefly from clinical trials on men, but key features of the disease differ in women. This article reports findings from the first Canadian national survey of women that focuses on knowledge, perceptions, and lifestyle related to heart health.

Methods

A cross-country survey using an adaptation of an instrument used in the United States was undertaken in spring of 2013. Based on online (208) and telephone (1446) responses from a randomly selected sample of women aged 25 or older, a total sample of 1654 weighted percentage estimates were produced. The overall response rate was 12.5%.

Results

Just under half of women were able to name smoking as a risk factor of heart disease, and less than one quarter named hypertension or high cholesterol. Fewer than half of women knew the major symptoms of heart disease. Most women prefer to receive information on heart health from their doctor, but only slightly more than half report that their doctor includes discussion of prevention and lifestyle during clinical consultations.

Conclusions

Most women lack knowledge of heart disease symptoms and risk factors, and significant proportions are unaware of their own risk status. The findings underscore the opportunity for patient education and intervention regarding risk and prevention of heart disease.     

The consequences expected from alcohol and drinking behavior: a factor analysis of data from a panel study of adolescents

The consequences people expect from behavior are central to many theories. In this longitudinal study, 1,423 adolescents assessed the likelihood and desirability associated with 57 consequences of drinking beer and hard liquor. Factor analyses yielded seven factors for beer and six for hard liquor. In multivariate analyses the pleasure, psychological, and deviance factors were related to the initiation of beer drinking; the pleasure and psychological factors were associated with beginning to drink hard liquor. Among those who were drinkers when first studied, the trouble with authority factor was related to an increase in beer drinking and the psychological factor was related to an increase in drinking hard liquor. The findings are discussed in the context of earlier research on the determinants of behavior with alcohol and the value of the factors for future research.     

Changes in per capita alcohol sales during the partial privatization of British Columbia's retail alcohol monopoly 2003–2008: a multi-level local area analysis

Aim   To investigate the independent effects on liquor sales of an increase in (a) the density of liquor outlets and (b) the proportion of liquor stores in private rather than government ownership in British Columbia between 2003/4 and 2007/8.
Design   The British Columbia Liquor Distribution Branch provided data on litres of ethanol sold through different types of outlets in 89 local health areas of the province by beverage type. Multi-level regression models were used to examine the relationship between per capita alcohol sales and outlet densities for different types of liquor outlet after adjusting for potential confounding social, economic and demographic factors as well as spatial and temporal autocorrelation.
Setting   Liquor outlets in 89 local health areas of British Columbia, Canada.
Findings   The number of private stores per 10 000 residents was associated significantly and positively with per capita sales of ethanol in beer, coolers, spirits and wine, while the reverse held for government liquor stores. Significant positive effects were also identified for the number of bars and restaurants per head of population. The percentage of liquor stores in private versus government ownership was also associated significantly with per capita alcohol sales when controlling for density of liquor stores and of on-premise outlets ( P  < 0.01).
Conclusion   The trend towards privatisation of liquor outlets between 2003/04 and 2007/08 in British Columbia has contributed to increased per capita sales of alcohol and hence possibly also to increased alcohol-related harm.     

Should we worry about meconium? A controlled study of neonatal outcome

Over a 7 month period 131 cases with intrapartum draining of meconium-stained liquor (MSL) were reviewed and the neonatal outcome compared to that of all deliveries during the same time. Mean Apgars were significantly lower and the proportion of neonates with poor Apgar scores was higher if thick meconium was present, but not for thin meconium. Prolonged labour was more common and associated with a particularly worse outcome in the MSL group. Caesarean sections were performed twice as frequently, failure to progress being the indication in more than half the cases. Close monitoring of labour in the presence of MSL (particularly thick MSL) is important to detect failure to progress and fetal distress early.     

Immunization of mice with concentrated liquor from male zooid of Antheraea pernyi

AIM: To study the effects of concentrated liquor from male zooid of Antheraea pernyi on immunological mice. METHODS: For each experiment, 40 mice were randomly divided into normal saline group (control group) and three tested groups that were administered different dosages of concentrated liquor from male zooid of A. pernyi and food for 15 d. The typical FSR and HC50 value, rnonocyte-phagocytic exponent Kand emendated monocyte-phagocytic exponent a were determined and calculated respectively. RESULTS: After 24 and 48 h, the FSR values of the three tested groups improved significantly in comparison to the control group by variance analysis. The HC50 values showed a significant difference between the high dosage group and the control group, as well as between the high dosage group and other two tested groups. The nronocyte-phagocytic exponent Kand emendated exponent a showed rising tendencies, but no significant differences were found by variance analysis. CONCLUSION: The concentrated liquor from male zooid of A. pernyi can significantly enhance cellular and humoral immune function in mice, but has no distinct influence on the monocyte-phagocytic system in mice.     

Systematic Review of Hepatitis C Virus Prevalence in the WHO Western Pacific Region

Background: This review aimed to identify hepatitis C virus (HCV) prevalence estimates among the general population and six key populations (people who inject drugs, men who have sex with men, sex workers, prisoners/detainees, Indigenous people, and migrants) in the World Health Organization Western Pacific Region (WHO WPR). Methods: Original research articles published between 2016 and 2020 were identified from bibliographic databases. Publications were retrieved, replicas removed, and abstracts screened. Retained full texts were assessed and excluded if inclusion criteria were not met. Methodological quality was assessed using the Johanna Briggs Institute critical appraisal checklist for prevalence data. Data on HCV exposure and active infection were extracted and aggregated and forest plots generated for each population by country. Results: There were no HCV prevalence estimates in any population for more than half of WPR countries and territories. Among the 76 estimates, 97% presented prevalence of exposure and 33% prevalence of active infection. General population viraemic prevalence was 1% or less, except in Mongolia. Results confirm the endemic nature of HCV among people who inject drugs, with estimates of exposure ranging from 30% in Cambodia to 76% in Hong Kong. Conclusions: Countries require detailed knowledge of HCV prevalence in diverse populations to evaluate the impact of efforts to support WHO HCV elimination goals. Results provide baseline estimates from which to monitor and evaluate progress and by which to benchmark future elimination efforts.     

Epidemiological and histopathological study of relevance of Guizhou Maotai liquor and liver diseases

AIM：To explore the relevance of Maotai liquor and liver diseases.METHODS:Epidemiological study was conducted on groups of subjects,each consisting of 3 subjects from the Maotai liquor roup consisting of 99 individuals and one from the non-alcoholic control group consisting of 33 individuals Liver biopsy was performed on 23 volunteere from Guizhou Maotai Distillery who had a constant and long history of drinking Maotai liquor.Experimental histopathological study was conducted as follows:Sixty male Wistar rate were divided into 3 groups randomly and fed with Maotai liquor,ordinary white wine,and physiological saline respectively for a period of 8and 12 weeks,The rats were sacrificed in batches,then serum ALT,AST,TBil,and AKP were measured.Rat livers were harvested to Measure the liver indexes GSH,and MDA.Histopathological examinations were also performed.Another eighty mice were randomly divided into 4 groups and fed with Maotai(at different dosages of 10ml.kg^-1 and 20ml.kg^-1),ethanol,and physiological saline.The animals were sacrificed after 4 weeks and serum ALT was determined ,Then the livers were harvested and liver indexes and MDA were measured.RESULTS:The incidence rate of hepatic symptoms splenomegaly,liver function impairment,reversal of Albumin/Globulin and increased diameter of portal verins in the Maotai liquor group were 1.0%(1/99),1.0%(1/99),1.0%(1/99),1.0%(1/99),9(9/99)and 9(0/99),0(0/99),0(0/99),0(0/99),0(0/99),respectively,There was no significant difference between the Maotai group[ and the non-alcoholic control group(P&gt;0\05),Various degree of fatty infiltration of hepatocytes was found in the 23 volunteers receiving liver biopsy.but there was no obvious hepatic fibrosis or cirrhosis.A comparison was made between the Maotai liquor group and the ordinary white wine group,It was found that hepatic MAD in rats and mice,were 0.33&#177;0.10and 0.49&#177;0.23respectively in Maotai group and 0.61&#177;0.22and 0.66&#177;0.32inthe ordinary white wine group;MDA had an obvious decrease in the Maotai liquor group(P&lt;0.05)hepatic GSH were 0.12mg.g^-1&#177;0.06mg.g^-1 in rats of the Maotai liquor group and (0.08&#177;0.02)mg.g^-1 in white wine group,it was obviously increased in the Maotai liquor group(P&lt;0.05),Atfer the 20 rats had been fed with ordinary white wine for 8 Weeks consecutively,disarranged hepatocyte cords,fatty infiltration of hepatocytes,and fibrous septa of varying widths due to hepatic connective tissues proliferation were observed;after 12 weeks,the fibrous tissue proliferation continued and early cirrhosis appeared.COmpared with the ordinary whtite wine group fatty infiltration was observed in the 8-week and 12-week groups,but no necrosis or filbrosis or cirrhosis was found in the Maotai liquor group(P&lt;0.05）。CONCLUSION:Maotai liquor may cause fatty liver but not hepatic fibrosis or cirrhosis,and it can strengthen lipid peroxidation in the liver。     

Impact on alcohol-related mortality of a rapid rise in the density of private liquor outlets in British Columbia: a local area multi-level analysis

Aims To study relationships between rates of alcohol‐related deaths and (i) the density of liquor outlets and (ii) the proportion of liquor stores owned privately in British Columbia (BC) during a period of rapid increase in private stores. Design Multi‐level regression analyses assessed the relationship between population rates of private liquor stores and alcohol‐related mortality after adjusting for potential confounding. Setting The 89 local health areas of BC, Canada across a 6‐year period from 2003 to 2008, for a longitudinal sample with n = 534. Measurements Population rates of liquor store density, alcohol‐related death and socio‐economic variables obtained from government sources. Findings The total number of liquor stores per 1000 residents was associated significantly and positively with population rates of alcohol‐related death (P < 0.01). A conservative estimate is that rates of alcohol‐related death increased by 3.25% for each 20% increase in private store density. The percentage of liquor stores in private ownership was also associated independently with local rates of alcohol‐related death after controlling for overall liquor store density (P < 0.05). Alternative models confirmed significant relationships between changes in private store density and mortality over time. Conclusions The rapidly rising densities of private liquor stores in British Columbia from 2003 to 2008 was associated with a significant local‐area increase in rates of alcohol‐related death.     

Ability of laypersons to estimate short time intervals in cardiac arrest

STUDY OBJECTIVE: Estimates of time intervals by bystanders are considered critical in cardiac arrest, and are often used in other disorders such as stroke and myocardial infarction. Because they have never been previously studied, we sought to determine their accuracy. METHODS: This study was performed by prospective collection of bystander estimates (made at the time of the arrest) of the time from calling 911 to the arrival of urban fire department first responders, and comparison with actual measured response interval from computerized records, in all out-of-hospital cardiac arrests from January 1996 through June 1998. RESULTS: The fire department responded to 1,015 patients in cardiac arrest during the study period. First responders arrived before advanced life support providers to 831 patients, who thus met study entry criteria. Bystander estimates were obtained in 497 of these 831 patients, who did not differ in key characteristics from those lacking estimates. The bystander's average estimated fire department response interval was 5.6 minutes (95% confidence interval [CI] 5.2 to 5.9 minutes) and the actual measured interval to the patient's side from computer records was 6.1 minutes (95% CI 5.9 to 6.4 minutes). However, the median error of the bystander estimate (1.3 minutes) was 32% of the median of the actual measured on-scene interval, and there was no correlation between the bystander estimates and the measured interval in individual cases (R 相似文献   

Bias due to Non-response in a Dutch Survey on Alcohol Consumption

Increasing non-response rates force survey researchers to focus on the danger of biased results. In this study two methods were used to determine whether a non-response rate of 31% in a survey of drinking habits in the Netherlands seriously affects estimates of alcohol consumption. Firstly, several indices of mean consumption were corrected for differences in response probabilities of the distinguished substrata. Secondly, data from a follow-up among non-respondents were used to study differences in consumption between the response and non-response stratum. Both methods led to the general conclusion that the effect of non-response on estimates of consumption for the entire population appears to be small. Among female non-respondents, a higher proportion of abstainers and a lower average consumption was found. Although occasional heavy alcohol use in the previous 6 months was more frequent among male non-respondents than among male respondents, the reverse was true for frequent, weekly heavy use.     

酒精肝造模过程中的酒质对体重变化的影响

目的研究小鼠酒精性肝病造模过程中的不同酒质的作用。方法小鼠慢性喂养工业酒精2个月,或喂养食用酒A或食用酒B 40 d。检查小鼠空腹体重及病理组织学的变化。结果工业酒精慢性喂养2个月后,体重比对照组显著下降,说明工业酒精作为慢性酒精喂养模型的不适用问题。于是,我们进一步使用食用酒A,食用酒B分别慢性酒精喂养40 d后,体重仍然下降约20%。于是比较两种使用食用酒间隔5 d或10 d的慢性喂养85 d情况下(含酒精为40 d),食用酒B的体重降低有明显改善。三种酒喂养情况下,组织学均未见显著性差异。结论从体重的变化看,酒精质量对此模型具有重要的意义。     

Time pattern of reduction in risk of oesophageal cancer following alcohol cessation--a meta-analysis

Aim To establish the current level of knowledge of the effect of drinking cessation on the risk of developing oesophageal cancer. Method A meta‐analysis was conducted based on relevant studies identified through a systematic literature review. A generalized least squares model for trend estimation of summarized dose–response data were utilized in order to estimate the effect of years since drinking cessation on risk of oesophageal cancer. Result Seventeen studies that estimate the risk reduction after quantified drinking cessation were identified in the systematic literature review. Nine of these were appropriate for inclusion in the meta‐analysis. A large degree of heterogeneity existed between the studies, but this was explainable and the increased risk of oesophageal cancer caused by alcohol consumption was found to be reversible, with a common trend between studies. A required time‐period of 16.5 years (95% confidence interval 12.7–23.7) was estimated until no risk from former drinking remained, although this might have been an overestimation due to sample characteristics. The dose–response relationship was found to have an exponential decay. This means that about half the reduction in alcohol‐related risk occurred after just a third of the time‐period required to eliminate the additional risk. Conclusion The alcohol‐related increased risk of oesophageal cancer is reversible following drinking cessation. It is most likely that about 16 years are required until all elevated risk has disappeared. Due to lack of research and data, more research is urgently required to increase the robustness of the estimates and to approach study limitations.