Background: Long-term alcohol consumption patterns play a critical role in human health. Objectives: We aimed to identify alcohol consumption trajectories and analyze their associations with coronary heart disease (CHD) and all-cause mortality in the Framingham Heart Study (FHS). Methods: We used a growth mixture model to identify sex-specific alcohol consumption trajectories over 15 years and Cox regression to examine associations of these trajectories with incident events that occurred during an additional 10-year follow-up, adjusting for covariates. Results: We identified four distinct trajectory groups among 6,570 participants (mean age 52; 55% women): Group 1 (n=2,713, reference) consisted of low-level drinkers; Group 2 (n=1,818) mainly included abstainers; Groups 3 (n=805) and 4 (n=1,234) comprised drinkers with varying patterns, with Group 4 consuming the most. Over 10 years of follow-up, women in Groups 2 to 4 had hazard ratios (HR) for CHD of 1.57 (95% CI = 1.11-2.22), 1.57 (95% CI = 1.08-2.29), and 1.27 (95% CI = 1.05-1.55) compared to Group 1. Women in Groups 2 (HR = 1.26, 95% CI = 1.05-1.50) and 3 (HR = 1.27, 95% CI = 1.05-1.55) also had higher all-cause mortality risks. Men in Group 2 had higher mortality (HR = 1.18, 95% CI = 1.02-1.37, P = 0.030) and CHD (HR = 1.56, 95% CI = 1.07-1.52, P = 0.001) risks compared to Group 1, while men in Group 4 had the highest mortality risk (HR = 1.27, 95% CI = 1.02-1.37). Conclusion: This study identified four distinct alcohol consumption trajectories and demonstrated that maintaining low to moderate levels of alcohol drinking over time is likely associated with a lower risk of CHD and mortality in both women and men. 

Fifteen-year Alcohol Consumption Trajectories and Their Association with Cardiovascular Events and Mortality: the Framingham Heart Study

Abstract Prognosis determines major decisions regarding treatment for critically ill patients. Statistical models have been developed to predict the probability of survival and other outcomes of intensive care. Although they were trained on the characteristics of large patient cohorts, they often do not represent very old patients (age ≥ 80 years) appropriately. Moreover, the heterogeneity within this particular group impairs the utility of statistical predictions for informing decision-making in very old individuals. In addition to these methodological problems, the diversity of cultural attitudes, available resources as well as variations of legal and professional norms limit the generalisability of prediction models, especially in patients with complex multi-morbidity and pre-existing functional impairments. Thus, current approaches to prognosticating outcomes in very old patients are imperfect and can generate substantial uncertainty about optimal trajectories of critical care in the individual. This article presents the state of the art and new approaches to predicting outcomes of intensive care for these patients. Special emphasis has been given to the integration of predictions into the decision-making for individual patients. This requires quantification of prognostic uncertainty and a careful alignment of decisions with the preferences of patients, who might prioritise functional outcomes over survival. Since the performance of outcome predictions for the individual patient may improve over time, time-limited trials in intensive care may be an appropriate way to increase the confidence in decisions about life-sustaining treatment. 

pdf/prognosticating-the-outcome-of-intensive-care-in-older-5ebm119si1.pdf

Prognosticating the outcome of intensive care in older patients—a narrative review

AIMS
To determine whether insulin controls hepatic de novo lipogenesis (DNL) through an HCF-1-dependent modulation of ChREBP that is distinct from the canonical SREBP1c pathway.


MATERIALS AND METHODS
AML-12 mouse hepatocytes were subjected to 10 μg/mL insulin and 25 mM glucose for 6 h. IRβ or HCF-1 was knocked down with lentiviral shRNA (≈80 % efficiency). Lipid droplets were quantified by Nile-Red staining; mRNA and protein levels were measured by RT-qPCR, Western blot, immunofluorescence and RNA-seq. Co-immunoprecipitation was used to test complex formation.


KEY FINDINGS
Insulin reduced lipid accumulation and suppressed ChREBP protein and its nuclear localization in AML-12 hepatocytes without altering SREBP1c. Knock-down of IRβ or HCF-1 abolished insulin-mediated ChREBP suppression, increased lipid droplets and up-regulated lipogenic genes. HCF-1 co-immunoprecipitated with IRβ, indicating formation of an insulin-responsive IRβ/HCF-1 complex that restrains ChREBP-driven lipogenesis.


SIGNIFICANCE
We identify an IRβ/HCF-1/ChREBP regulatory node in hepatocytes that can repress lipogenic genes independently of SREBP1c. The axis constitutes a testable target for understanding selective insulin action on hepatic lipid metabolism and for future in-vivo studies of fatty-liver disease.

The IRβ/HCF-1/ChREBP axis: A new paradigm in insulin-regulated hepatic lipogenesis

Background Although severity scoring systems are used to support decision making and assess ICU performance, the likelihood of bias based on age, gender, and primary language has not been studied. We aimed to identify the potential bias of them such as Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation IVa (APACHE IVa) by evaluating hospital mortality across subgroups divided by age, gender, and primary language via two large intensive care unit (ICU) databases. Methods This multicenter, retrospective study was conducted using data from the Medical Information Mart for Intensive Care (MIMIC, 2001-2019) database and the electronic ICU Collaborative Research Database (eICU-CRD, 2014-2015). SOFA and APACHE IVa scores were obtained from the first 24 hours of ICU admission. Hospital mortality was the primary outcome. Patients were stratified by age (16-44, 45-64, 64-79, and 80-), gender (female and male), and primary language (English and non-English) then assessed for discrimination and calibration in all subgroups. To evaluate for discrimination, the area under receiver operating characteristic (AUROC) curve and area under precision-recall curve (AUPRC) were used. Standardized mortality ratio (SMR) and calibration belt plot were used to evaluate calibration. Findings A total of 173,930 patient encounters (78,550 MIMIC and 95,380 eICU-CRD) were studied. Measurements of discrimination performed best for the youngest age ranges and worsened with increasing age (AUROC ranging from 0.812 to 0.673 for SOFA and 0.882 to 0.754 for APACHE IVa, p <0.001). There was a significant difference in discrimination between male and female patients, with female patients performing worse. With MIMIC data, patients whose primary language was not English performed worse than English speaking patients (AUROC ranging 0.771 to 0.709 [p <0.001] for SOFA). Measurements of calibration applied to SOFA showed a statistically significant overestimation of mortality in the youngest patients (SMR 0.55-0.6) and underestimation of mortality in the oldest patients (SMR 1.54-1.57). When using SOFA, mortality is overestimated for male patients (SMR 0.92-0.97) and underestimated for female patients (SMR 1.05-1.11) while mortality is overestimated for English-speaking patients (SMR 0.85) and greatly underestimated for non-English speaking patients (SMR 1.4). In contrast, the calibration applied to APACHE-IVa shows underestimation of mortality for all age groups and genders. Interpretation The differences in discrimination and calibration with increasing age, female gender, and non-English speaking patients suggest that illness severity scores are prone to bias in their mortality predictions. Caution must be taken when using these illness severity scores for quality benchmarking across ICUs and decision-making for practices among a diverse population.

Evaluating Prognostic Bias of Critical Illness Severity Scores Based on Age, Gender, and Primary Language in the USA: A Retrospective Multicenter Study

Background: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD. Methods: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine and liquor on average of 19 years in 2,428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure). Results: We identified 60 metabolites associated with cumulative average alcohol consumption (p<0.05/211=0.00024). For example, one g/day increase of alcohol consumption was associated with higher levels of cholesteryl esters (e.g., CE 16:1, beta=0.023, SE=0.002, p=6.3e-45) and phosphatidylcholine (e.g., PC 32:1, beta=0.021, SE=0.002, p=3.1e-38). Survival analysis identified that 10 alcohol-associated metabolites were also associated with a differential CVD risk after adjusting for age, sex, and batch. Further, we built two alcohol consumption weighted metabolite scores using these 10 metabolites and showed that, with adjustment age, sex, batch, and common CVD risk factors, the two scores had comparable but opposite associations with incident CVD, hazard ratio 1.11(95% CI=[1.02, 1.21], p=0.02) vs 0.88 (95% CI=[0.78, 0.98], p=0.02). Summary: We identified 60 long-term alcohol consumption-associated metabolites. The association analysis with incident CVD suggests a complex metabolic basis between alcohol consumption and CVD.

https://www.medrxiv.org/content/medrxiv/early/2023/05/29/2023.05.24.23290487.full.pdf

Circulating Metabolites May Illustrate Relationship of Alcohol Consumption with Cardiovascular Disease

Objective: To investigate the prevalence and independent risk factors of non-alcoholic fatty liver disease (NAFLD) and advanced chronic liver disease among the type 2 diabetes mellitus (T2DM) population in the Shenyang community, so as to provide evidence for the prevention and control of T2DM combined with NAFLD. Methods: This cross-sectional study was conducted in July 2021. 644 T2DM cases from 13 communities in Heping District, Shenyang City were selected. All the surveyed subjects underwent physical examination (measurements of height, body mass index, neck circumference, waist circumference, abdominal circumference, hip circumference, and blood pressure), infection screening (excluding hepatitis B and C, AIDS, and syphilis), random fingertip blood glucose, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). The study subjects were divided into the non-advanced chronic liver disease group and the advanced chronic liver disease group according to whether the LSM value was greater than 10 kPa. Cirrhotic portal hypertension development was indicated in patients with LSM ≥ 15 kPa. The comparison of multiple mean values among the sample groups was performed by analysis of variance when the normal distribution was met. Results: In the T2DM community population, there were 401 cases (62.27%) combined with NAFLD, 63 cases (9.78%) combined with advanced chronic liver disease, and 14 cases (2.17%) combined with portal hypertension. There were 581 cases in the non-advanced chronic liver disease group and 63 cases (9.78%) in the advanced chronic liver disease group (LSM ≥10 kPa), including 49 cases (7.61%) with 10 kPa≤LSM<15 kPa, 11 cases (1.71%) with 15 kPa ≤LSM<25 kPa, and 3 cases (0.47%) with LSM ≥ 25 kPa. Age, body mass, body mass index, neck circumference, waist circumference, hip circumference, waist-to-height ratio, systolic blood pressure, and CAP were all statistically different between the non-advanced chronic liver disease group and the advanced chronic liver disease group (F=-1.983,-2.598,-4.091,-2.062,-3.909, -4.581,-4.295,-2.474, and -5.191, respectively; P<0.05). There was a statistically significant difference in terms of whether or not there was combined cerebrovascular disease (2=4.632, P=0.031); however, there were no statistically significant differences in terms of lifestyle, diabetes complications, and other complications (P>0.05). Conclusion: Patients with T2DM have a higher prevalence of NAFLD (62.27%) than those with advanced chronic liver disease (9.78%). 2.17% of T2DM cases in the community may not have had early diagnosis and early intervention, and they might have been combined with cirrhotic portal hypertension. So, the management of these patients should be strengthened.

[Characteristic analysis of patients with type 2 diabetes mellitus combined with advanced stage chronic liver disease: a community population-based cross-sectional study in Heping District, Shenyang City (CHESS-LN 2101)].

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Evaluating Prognostic Bias of Critical Illness Severity Scores Based on Age, Gender, and Primary Language in the USA: A Retrospective Multicenter Study

Circulating Metabolites May Illustrate Relationship of Alcohol Consumption with Cardiovascular Disease

[Characteristic analysis of patients with type 2 diabetes mellitus combined with advanced stage chronic liver disease: a community population-based cross-sectional study in Heping District, Shenyang City (CHESS-LN 2101)].