GHSR blockade, but not reduction of peripherally circulating ghrelin via ß1-adrenergic receptor antagonism, decreases binge-like alcohol drinking in mice.

Alcohol use disorder (AUD) and binge drinking are highly prevalent public health issues. The stomach-derived peptide ghrelin, and its receptor, the growth hormone secretagogue receptor (GHSR), both of which are expressed in the brain and periphery, are implicated in alcohol-related outcomes. We previously found that systemic and central administration of GHSR antagonists reduced binge-like alcohol drinking, whereas a ghrelin vaccine did not. Thus, we hypothesized that central GHSR drives binge-like alcohol drinking independently of peripheral ghrelin. To investigate this hypothesis, we antagonized ß1-adrenergic receptors (ß1ARs), which are required for peripheral ghrelin release, and combined them with GHSR blockers. We found that both systemic ß1AR antagonism with atenolol (peripherally restricted) and metoprolol (brain permeable) robustly decreased plasma ghrelin levels. Also, ICV administration of atenolol had no effect on peripheral endogenous ghrelin levels. However, only metoprolol, but not atenolol, decreased binge-like alcohol drinking. The ß1AR antagonism also did not prevent the effects of the GHSR blockers JMV2959 and PF-5190457 in decreasing binge-like alcohol drinking. These results suggest that the GHSR rather than peripheral endogenous ghrelin is involved in binge-like alcohol drinking. Thus, GHSRs and ß1ARs represent possible targets for therapeutic intervention for AUD, including the potential combination of drugs that target these two systems.

PET imaging in rat brain shows opposite effects of acute and chronic alcohol exposure on phosphodiesterase-4B, an indirect biomarker of cAMP activity.

The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [18F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [18F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [18F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption.

Centrally administered growth hormone secretagogue receptor antagonist DLys decreases alcohol intake and preference in male mice.

Alcohol use disorder (AUD) is a highly prevalent public health problem. The ghrelin system has been identified as a potential target for therapeutic intervention for AUD. Previous work showed that systemic administration of the growth hormone secretagogue receptor (GHSR) antagonist DLys reduced alcohol intake and preference in male mice. Yet, it is unclear whether central or peripheral GHSRs mediated these effects. We hypothesized that alcohol consumption is driven by central GHSRs and addressed this hypothesis by testing the effects of central administration of DLys. Male C57BL/6J mice consumed alcohol in a two-bottle choice procedure (10% ethanol versus water). DLys (2 nmol) was administered intracerebroventricularly for 7 days to examine alcohol intake and preference. DLys decreased alcohol intake and preference but had no effect on food intake. The effects on alcohol intake and preference persisted after several administrations, indicating lack of tolerance to DLys' effects. These results suggest that central administration of DLys is sufficient to reduce alcohol drinking and that DLys remains effective after several administrations when given intracerebroventricularly. Moreover, this work suggests that the effects of intracerebroventricularly administered DLys are specific to alcohol and do not generalize to other calorie-driven behaviors.

IUPHAR review - Glucagon-like peptide-1 (GLP-1) and substance use disorders: An emerging pharmacotherapeutic target.

Addiction is a chronic relapsing disease with high morbidity and mortality. Treatments for addiction include pharmacological and psychosocial interventions; however, currently available medications are limited in number and efficacy. The glucagon-like-peptide-1 (GLP-1) system is emerging as a potential novel pharmacotherapeutic target for alcohol and other substance use disorders (ASUDs). In this review, we summarize and discuss the wealth of available evidence from testing GLP-1 receptor (GLP-1R) agonist medications in preclinical models and humans with ASUDs, possible mechanisms underlying the impact of GLP-1R agonists on alcohol/substance use, gaps in knowledge, and future directions. Most of the research with GLP-1R agonists has been conducted in relation to alcohol use; psychostimulants, opioids, and nicotine have also been investigated. Preclinical evidence suggests that GLP-1R agonists reduce alcohol/substance use and other related outcomes. The main proposed mechanisms are related to reward processing, stress, and cognitive function, as well as broader mechanisms related to satiety, changes in gastric motility, and glucose homeostasis. More in-depth mechanistic studies are warranted. Clinical studies have been limited and their findings have been less conclusive; however, most support the safety and potential efficacy of GLP-1R agonists in ASUD treatment. Identifying preferred compounds, as well as possible subgroups who are most responsive to GLP-1R agonists are some of the key research questions to translate the promising preclinical data into clinical settings. Several clinical trials are underway to test GLP-1R agonists in people with ASUDs.

Time trends in hypertension and diabetes prevalence by body mass index categories in Brazilian adults from 2006 to 2023.

AIM: The prevalence of diabetes and hypertension according to body mass index (BMI) status in Brazilian adults has not been described yet. Herein, we aimed to identify the time trends in hypertension and diabetes, individually and combined (multimorbidity), by BMI in Brazilian adults. METHODS: In this time series cross-sectional study, we retrieved self-reported data from 806 169 adults between 2006 and 2023, using the Surveillance System of Risk and Protective Factors from Chronic Diseases by Telephone Survey (Vigitel). Weight and height were used to classify participants into normal/underweight (<25 kg/m2), pre-obesity (25 to 29.9 kg/m2), and obesity (≥ 30 kg/m2). We calculated the prevalence of medical diagnoses of hypertension and diabetes, individually and combined, by BMI categories, and by sociodemographic characteristics (sex, age group, educational attainment) for participants with obesity. We performed Prais-Winsten linear regression models to identify temporal trends. RESULTS: The prevalence of hypertension and diabetes increased between 2006 and 2023. Among adults with obesity, we observed a slight decrease in the prevalence of hypertension (from 44.5% in 2006 to 41.7% in 2023) and the prevalence of either hypertension or diabetes (47.1% to 45.5%); an increase in the prevalence of diabetes (12.8% to 15.13) and both conditions combined (10.2% to 11.2%). Participants with obesity had more than twice the prevalence of hypertension and diabetes compared with those who were normal/underweight. We observed a differential time trend by sex, age group, and educational attainment. CONCLUSION: Our findings indicate the need for differentiated approaches for interventions for hypertension and diabetes, considering variations over time by sociodemographic characteristics.

Cryo-EM architecture of a near-native stretch-sensitive membrane microdomain.

Biological membranes are partitioned into functional zones termed membrane microdomains, which contain specific lipids and proteins1-3. The composition and organization of membrane microdomains remain controversial because few techniques are available that allow the visualization of lipids in situ without disrupting their native behaviour3,4. The yeast eisosome, composed of the BAR-domain proteins Pil1 and Lsp1 (hereafter, Pil1/Lsp1), scaffolds a membrane compartment that senses and responds to mechanical stress by flattening and releasing sequestered factors5-9. Here we isolated near-native eisosomes as helical tubules made up of a lattice of Pil1/Lsp1 bound to plasma membrane lipids, and solved their structures by helical reconstruction. Our structures reveal a striking organization of membrane lipids, and, using in vitro reconstitutions and molecular dynamics simulations, we confirmed the positioning of individual PI(4,5)P2, phosphatidylserine and sterol molecules sequestered beneath the Pil1/Lsp1 coat. Three-dimensional variability analysis of the native-source eisosomes revealed a dynamic stretching of the Pil1/Lsp1 lattice that affects the sequestration of these lipids. Collectively, our results support a mechanism in which stretching of the Pil1/Lsp1 lattice liberates lipids that would otherwise be anchored by the Pil1/Lsp1 coat, and thus provide mechanistic insight into how eisosome BAR-domain proteins create a mechanosensitive membrane microdomain.

Device-measured sedentary time and intensity-specific physical activity in relation to all-cause and cardiovascular disease mortality: the UK Biobank cohort study.

BACKGROUND AND AIMS: Understanding the amounts of intensity-specific movement needed to attenuate the association between sedentary time and mortality may help to inform personalized prescription and behavioral counselling. Herein, we examined the joint associations of sedentary time and intensity-specific physical activity with all-cause and cardiovascular disease (CVD) mortality. METHODS: Prospective cohort study including 73,729 adults from the UK Biobank who wore an Axivity AX3 accelerometer on their dominant wrist for at least 3 days, being one a weekend day, between June 2013 and December 2015. We considered the median tertile values of sedentary time and physical activity in each intensity band to determine the amount of physical activity needed to attenuate the association between sedentary time and mortality. RESULTS: During a median of 6.9 years of follow-up (628,807 person-years), we documented 1521 deaths, including 388 from CVD. Physical activity of any intensity attenuated the detrimental association of sedentary time with mortality. Overall, at least a median of 6 min/day of vigorous physical activity, 30 min/day of MVPA, 64 min/day of moderate physical activity, or 163 min/day of light physical activity (mutually-adjusted for other intensities) attenuated the association between sedentary time and mortality. High sedentary time was associated with higher risk of CVD mortality only among participants with low MVPA (HR 1.96; 95% CI 1.23 to 3.14). CONCLUSIONS: Different amounts of each physical activity intensity may attenuate the association between high sedentary time and mortality.

Impact of obesity and roux-en-Y gastric bypass on the pharmacokinetics of (R)- and (S)-omeprazole and intragastric pH.

This study employed physiologically-based pharmacokinetic-pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on the pharmacokinetics and intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched the observed data from non-obese, morbidly obese, and post-gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]/[omeprazole] and [5-hydroxy-omeprazole]/[omeprazole]. The morbidly obese model accounted for the down-regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (S)-omeprazole, while hepatic CYP2C19 affected both (R)- and (S)-omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism-based PD model to assess the effect of omeprazole on intragastric pH. Following 40 mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non-obese, obese, and post-gastric bypass populations, and the daily time with pH >4 was 14.7, 16.4, and 24 h. Our PBPK/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post-RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population.

The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats.

RATIONALE: Cocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders. OBJECTIVE: In the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history. METHODS: We used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion [0.1 ml]) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle. RESULTS: Both intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions. CONCLUSIONS: These findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.

Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet.

The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.

Nutritional and productive performance of purebred Nellore heifers and crossed with Brangus and Braford finished in a feedlot system.

This study evaluated the nutritional and productive performance of Nellore purebred heifers and crossbred Brangus x Nellore (BGNE) and Braford x Nellore (BFNE) in a feedlot system. Thirty heifers (10 of each genetic group) with an average age of 18 months and an initial body weight of 261 kg were used. The experiment was structured and conducted according to a completely randomized design, with three treatments. Heifers received two diets (60 days each) during the experimental period. The experiment lasted 120 days with four experimental periods. Nellore heifers had a lower intake than crossbred heifers (P <0.05). There were no differences between BGNE and BFNE heifers, which had higher final body weight, average daily gain, feed efficiency, hot carcass weight and carcass length than NE heifers. Crossed heifers presented better fat cover than NE heifers. However, NE heifers had higher carcass dressing Despite presenting lower carcass yields than Nellore heifers, crossed heifers are more efficient and have higher performance and better fat cover on the carcass than purebred Nellore heifers. Crossbreeding synthetic breeds, such as Brangus and Braford breeds, with the Nellore breed is an effective way to increase the productivity and efficiency of feedlot heifers in tropical regions.

Indulging Curiosity: Preliminary Evidence of an Anxiolytic-like Effect of Castor Oil and Ricinoleic Acid.

In the process of validating the elevated zero maze, a common test of anxiety-like behavior, in our laboratory, we demonstrated an anxiolytic-like effect of castor oil and its primary component, ricinoleic acid. We tested the effects of vehicle and chlordiazepoxide in male mice in the elevated zero maze following a 30-min pretreatment time. Chlordiazepoxide is a United States Food and Drug Administration-approved drug that was previously shown to exert anxiolytic-like effects in both the elevated zero maze and elevated plus maze. Chlordiazepoxide was administered at doses of 5 or 10 mg/kg. We used 5% polyoxyl 35 castor oil (Kolliphor® EL) and saline as treatment vehicles and found that the effect of chlordiazepoxide on open zone occupancy and open zone entries was blunted when 5% Kolliphor was used as the vehicle. These tests demonstrated that chlordiazepoxide increased open zone occupancy and entries in the elevated zero maze more effectively when saline was used as the treatment vehicle and that Kolliphor dampened the anxiolytic-like effect of chlordiazepoxide when it was used as the treatment vehicle. Notably, 5% Kolliphor alone slightly increased baseline open zone occupancy and entries. Given that Kolliphor is a derivative of castor oil, we next tested the effect of 5% castor oil and 5% ricinoleic acid, which is a major component of castor oil. We found that both castor oil and ricinoleic acid increased open zone occupancy but not entries compared with saline. Altogether, our findings demonstrate that Kolliphor, castor oil, and ricinoleic acid may exert anxiolytic-like effects in male mice in the elevated zero maze. This potential anxiolytic-like effect of castor oil is consistent with its well-established beneficial effects, including anti-inflammatory, antioxidant, antifungal, and pain-relieving properties.

Even worse for Black girls: the longitudinal association of racial bullying with the initiation of alcohol and tobacco use.

We used Poisson's linear regression to examine the association between racial bullying (RB) and the initiation of alcohol and tobacco uses after 9 months. Two cluster-randomized controlled trials were conducted in 2019 with children in grades five (girls: 50.0%; 10 years old: 82.0%; White: 36.8%; Black: 58.7%; others: 4.5%) and seven (girls: 49.5%; 12 years old: 78.1%; White: 33.2%; Black: 60.4%; others: 6.4%) from 30 public schools in the municipality of São Paulo, Brazil. We restricted our analyses to 2 subsets of students in each grade: those who reported no lifetime alcohol use at baseline and those who reported no lifetime baseline tobacco use. At baseline, 16.2% of fifth and 10.7% of seventh graders reported suffering from RB in the 30 days before data collection. After 9 months, 14.9% of fifth graders started using alcohol and 2.5%, tobacco. Among seventh graders, the figures were 31.2% and 7.7%, respectively. RB predicted the initiation of use of alcohol (risk ratio [RR] = 1.36; 95% CI, 1.07-1.70) and tobacco (RR = 1.81; 95% CI, 1.14-2.76) among seventh graders, with race-gender differences, particularly in Black girls (alcohol: RR = 1.45; 95% CI, 1.07-1.93; tobacco: RR = 2.34; 95% CI, 1.31-3.99). School-based programs and policies must explicitly address issues related to racism and gender in alcohol and tobacco prevention strategies.

PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury.

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure.

Social support and suicidality during the COVID-19 pandemic among Brazilian healthcare workers: a longitudinal assessment of an online repeated cross-sectional survey.

INTRODUCTION: Healthcare workers (HCWs) are at an increased risk of suicide compared to non-healthcare workers. This study aims to investigate the association between social support and suicidal ideation and behavior (SIB) during the COVID-19 pandemic among Brazilian HCWs. METHODS: This study utilizes data from 10,885 participants who answered the first (time point 1 - between May and June of 2020) and second (time point 2 - between December 2020 and February 2021) assessments of an online repeated cross-sectional survey for evaluating mental health and quality of life of HCWs during the COVID-19 pandemic in Brazil. Logistic regression analysis was conducted to investigate the relationship between social support as the independent variable (time point 1) and SIB as the outcomes (time point 2). RESULTS: Higher social support was associated with a significantly lower chance of reporting SIB in the month prior to follow-up assessment (adjusted odds ratio [AOR]: 0.71, CI 95% 0.66 - 0.76 and AOR 0.61, CI 95% 0.54 - 0.68, respectively). These associations were independent of sex, age, feelings of loneliness, and self-reported psychiatric disorders. CONCLUSION: Social support is associated with a lower chance of suicidality among HCWs, a protective role that is probably more evident for suicidal behavior.

Joint Associations of Diet and Device-Measured Physical Activity with Mortality and Incident CVD and Cancer: A Prospective Analysis of the UK Biobank Study.

BACKGROUND: We examined the joint associations of diet and device-measured intensity-specific physical activity (PA) with all-cause mortality (ACM), cardiovascular disease (CVD), and cancer incidence. METHODS: We used data from 79,988 participants from the UK Biobank, a population-based prospective cohort study. Light PA (LPA), moderate-to-vigorous PA (MVPA), vigorous PA (VPA), and total PA (TPA) were measured using a wrist-worn accelerometer. Diet quality score (DQS) was based on 10 foods and ranged from 0 (unhealthiest) to 100 (healthiest) points. We derived joint PA and diet variables. Outcomes were ACM, CVD, and cancer incidence including PA, diet and adiposity-related (PDAR) cancer. RESULTS: During a median follow-up of 8 years, 2,863 deaths occurred, 11,053 participants developed CVD, 7,005 developed cancer, and 3,400 developed PDAR cancer. Compared with the least favorable referent group (bottom PA tertile/low DQS), participants with middle and high (total and intensity specific) PA, except for LPA, had lower ACM risk and incident CVD risk, regardless of DQS. For example, among middle and high VPA and high DQS groups, CVD HR were 0.79 (95% CI, 0.74-0.86) and 0.75 (95% CI, 0.69-0.82), respectively. The pattern of cancer results was less pronounced but in agreement with the ACM and CVD incidence findings (e.g., HR, 0.90, 95% CI, 0.81-0.99; 0.88, 0.79-0.98; and 0.82, 0.74-0.92 among high VPA for low, moderate, and high DQS groups, respectively). CONCLUSIONS: Device-measured PA reveals novel joint associations with diet on health outcomes. IMPACT: Our results emphasize the crucial role of PA in addition to a healthy diet for reducing chronic diseases and mortality risk.

Do the associations of daily steps with mortality and incident cardiovascular disease differ by sedentary time levels? A device-based cohort study.

OBJECTIVES: This study aims to examine the associations of daily step count with all-cause mortality and incident cardiovascular disease (CVD) by sedentary time levels and to determine if the minimal and optimal number of daily steps is modified by high sedentary time. METHODS: Using data from the UK Biobank, this was a prospective dose-response analysis of total daily steps across low (<10.5 hours/day) and high (≥10.5 hours/day) sedentary time (as defined by the inflection point of the adjusted absolute risk of sedentary time with the two outcomes). Mortality and incident CVD was ascertained through 31 October 2021. RESULTS: Among 72 174 participants (age=61.1±7.8 years), 1633 deaths and 6190 CVD events occurred over 6.9 (±0.8) years of follow-up. Compared with the referent 2200 steps/day (5th percentile), the optimal dose (nadir of the curve) for all-cause mortality ranged between 9000 and 10 500 steps/day for high (HR (95% CI)=0.61 (0.51 to 0.73)) and low (0.69 (0.52 to 0.92)) sedentary time. For incident CVD, there was a subtle gradient of association by sedentary time level with the lowest risk observed at approximately 9700 steps/day for high (0.79 (0.72 to 0.86)) and low (0.71 (0.61 to 0.83)) sedentary time. The minimal dose (steps/day associated with 50% of the optimal dose) of daily steps was between 4000 and 4500 steps/day across sedentary time groups for all-cause mortality and incident CVD. CONCLUSIONS: Any amount of daily steps above the referent 2200 steps/day was associated with lower mortality and incident CVD risk, for low and high sedentary time. Accruing 9000-10 500 steps/day was associated with the lowest mortality risk independent of sedentary time. For a roughly equivalent number of steps/day, the risk of incident CVD was lower for low sedentary time compared with high sedentary time.

Lifestyle risk factors and all-cause and cause-specific mortality in the Mexico City prospective study: Assessing the influence of reverse causation.

BACKGROUND: We examined the association between individual lifestyle risk factors with all-cause and cause-specific mortality. METHODS: Prospective cohort study including 155,002 participants from the Mexico City Prospective Study. Cox regression models were used to estimate the association between individual lifestyle risk factors and all-cause and cause-specific mortality. Participants with prevalent diseases at baseline and participants who died during the first 2, 5, 10, and 15 years of follow-up were excluded to account for reverse causation. RESULTS: 27,469 people died during 18.3 years of follow-up years. Overweight and moderate alcohol consumption were inversely associated with all-cause mortality, while low physical activity and smoking were positively associated when all participants were included, regardless of prevalent disease or duration of follow-up. The direction of the association of overweight with all-cause mortality changed from inverse to positive after excluding the first 10 years of follow-up. Compared with normal weight, the hazard ratio (95 % confidence interval) was 1.17 (1.13,1.22) for obesity after excluding those who died in the first 5 years of follow-up and 1.71 (1.59,1.84) after excluding the first 15 years of follow-up. The magnitude of the association of alcohol intake, low physical activity, and smoking with mortality attenuated, whereas for fruits and vegetables increased, after excluding longer periods of follow-up. LIMITATIONS: The data were collected exclusively in Mexico City; lifestyle risk factors were self-reported and thus prone to misclassification bias. CONCLUSIONS: Reverse causation may influence both the magnitude and the direction of the associations between lifestyle risk factors and mortality.