A fragment based competitive 19F LB-NMR platform for hotspot directed ligand profiling.

Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting interactions with these hotspots maximises the efficiency of ligand binding. Existing methods are capable of identifying hotspots but often lack assays to quantify ligand binding and direct elaboration at these sites. Herein, we describe a fragment-based competitive 19F Ligand Based-NMR (LB-NMR) screening platform that enables routine, quantitative ligand profiling focused at ligand-binding hotspots. As a proof of concept, the method was applied to 4'-phosphopantetheine adenylyltransferase (PPAT) from Mycobacterium abscessus (Mabs). X-ray crystallographic characterisation of the hits from a 960-member fragment screen identified three ligand-binding hotspots across the PPAT active site. From the fragment hits a collection of 19F reporter candidates were designed and synthesised. By rigorous prioritisation and use of optimisation workflows, a single 19F reporter molecule was generated for each hotspot. Profiling the binding of a set of structurally characterised ligands by competitive 19F LB-NMR with this suite of 19F reporters recapitulated the binding affinity and site ID assignments made by ITC and X-ray crystallography. This quantitative mapping of ligand binding events at hotspot level resolution establishes the utility of the fragment-based competitive 19F LB-NMR screening platform for hotspot-directed ligand profiling.

Covalent fragment-based drug discovery for target tractability.

An important consideration in drug discovery is the prioritization of tractable protein targets that are not only amenable to binding small molecules, but also alter disease biology in response to small molecule binding. Covalent fragment-based drug discovery has emerged as a powerful approach to aid in the identification of such protein targets. The application of irreversible binding mechanisms enables the identification of fragment hits for challenging-to-target proteins, allows proteome-wide screening in a cellular context, and makes it possible to determine functional effects with modestly potent ligands without the requirement for extensive compound optimization. Here, we provide an overview of recent approaches to covalent fragment-based screening and discuss how these have been applied to establish the tractability of unexplored binding sites on protein targets.

EEG microstate quantifiers and state space descriptors during anaesthesia in patients with postoperative delirium: a descriptive analysis.

Postoperative delirium is a serious sequela of surgery and surgery-related anaesthesia. One recommended method to prevent postoperative delirium is using bi-frontal EEG recording. The single, processed index of depth of anaesthesia allows the anaesthetist to avoid episodes of suppression EEG and excessively deep anaesthesia. The study data presented here were based on multichannel (19 channels) EEG recordings during anaesthesia. This enabled the analysis of various parameters of global electrical brain activity. These parameters were used to compare microstate topographies under anaesthesia with those in healthy volunteers and to analyse changes in microstate quantifiers and EEG global state space descriptors with increasing exposure to anaesthesia. Seventy-three patients from the Surgery Depth of Anaesthesia and Cognitive Outcome study (SRCTN 36437985) received intraoperative multichannel EEG recordings. Altogether, 720 min of artefact-free EEG data, including 210 min (29.2%) of suppression EEG, were analysed. EEG microstate topographies, microstate quantifiers (duration, frequency of occurrence and global field power) and the state space descriptors sigma (overall EEG power), phi (generalized frequency) and omega (number of uncorrelated brain processes) were evaluated as a function of duration of exposure to anaesthesia, suppression EEG and subsequent development of postoperative delirium. The major analyses involved covariate-adjusted linear mixed-effects models. The older (71 ± 7 years), predominantly male (60%) patients received a median exposure of 210 (range: 75-675) min of anaesthesia. During seven postoperative days, 21 patients (29%) developed postoperative delirium. Microstate topographies under anaesthesia resembled topographies from healthy and much younger awake persons. With increasing duration of exposure to anaesthesia, single microstate quantifiers progressed differently in suppression or non-suppression EEG and in patients with or without subsequent postoperative delirium. The most pronounced changes occurred during enduring suppression EEG in patients with subsequent postoperative delirium: duration and frequency of occurrence of microstates C and D progressed in opposite directions, and the state space descriptors showed a pattern of declining uncorrelated brain processes (omega) combined with increasing EEG variance (sigma). With increasing exposure to general anaesthesia, multiple changes in the dynamics of microstates and global EEG parameters occurred. These changes varied partly between suppression and non-suppression EEG and between patients with or without subsequent postoperative delirium. Ongoing suppression EEG in patients with subsequent postoperative delirium was associated with reduced network complexity in combination with increased overall EEG power. Additionally, marked changes in quantifiers in microstate C and in microstate D occurred. These putatively adverse intraoperative trajectories in global electrical brain activity may be seen as preceding and ultimately predicting postoperative delirium.

A statewide study of disparities in local policies and tobacco, vape, and cannabis retail environments.

The current study: (1) assesses sociodemographic disparities in local policies related to tobacco and cannabis retail, and (2) examines the cross-sectional association between policy strength and retailer densities of tobacco, e-cigarette (vape), and cannabis retailers within California cities and county unincorporated areas (N = 539). We combined (a) American Community Survey data (2019 5-year estimates), (b) 2018 tobacco, vape, and cannabis retailer locations from a commercial data provider, (c) 2017 tobacco and vape retail environment policy data from American Lung Association, and (d) 2018 cannabis policy data from California Cannabis Local Laws Database. Conditional autoregressive models examined policy strength associations with sociodemographic composition and retailer density in California jurisdictions. Jurisdictions with larger percentages of Black and foreign-born residents had stronger tobacco and vape policies. For cannabis policy, only income had a small, significant positive association with policy strength. Contrary to hypothesis, tobacco/vape policies were not significantly associated with retailer density, but cannabis policy strength was associated with lower cannabis retailer density (relative rate = 0.58, 95% Uncertainty Interval 0.47-0.70)-this effect was completely driven by storefront bans. Thus, storefront cannabis bans were the only policy studied that was associated with lower cannabis retailer density. Further research is needed to understand policies and disparities in retail environments for tobacco, vape, and cannabis, including data on the prospective association between policy implementation and subsequent retailer density, and the role of enforcement.

Randomized Comparative Effectiveness Trial of 2 Federally Recommended Strategies to Reduce Excess Body Fat in Overweight, Low-Income Patients: MyPlate.gov vs Calorie Counting.

PURPOSE: Since 2011, US authorities have supported the following 2 approaches to healthier body fat composition: the Centers for Disease Control and Prevention National Diabetes Prevention Program's calorie counting (CC) approach and the US Department of Agriculture's MyPlate (adherence to federal nutrition guidelines). The purpose of this study was to compare the effect of CC vs MyPlate approaches on satiety/satiation and on achieving healthier body fat composition among primary care patients. METHODS: We conducted a randomized controlled trial comparing the CC and MyPlate approaches from 2015 to 2017. The adult participants were overweight, of low income, and were mostly Latine (n = 261). For both approaches, community health workers conducted 2 home education visits, 2 group education sessions, and 7 telephone coaching calls over a period of 6 months. Satiation and satiety were the primary patient-centered outcome measures. Waist circumference and body weight were the primary anthropometric measures. Measures were assessed at baseline, 6 months, and 12 months. RESULTS: Satiation and satiety scores increased for both groups. Waist circumference was significantly decreased in both groups. MyPlate, but not CC, resulted in lower systolic blood pressure at 6 months but not at 12 months. Participants for both MyPlate and CC reported greater quality of life and emotional well-being and high satisfaction with their assigned weight-loss program. The most acculturated participants showed the greatest decreases in waist circumference. CONCLUSIONS: A MyPlate-based intervention might be a practical alternative to the more traditional CC approach to promoting satiety and facilitating decreases in central adiposity among low-income, mostly Latine primary care patients.

Chemical Validation of Mycobacterium tuberculosis Phosphopantetheine Adenylyltransferase Using Fragment Linking and CRISPR Interference.

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a KD <20 µM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.

"Ancestral recipes": a mixed-methods analysis of MyPlate-based recipe dissemination for Latinos in rural communities.

BACKGROUND: The Latinx population experiences some of the highest rates of chronic disease, including obesity and type II diabetes. Such conditions may be especially burdensome in rural Latinx communities that often face barriers to accessing disease prevention resources and public health programs. METHODS: Diverse stakeholders (i.e., patients, community members, system of healthcare clinics, community food bank) tailored an existing cookbook, based on the U.S. Department of Agriculture MyPlate healthy eating and dietary guidelines, for local ingredients, health literacy, and language for rural Latinx and Indigenous Latin Americans. The cookbook recipes were disseminated widely via virtual cooking demonstrations, food distribution events, and social media. Pre- and posttest surveys were used to assess changes in diabetes knowledge measured by the 24-item American Diabetes Association Diabetic Knowledge Questionnaire and confidence in dietary behavior change over time measured by 4 questions of the 17-item Mediterranean Diet Index. A mixed effects, repeated measures analysis was conducted with gender ID, age range and educational attainment included as covariates and assessment interval as the predictor (pretest vs posttest) and change in confidence about adhering to four specific components of the Mediterranean diet. Focus groups elicited information on participants' motivation and ability to use the recipes and eat healthy foods following the virtual cooking demonstration participation. RESULTS: A total of 20 virtual cooking demonstrations were conducted and 60 participants completed a pretest survey and 54 a posttest survey, a subsample (n = 19) participated in one of three focus groups. Most participants were female, identified as Latinx/Hispanic, were between the ages of 40-49, and spoke Spanish. 17% identified as Indigenous Latin American specifically as Purépecha, an indigenous group from Michoacán, Mexico. Survey and focus group findings indicated at posttest an increase in diabetes knowledge among participants with no prior diagnosis of chronic health conditions and more confidence in limiting sugary beverages and refined wheat pasta/white rice among indigenous participants. Focus group discussions explicated the quantitative findings. CONCLUSION: This study brought together patients and key stakeholders committed to addressing the social determinants of health and it mobilized the community to develop culturally vetted health education materials. The findings indicate the need for increased access to evidence-based nutrition education and to culturally appropriate food products that can be easily incorporated into daily food preparation.

Chemical Validation of Mycobacterium tuberculosis Phosphopantetheine Adenylyltransferase Using Fragment Linking and CRISPR Interference.

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a K D <20 µM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.

Development of potent inhibitors by fragment-linking strategies.

Fragment-based drug discovery (FBDD) is a method of identifying small molecule hits that can be elaborated rationally through fragment growing, merging and linking, to afford high-affinity ligands for biological targets. Despite the promised theoretical potential of fragment linking, examples are still surprisingly sparse and remain overshadowed by the successes of fragment growing. The aim of this review was to outline a number of key examples of fragment-linking strategies and discuss their strengths and limitations. Structure-based approaches including X-ray crystallography and in silico methods of fragment optimization are discussed, as well as fragment linking guided by NMR experiments. Target-guided approaches, exploiting the biological target to assemble its own inhibitors through dynamic combinatorial chemistry (DCC) and kinetic target-guided synthesis (KTGS), are identified as alternative efficient methods for fragment linking.

Structural Characterization of Mycobacterium abscessus Phosphopantetheine Adenylyl Transferase Ligand Interactions: Implications for Fragment-Based Drug Design.

Anti-microbial resistance is a rising global healthcare concern that needs urgent attention as growing number of infections become difficult to treat with the currently available antibiotics. This is particularly true for mycobacterial infections like tuberculosis and leprosy and those with emerging opportunistic pathogens such as Mycobacterium abscessus, where multi-drug resistance leads to increased healthcare cost and mortality. M. abscessus is a highly drug-resistant non-tuberculous mycobacterium which causes life-threatening infections in people with chronic lung conditions such as cystic fibrosis. In this study, we explore M. abscessus phosphopantetheine adenylyl transferase (PPAT), an enzyme involved in the biosynthesis of Coenzyme A, as a target for the development of new antibiotics. We provide structural insights into substrate and feedback inhibitor binding modes of M. abscessus PPAT, thereby setting the basis for further chemical exploration of the enzyme. We then utilize a multi-dimensional fragment screening approach involving biophysical and structural analysis, followed by evaluation of compounds from a previous fragment-based drug discovery campaign against M. tuberculosis PPAT ortholog. This allowed the identification of an early-stage lead molecule exhibiting low micro molar affinity against M. abscessus PPAT (Kd 3.2 ± 0.8 µM) and potential new ways to design inhibitors against this enzyme. The resulting crystal structures reveal striking conformational changes and closure of solvent channel of M. abscessus PPAT hexamer providing novel strategies of inhibition. The study thus validates the ligandability of M. abscessus PPAT as an antibiotic target and identifies crucial starting points for structure-guided drug discovery against this bacterium.

Undergraduate support for university smoke-free and vape-free campus policies and student engagement: a quasi-experimental intervention.

BackgroundCollege campuses have policies restricting smoking/vaping on campus. Previous studies involving mostly European-American students showed smoking prevalence declines following implementation of such policies.ObjectiveTo evaluate a social media campaign promotive of stronger campus support for an existing campus no-smoking/no-vaping policy where most (∼75%) of the undergraduates were non-European-American. A demographically comparable university served as a no-intervention control.ParticipantsTarget was 200 random intercept surveys at each university during fall 2016, spring 2017. Of 800 respondents, 681 were undergraduates.MethodsBaseline and post-intervention surveys assessed awareness of and support for campus-wide smoke-free/vape-free policies. Staged smoke-free/vape-free policy violations assessed students' propensity to intervene in support of the policy.ResultsRespondent support for the no-smoking/no-vaping policy did not change.ConclusionsThe social media campaign and Policy Ambassadors program did not increase support for the campus no-smoking/no-vaping policy. Most (∼90%) respondents agreed that the campus no-smoking/no-vaping policy was important for public health.

Neighbourhood tobacco retail access and tobacco use susceptibility in young adolescents in urban India.

BACKGROUND: Neighbourhood tobacco retail access may influence adolescent tobacco use. In India, we examined the association between neighbourhood tobacco retail access and cognitive risks for tobacco use during early adolescence. METHODS: In 2019-2020, a population-based sample (n=1759) of adolescents aged 13-15 years was surveyed from 52 neighbourhoods in Mumbai and Kolkata. Neighbourhood tobacco retail access was measured as the frequency of visits to tobacco retailers, mapped tobacco retailer density and perceived tobacco retailer density. We estimated associations between neighbourhood tobacco retail access and cognitive risks for tobacco use (perceived ease of access to tobacco, perceived peer tobacco use and intention to use tobacco). RESULTS: There was high neighbourhood tobacco retail access. Tobacco retailer density was higher in lower income neighbourhoods (p<0.001). Adolescent frequency of tobacco retailer visits was positively associated with cognitive tobacco use risks. Mapped tobacco retailer density was associated with perceived ease of access in Kolkata but not in Mumbai, and it was not associated with perceived peer tobacco use nor intention. Perceived tobacco retailer density was associated with perceived ease of access and perceived peer use, but not with intention. In Kolkata, higher perceived retailer density and frequency of tobacco retailer visits were negatively associated with perceived ease of access. CONCLUSIONS: Efforts to reduce neighbourhood tobacco retail access in India may reduce cognitive tobacco use risk factors in young adolescents. The frequency of tobacco retailer visits and perceived tobacco retailer density increased cognitive risks, though there were some exceptions in Kolkata that further research may explain.

Using a multilevel implementation strategy to facilitate the screening and treatment of tobacco use in the outpatient urology clinic: A prospective hybrid type I study.

BACKGROUND: Urologists frequently treat patients for tobacco-related conditions but infrequently engage in evidence-based practices (EBPs) that screen for and treat tobacco use. Improving the use of EBPs will help to identify smokers, promote cessation, and improve patients' health outcomes. METHODS: A prospective type I hybrid effectiveness-implementation study was performed to test the feasibility and effectiveness of using a multilevel implementation strategy to improve the use of tobacco EBPs. All urology providers at outpatient urology clinics within the Veterans Health Administration Greater Los Angeles and all patients presenting for a new urology consultation were included. The primary outcome was whether a patient was screened for tobacco use at the time of consultation. Secondary outcomes included a patient's willingness to quit, chosen quit strategy, and subsequent engagement in quit attempts. RESULTS: In total, 5706 consecutive veterans were seen for a new consultation during the 30-month study period. Thirty-six percent of all visits were for a tobacco-related urologic diagnosis. The percentage of visits that included tobacco use screening increased from 18% (before implementation) to 57% in the implementation phase and to 60% during the maintenance phase. There was significant provider-level variation in adherence to screening. Of all screened patients, 38% were willing to quit, and most patients chose a "cold turkey" method; 22% of the patients elected referral to a formal smoking cessation clinic, and 24% chose telephone counseling. Among those willing to quit, 39% and 49% made a formal quit attempt by 3 and 6 months, respectively. CONCLUSIONS: A strategy that includes provider education and a customized clinical decision support tool can facilitate provider use of tobacco EBPs in a surgery subspecialty clinic.

Macrocyclic vs. [2]catenane btp structures: influence of (aryl) substitution on the self templation of btp ligands in macrocyclic synthesis.

The synthesis of four 2,6-bis(1,2,3-triazol-4-yl)pyridine (btp) olefin based ligands 3, 4, 11 and 12 is described and their attempted use to form mechanically interlocked molecules using ring closing metatheses (RCM) reactions. The btp ligands were modified in two ways, in 3 and 4 the aryl substitution pattern was changed from 4th position to 3rd position and in the case of 11 and 12, the arms were replaced with aliphatic chains. Our study demonstrates that for all four ligands, the RCM reactions only result in the formation of macrocyclic structures, which in three of the cases, were structurally characterised in both solution (using NMR and HRMS) and in the solid-state using X-ray crystallography. NMR studies were also carried out to investigate if these ligands could preorganise in solution via hydrogen bonding interactions. This study provides a handle of how such precursor substitution can be used to direct the formation of macrocycles or mechanically interlocked structures.

Prevalence and Correlates of Successful Smoking Cessation in Bladder Cancer Survivors.

OBJECTIVE: To assess the prevalence and correlates of successful smoking cessation in bladder cancer survivors. MATERIALS AND METHODS: A population-based sample of bladder cancer survivors diagnosed over a 3 year period was obtained from the California Cancer Registry. Respondents completed a survey about their tobacco use and attempts at smoking cessation. Contingency tables and logistic regression analyses were used to evaluate for correlates of successful smoking cessation. RESULTS: Of total survey respondents, 19% (151 of 790) were active smokers at bladder cancer diagnosis and made up our analytic cohort. The majority of included respondents were male, older than 60, and had smoked for >40 years prior to diagnosis. After diagnosis, 76% (115 of 151) of active smokers made a quit attempt and 56% (65 of 115) were successful. Success with smoking cessation was more frequent among those who attempted to quit around the time of initial bladder cancer diagnosis. The majority (66%) of successful quitters did so "cold turkey" without pharmacotherapy or behavioral therapy. After adjustment for demographic and tobacco-related factors, quit attempts specifically motivated by the bladder cancer diagnosis were highly associated with smoking cessation success (OR 11.6; 95% CI 3.73-35.8). Use of pharmacologic or behavioral therapies in the quit attempt were not significantly associated with successful smoking cessation. CONCLUSION: Our data underscore the importance of motivation, timing, and the role of the urologist in the quit attempts of bladder cancer survivors. Emphasis should be placed on ensuring the newly diagnosed make a timely quit attempt informed by the causal role of smoking in their malignancy.

Cross-Sectional and Longitudinal Construct Validity of the Generic KINDL-A(dult)B(rief) Questionnaire in Adults with Thrombophilia or with Hereditary and Acquired Bleeding Disorders.

BACKGROUND/AIMS: The newly adapted generic KINDL-A(dult)B(rief) questionnaire showed satisfactory cross-sectional psychometric properties in adults with bleeding disorders or thrombophilia. This investigation aimed to evaluate its cross-sectional and longitudinal construct validity. METHODS: After ethical committee approval and written informed consent, 335 patients (mean age 51.8 ± 16.6 years, 60% women) with either predominant thrombophilia (n = 260) or predominant bleeding disorders (n = 75) participated. At baseline, patients answered the KINDL-AB, the MOS 36-item Short-Form Health Survey (SF-36), and the EQ-5D-3L. A subgroup of 117 patients repeated the questionnaire after a median follow-up of 2.6 years (range: 0.4-3.5). A priori hypotheses were evaluated regarding convergent correlations between KINDL-AB overall well-being and specific subscales, EQ-5D-3L index values (EQ-IV), EQ-5D visual analog scale (EQ-VAS), and SF-36 subscales. RESULTS: Contrary to hypothesis, baseline correlations between the KINDL-AB and EQ-IV/EQ-VAS were all moderate while, as hypothesized, several KINDL-AB subscales and SF-36 subscales correlated strongly. At follow-up, no significant changes in all three instruments occurred. Correlations between instruments over the follow-up were mostly moderate and partially strong. Contrary to hypothesis but consistent with no significant changes in health-related quality of life, convergent correlations between changes in KINDL-AB overall well-being, physical and psychological well-being, and EQ-IV/EQ-VAS were all weak. CONCLUSIONS: While repeated measures of KINDL-AB showed moderate to strong correlations, changes in KINDL-AB overall well-being and subscales correlated more weakly than expected with changes involving two established instruments of generic health status.

Incorporating an Increase in Plant-Based Food Choices into a Model of Culturally Responsive Care for Hispanic/Latino Children and Adults Who Are Overweight/Obese.

Introduction: The national rate of obesity in US Hispanic/Latinos exceeds all other major ethnic subgroups and represents an important health disparity. Plant-based diet interventions that emphasize whole plant foods with minimal processing and less refined grains and sugar have shown great promise in control of obesity, but there is a paucity of data translating this treatment effect to disparate populations. The objective of our study was to evaluate the efficacy of the Healthy Eating Lifestyle Program (HELP) for accomplishing weight management in a hospital-based, family centered, culturally tailored, plant-based diet intervention for Hispanic/Latino children who were overweight or obese. Methods: Our mixed methods evaluation included: (1) A one arm study to measure changes in body mass index (BMI) from pre- to post-intervention, and (2) A stakeholder analysis of the program staff. Results: For children ages 5-12 years who were overweight/obese, we found no evidence of excess weight gain evidenced by BMI Z scores (Zpost-pre = -0.02, p = 0.11). Among the parent/guardians who were overweight or obese, we found a decrease in BMI that was stronger in men (BMI post-pre = -0.75 kg/m2, p = 0.01) than in women (BMI post-pre = -0.12 kg/m2, p = 0.30). A program strength was the cultural tailoring of the plant-based diet choices. Conclusions: The evaluation raises the possibility that incorporating intervention components of HELP (plant-based food choices, family-based, cultural tailoring) into pediatric weight management can improve the standard of care.

Risk of developing pre-diabetes or diabetes over time in a cohort of Mexican health workers.

AIM: To determine the association between known risk factors (e.g., obesity, metabolic syndrome and its components) and the development of pre-diabetes or diabetes over time in a cohort of Mexican health workers. METHODS: Participants in the Mexican Health Worker Cohort Study with complete information at two waves of data collection, 2004-2006 (W1) and 2011-2013 (W2), were included in the analysis (n = 1,174). Multivariable binary and multinomial logistic regression were used to examine the cross-sectional associations between specific risk factors and diabetes status (diabetes, pre-diabetes, or neither) at W1 and the longitudinal associations between changes in risk factors and progression of diabetes status from W1 to W2, respectively. RESULTS: Mean time between waves was 7.0 years (SD 1.1). Prevalence of pre-diabetes and diabetes was 16% and 10% at W1 and increased to 30% and 16% at W2, respectively. The cross-sectional prevalence of pre-diabetes and diabetes was significantly higher among men, participants over the age of 45 years, and individuals who were overweight or obese or had metabolic syndrome (MS), three or more components of the MS, elevated alanine aminotransferase (ALT) levels, or elevated uric acid. In longitudinal analyses, remaining obese or gaining weight between waves was associated with an increased risk of developing pre-diabetes. A greater risk of developing pre-diabetes or diabetes was also observed among individuals who either maintained or acquired MS, elevated ALT, or elevated uric acid (only for diabetes) from W1 to W2. CONCLUSIONS: Weight gain and acquiring or maintaining MS, elevated ALT levels, or elevated uric acid were associated with a significant risk of developing pre-diabetes or diabetes. Our findings, especially in the context of the obesity epidemic in Mexico, point towards an urgent need for initiatives to help reduce excess weight in order to avert future cases of pre-diabetes and diabetes.

Secondary analysis of an RCT on Emergency Department-Initiated Tobacco Control: Repeatedly assessed point-prevalence abstinence up to 12 months and extension of results through a 10-year follow-up.

INTRODUCTION: Emergency departments (EDs) are opportune places for tobacco control interventions. The 'Tobacco Control in an Urban Emergency Department' (TED) study, ISRCTN41527831, originally evaluated the effect of motivational interviewing on-site plus up to four booster telephone calls on 12-month abstinence. This study's aim was to evaluate the effect of the intervention on 7-day point-prevalence abstinence at 10 years follow-up (primary outcome) as well as on repeated point-prevalence abstinence at 1, 3, 6, 12 months and at 10 years (continual smoking abstinence, secondary outcome). METHODS: At the 10 years follow-up and after informed consent, study participants responded to a mailed questionnaire. The primary outcome was analyzed in observed-only and in all-cases analyses. The secondary outcomes were analyzed using a multiple adjusted GLMM for binary outcomes. RESULTS: Out of 1012 TED-study participants, 986 (97.4%) were alive and 231 (23.4% of 986) responded to the follow-up at 10 years. For observed-only and all-cases analyses, the effect of the baseline intervention on 7-day point-prevalence abstinence at the 10 years follow-up was statistically non-significant. However, when taking into account all repeated measures, the intervention significantly influenced continual abstinence with odds ratio 1.32 (95% CI: 1.01-1.73; p=0.042). Baseline motivation, perceived self-efficacy to stop smoking, and nicotine dependency were independently associated with long-term continual smoking abstinence (all p<0.05). CONCLUSIONS: A conventional analysis failed to confirm a significant effect of the ED-initiated tobacco control intervention on the point-prevalence abstinence at 10 years. Results from a more integrative analysis nonetheless indicated an enduring intervention effect on continual abstinence among smokers first encountered in the emergency department setting 10 years earlier.