Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action.

Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading to covalent adducts, there has been success in developing covalent inhibitors, especially within the field of anticancer therapy. Covalent inhibitors can have an advantage over noncovalent inhibitors since the formation of a covalent adduct may serve as an additional mode of selectivity due to the intrinsic reactivity of the target protein that is absent in many other proteins. Unfortunately, many covalent inhibitors form irreversible adducts with off-target proteins, which can lead to considerable side-effects. By designing the inhibitor to form reversible covalent adducts, one can leverage competing on/off kinetics in complex formation by taking advantage of the law of mass action. Although covalent adducts do form with off-target proteins, the reversible nature of inhibition prevents accumulation of the off-target adduct, thus limiting side-effects. In this perspective, we outline important characteristics of reversible covalent inhibitors, including examples and a guide for inhibitor development.

Use of geofencing interventions in population health research: a scoping review.

OBJECTIVES: Technological advancements that use global positioning system (GPS), such as geofencing, provide the opportunity to examine place-based context in population health research. This review aimed to systematically identify, assess and synthesise the existing evidence on geofencing intervention design, acceptability, feasibility and/or impact. DESIGN: Scoping review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidance for reporting. DATA SOURCES: PubMed, CINAHL, EMBASE, Web of Science, Cochrane and PsycINFO for articles in English published up to 31 December 2021. ELIGIBILITY CRITERIA: Articles were included if geofencing was used as a mechanism for intervention delivery. EXCLUSION CRITERIA: (1) a component or combination of GPS, geographical information system or ecological momentary assessment was used without delivery of an intervention; (2) did not include a health or health-related outcome from the geofencing intervention; or (3) was not a peer-reviewed study. DATA EXTRACTION AND SYNTHESIS: Several researchers independently reviewed all abstracts and full-text articles for final inclusion. RESULTS: A total of 2171 articles were found; after exclusions, nine studies were included in the review. The majority were published in 5 years preceding the search (89%). Geofences in most studies (n=5) were fixed and programmed in the mobile application carried by participants without their input. Mechanisms of geofencing interventions were classified as direct or indirect, with five studies (56%) using direct interventions. There were several different health outcomes (from smoking to problematic alcohol use) across the five studies that used a direct geofencing intervention. CONCLUSIONS: This scoping review found geofencing to be an emerging technology that is an acceptable and feasible intervention applied to several different populations and health outcomes. Future studies should specify the rationale for the locations that are geofenced and user input. Moreover, attention to mechanisms of actions will enable scientists to understand not only whether geofencing is an appropriate and effective intervention but why it works to achieve the outcomes observed.

Associations between police harassment and distrust in and reduced access to healthcare among Black sexual minority men: A longitudinal analysis of HPTN 061.

OBJECTIVE: Evaluate associations between racialized and homophobia-based police harassment (RHBPH) and healthcare distrust and utilization among Black Sexual Minority Men (BSMM). METHODS: We utilized data from a longitudinal cohort study from HIV Prevention Trials Network (HPTN) 061 with baseline, six and 12 month follow-up assessments. Using multivariable analysis, we evaluated associations between RHBPH and healthcare distrust and utilization reported at the 6 and 12 month visits. RESULTS: Of 1553 BSMM present at baseline, 1160 were available at six-month follow-up. In multivariable analysis, increasing frequency of RHBPH was associated with increasing levels of distrust in healthcare providers (aOR 1.31, 95% CI: 1.00, 1.74) and missing 50% or more of healthcare visits at six-month follow-up (aOR 1.93, 95% CI: 1.09, 3.43). CONCLUSIONS: Recent experiences of RHBPH are associated with reduced trust in and access to healthcare among BSMM, with more frequent RHBPH associated with greater vulnerability.

Polysubstance use in a community sample of Black cisgender sexual minority men and transgender women in Chicago during initial COVID-19 pandemic peak.

BACKGROUND: In response to COVID-19, the city of Chicago issued stay-at-home orders, which began on March 20, 2020, and restrictions meant to "flatten the curve" remained in effect until June 2, 2020. On June 3, 2020, Chicago entered the reopening phase. This study compares rates of polysubstance use by COVID-19 lockdown phase and across sociodemographic characteristics in a Chicago-based sample of Black cisgender sexual minority men (SMM) and transgender women. METHOD: Data come from the Neighborhood and Networks (N2) cohort, an ongoing study of Black cisgender SMM and transgender women living in Chicago. Participants (N = 226) completed a survey between April 20, 2020, and July 30, 2020, during the initial peak of the COVID-19 pandemic in Chicago. We conducted chi-square tests of independence and modified Poisson regression models with robust error variance and estimated adjusted prevalence ratios. RESULTS: Alcohol and marijuana were the most used substances, with 73.5% reporting at least one drinking day and 71.2% of the sample reporting marijuana use in the past 14 days. Tobacco was used by 41.6% of the sample, and illegal drug use, which does not include marijuana, was reported by 17.7% of the sample. Substance use was consistently associated with the use of other substances. As such, polysubstance use (i.e., using two or more substances) was common in this sample (63.7%). Few sociodemographic differences emerged, and substance use was not associated with lockdown phase. CONCLUSION: Substance use, including polysubstance use, was high in our sample of Black SMM and transgender women during the initial peak of the COVID-19 pandemic. Continued monitoring is needed given the duration of the COVID-19 pandemic and the negative health consequences associated with substance use in this population.

Effect of pH on the antimicrobial activity of the macrophage metabolite itaconate.

The production of itaconate by macrophages was only discovered in 2011. An increasing number of studies have since revealed essential biological functions for this small molecule, ranging from antimicrobial to immunomodulator. The antibacterial role of itaconate has however been questioned because the estimated concentration of itaconate in macrophages (low-millimolar) is lower than the minimum inhibitory concentration (MIC) of itaconate reported for several bacterial strains (low-to-mid-millimolar). We note that some of these investigations have tended to ignore the high acidity of this small diacid (pKas 3.85 and 5.45), thereby potentially biassing activity measurements. We measured the MIC of itaconate in Escherichia coli (not known to metabolize itaconate) and in Salmonella enterica serovar Typhimurium (known to metabolize itaconate) at varying pH values to probe the effect that pH has on itaconate toxicity. Herein, we demonstrate that the antimicrobial effect of itaconate is dependent upon the pH of the media and that itaconate does have antimicrobial activity at biologically relevant pH and concentrations. Under nutrient-poor conditions, the antimicrobial activity of itaconate in both E. coli and S. Typhimurium increased approximately 200-fold when the pH was dropped by one unit, whereas itaconate was not found to be toxic under nutrient rich conditions. Our results also reveal that the activity of itaconate is synergistic with acidity, yet is not a function of increased permeability with protonation. Similar experiments performed with succinate (a pKa-matched diacid) yielded drastically different results, consistent with a target-based mechanism of action for itaconate. Overall, our work shows the importance of controlling the pH when performing experiments with itaconic acid.

Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages.

Following activation, macrophages undergo extensive metabolic rewiring1,2. Production of itaconate through the inducible enzyme IRG1 is a key hallmark of this process3. Itaconate inhibits succinate dehydrogenase4,5, has electrophilic properties6 and is associated with a change in cytokine production4. Here, we compare the metabolic, electrophilic and immunologic profiles of macrophages treated with unmodified itaconate and a panel of commonly used itaconate derivatives to examine its role. Using wild-type and Irg1-/- macrophages, we show that neither dimethyl itaconate, 4-octyl itaconate nor 4-monoethyl itaconate are converted to intracellular itaconate, while exogenous itaconic acid readily enters macrophages. We find that only dimethyl itaconate and 4-octyl itaconate induce a strong electrophilic stress response, in contrast to itaconate and 4-monoethyl itaconate. This correlates with their immunosuppressive phenotype: dimethyl itaconate and 4-octyl itaconate inhibited IκBζ and pro-interleukin (IL)-1ß induction, as well as IL-6, IL-10 and interferon-ß secretion, in an NRF2-independent manner. In contrast, itaconate treatment suppressed IL-1ß secretion but not pro-IL-1ß levels and, surprisingly, strongly enhanced lipopolysaccharide-induced interferon-ß secretion. Consistently, Irg1-/- macrophages produced lower levels of interferon and reduced transcriptional activation of this pathway. Our work establishes itaconate as an immunoregulatory, rather than strictly immunosuppressive, metabolite and highlights the importance of using unmodified itaconate in future studies.

Gender Dysphoria, Mental Health, and Poor Sleep Health Among Transgender and Gender Nonbinary Individuals: A Qualitative Study in New York City.

Background: A vast amount of research has demonstrated the numerous adverse health risks of short sleep duration and poor sleep health among the general population, and increasing studies have been conducted among lesbian, gay, and bisexual individuals. However, although poor sleep health is disproportionately experienced by sexual and gender minority populations, little research has examined sleep quality and associated factors among transgender and gender nonbinary (TGNB) individuals. This study qualitatively explored the relationship that factors such as gender identity, mental health, and substance use have with sleep health among a sample of TGNB individuals in New York City. Methods: Forty in-depth interviews were conducted among an ethnically diverse sample who identified as transgender male, transgender female, and gender nonbinary from July to August 2017. All interviews were transcribed, coded, and thematically analyzed for domains affecting overall sleep, including mental health, gender identity, and various coping mechanisms to improve overall sleep. Results: TGNB interview participants frequently described one or more problems with sleeping. Some (15%) participants suggested that mental health issues caused them to have difficulty falling asleep, but that psychiatric medication was effective in reducing mental health issues and allowing them to sleep. An even larger number (35%) told us that their gender identity negatively impacted their sleep. Specifically, participants described that the presence of breasts, breast binding, stress and anxiety about their identity, and concerns about hormonal therapy and gender-affirming surgery were all reported as contributing to sleep problems. Given these sleep challenges, it is not surprising that most (60%) participants used various strategies to cope with and manage their sleep problems, including prescription and over-the-counter sleep medications (33%) and marijuana (18%). Conclusions: Our findings document that sleep health is frequently an issue for TGNB individuals, and they also offer insight into the various ways that TGNB individuals attempt to cope with these sleep problems. Sleep health promotion interventions should be developed for TGNB people, which would promote positive mental health, reduce the risk of pharmaceutical adverse events, and help alleviate psychosocial stress in this target population.

Neighborhood social environment and disability among Mexican older adults: a cohort-based analysis / O ambiente social da vizinhança e a incapacidade nos idosos mexicanos: uma análise de coorte / Ambiente social del vecindario y discapacidad entre adultos mayores mejicanos: un análisis basado en cohortes

Considering that the world population is rapidly aging and disability is a very frequent event in older adults, there is an increasing interest in studying their determinants, such as the neighborhood characteristics. Thus, this study aimed to explore the association between the social environment of the neighborhood and disability in older adults. A cohort study was assembled using waves 1 and 2 from the Study of Global Ageing and Adults Health (SAGE) in Mexico, which included adults with 55+ years old. Neighborhood characteristics - such as social participation, trust and safety - and individual covariates were measured only in wave 1 (baseline), while disability was measured in both waves to adjust for the score of wave 1. Multilevel negative binomial models with random intercepts at the municipality level were constructed for the disability score in wave 2, using each of the social environment variables as the main exposure and adjusting for the sociodemographic and health-related variables. Finally, interaction terms with sex, age, and socioeconomic quintiles were tested. Results showed that neighborhoods with a medium (IRR: 0.68; 95%CI: 0.53-0.87) or high (IRR: 0.67; 95%CI: 0.52-0.86) safety level were associated with a significant reduction in the disability score of adults older than 75 years, although there was no association between other characteristics of the social environment and disability in the general sample. Consequently, actions to improve safety in the neighborhoods should be carried out to help reduce the disability score in vulnerable older adults, especially in a context where safety is a critical issue, as in Mexico.

Considerando que la población mundial está envejeciendo rápidamente y la discapacidad es un hecho muy frecuente entre la tercera edad, existe un creciente interés por estudiar los determinantes de esta última, así como las características del vecindario. Por lo tanto, el objetivo de este estudio fue investigar la asociación entre el ambiente social del vecindario y la discapacidad en adultos mayores. La cohorte de estudio se formó usando las curvas 1 y 2, procedentes del Estudio Global sobre el Envejecimiento y la Salud del Adulto (SAGE por sus siglas en inglés) en México, que incluyó adultos de 55+ años. Características del vecindario como: participación social, confianza y seguridad, así como las covariables individuales se midieron sólo en la curva 1 (base de referencia), mientras que la discapacidad se midió en ambas curvas para ajustarla a la puntuación de la curva 1. Se realizaron modelos binomiales negativos multinivel con intercepciones aleatorias en el nivel municipal para el marcador de discapacidad en la curva 2, usando cada una de las variables socioambientales como las de principal exposición y ajustándolas a las variables sociodemográficas, así como a las relacionadas con la salud. Finalmente, se probaron los términos de interacción con sexo, edad, así como quintiles socioeconómicos. Los resultados mostraron que los vecindarios con una media (IRR: 0,68; IC95%: 0,53-0,87) o alto (IRR: 0,67; IC95%: 0,52-0,86) nivel de seguridad estuvieron asociados con una significativa reducción en el marcador de discapacidad de adultos 75+ años, pese a que no hubo asociación entre otras características del ambiente social y discapacidad en la muestra general. Consecuentemente, las acciones para mejorar la seguridad en los vecindarios deberían haber ayudado a reducir la puntuación en discapacidad en ancianos vulnerables, especialmente, en un contexto donde la seguridad es un asunto crítico, como en México.

Considerando o envelhecimento rápido da população mundial e o fato de a incapacidade ser um evento muito frequente nos idosos, há um interesse cada vez maior no estudo dos determinantes da incapacidade, que incluem as características da vizinhança. Portanto, o estudo procurou explorar a associação entre o ambiente social da vizinhança e a incapacidade nos idosos. Foi organizado um estudo de coorte com as ondas 1 e 2 do Estudo sobre Envelhecimento Global e Saúde do Adulto (SAGE) no México, que incluiu adultos com 55 anos ou mais. As características da vizinhança, tais como a participação social, confiança e segurança, e as covariáveis individuais foram medidas apenas na onda 1 (linha de base), enquanto a incapacidade era medida em ambas as ondas para ajustar para a pontuação da onda 1. Foram construídos modelos binomiais negativos multiníveis com interceptos no nível municipal para a pontuação da incapacidade na onda 2, usando cada uma das variáveis ambientais como a principal variável de exposição, e ajustando para as variáveis sociodemográficas e sanitárias. Finalmente, foram testados termos de interação com sexo, idade e quintis socioeconômicos. Os resultados mostraram que os bairros com nível de segurança médio (RTI: 0,68; IC95%: 0,53-0,87) ou alto (RTI: 0,67; IC95%: 0,52-0,86) estavam associados com uma redução significativa na escala de incapacidade nos idosos com 75 anos ou mais, embora não houvesse associação entre outras características do entorno e a incapacidade na amostra geral. Portanto, são necessárias medidas para melhorar a segurança dos bairros para ajudar a reduzir a escala da incapacidade nos idosos vulneráveis, principalmente em um contexto onde a segurança é uma questão crítica, como no México.

Combining sensor tracking with a GPS-based mobility survey to better measure physical activity in trips: public transport generates walking.

BACKGROUND: Policymakers need accurate data to develop efficient interventions to promote transport physical activity. Given the imprecise assessment of physical activity in trips, our aim was to illustrate novel advances in the measurement of walking in trips, including in trips incorporating non-walking modes. METHODS: We used data of 285 participants (RECORD MultiSensor Study, 2013-2015, Paris region) who carried GPS receivers and accelerometers over 7 days and underwent a phone-administered web mobility survey on the basis of algorithm-processed GPS data. With this mobility survey, we decomposed trips into unimodal trip stages with their start/end times, validated information on travel modes, and manually complemented and cleaned GPS tracks. This strategy enabled to quantify walking in trips with different modes with two alternative metrics: distance walked and accelerometry-derived number of steps taken. RESULTS: Compared with GPS-based mobility survey data, algorithm-only processed GPS data indicated that the median distance covered by participants per day was 25.3 km (rather than 23.4 km); correctly identified transport time vs. time at visited places in 72.7% of time; and correctly identified the transport mode in 67% of time (and only in 55% of time for public transport). The 285 participants provided data for 8983 trips (21,163 segments of observation). Participants spent a median of 7.0% of their total time in trips. The median distance walked per trip was 0.40 km for entirely walked trips and 0.85 km for public transport trips (the median number of accelerometer steps were 425 and 1352 in the corresponding trips). Overall, 33.8% of the total distance walked in trips and 37.3% of the accelerometer steps in trips were accumulated during public transport trips. Residents of the far suburbs cumulated a 1.7 times lower distance walked per day and a 1.6 times lower number of steps during trips per 8 h of wear time than residents of the Paris core city. CONCLUSIONS: Our approach complementing GPS and accelerometer tracking with a GPS-based mobility survey substantially improved transport mode detection. Our findings suggest that promoting public transport use should be one of the cornerstones of policies to promote physical activity.

Relationship between area mortgage foreclosures, homeownership, and cardiovascular disease risk factors: The Hispanic Community Health Study/Study of Latinos.

BACKGROUND: The risk of mortgage foreclosure disproportionately burdens Hispanic/Latino populations perpetuating racial disparities in health. In this study, we examined the relationship between area-level mortgage foreclosure risk, homeownership, and the prevalence of cardiovascular disease risk factors among participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). METHODS: HCHS/SOL participants were age 18-74 years when recruited from four U.S. metropolitan areas. Mortgage foreclosure risk was obtained from the U.S. Department of Housing and Urban Development. Homeownership, sociodemographic factors, and cardiovascular disease risk factors were measured at baseline interview between 2008 and 2011. There were 13,856 individuals contributing to the analysis (median age 39 years old, 53% female). RESULTS: Renters in high foreclosure risk areas had a higher prevalence of hypertension and hypercholesterolemia but no association with smoking status compared to renters in low foreclosure risk areas. Renters were more likely to smoke cigarettes than homeowners. CONCLUSION: Among US Hispanic/Latinos in urban cities, area foreclosure and homeownership have implications for risk of cardiovascular disease.

Examining Use of Mobile Phones for Sleep Tracking Among a National Sample in the USA.

Mobile technology has been designed to serve a number of functions relating to health, but we know little about individuals who use these tools to track sleep. This study utilized data from a cross-sectional, geographically diverse survey of adults in the USA (N = 934). Among the sample, 28.2% (n = 263) report current use of a mobile phone for sleep tracking. Income and gender were significant correlates of sleep tracking (p < 0.05). Compared to a poor diet, a reported "excellent" diet was associated with sleep tracking (p < 0.05). Interestingly, compared to individuals who never smoke, report of smoking "everyday" was associated with sleep tracking (p < 0.05). Finally, individuals who reported current use of their mobile device for other health functions (e.g., chat with their doctor or log symptoms) were more likely to report sleep tracking on their mobile device (p < 0.05). Results appear to suggest sleep tracking is common among individuals with good general health.

Evaluating State-Level Differences in E-cigarette and Cigarette Use Among Adults in the United States Between 2012 and 2014: Findings From the National Adult Tobacco Survey.

Objective: To examine the association between state-level tobacco control measures and current use estimates of both e-cigarettes and cigarettes, while accounting for socio-demographic correlates. Methods: Using the 2012-2013 and 2013-2014 National Adult Tobacco Survey (NATS), we assessed prevalence estimates of US adults' e-cigarette and cigarette current use. Four state groups were created based on the combined state-specific prevalence of both products: low cigarette/e-cigarette (n = 15), high cigarette/e-cigarette (n = 16), high cigarette/low e-cigarette (n = 11), and low cigarette/high e-cigarette) (n = 9). To evaluate the implementation of state-level tobacco control measures, Tobacco Control Index (TCI) was calculated using the State of Tobacco Control annual reports for 2012 and 2013. Multinomial logistic regression models were used to examine differences among the four groups on socio-demographic factors and TCI. Low cigarette/e-cigarette group was used as the referent group. Results: Current use estimates of each product varied substantially by state; current e-cigarette use was highest in Oklahoma (10.3%) and lowest in Delaware (2.7%), and current cigarette use was highest in West Virginia (26.1%), and lowest in Vermont (12.6%). Compared to low cigarette/e-cigarette, all other US-state categories had significantly lower TCI scores (high cigarette/e-cigarette: adjusted Relative Risk Ratio [aRRR] = 0.61; 95% confidence interval [CI]: 0.60-0.61, high cigarette/low e-cigarette: aRRR = 0.74; 95% CI: 0.73-0.74, and low cigarette/high e-cigarette: aRRR = 0.72; 95% CI: 0.71-073). Conclusions: Enforcing existing tobacco control measures likely interacts with e-cigarette use despite being cigarette-focused. Continuing to monitor e-cigarette use is critical to establish baseline use and evaluate future e-cigarette specific federal and state-level tobacco regulatory actions while accounting for the existing tobacco control environment. Implications: This study investigates state-level current use estimates of e-cigarettes and cigarettes among US adults; and their association with four existing tobacco control measures. The overall score of these measures was negatively associated with state-level current use estimates such that states with low current e-cigarette and cigarette use had the highest mean overall score. This study assesses the potential relationship between existing state-level tobacco control measures and e-cigarette use and calls for improving the enforcement of the known-to-work tobacco control measures across all US states, while developing evidence-based regulations and interventions specific to e-cigarettes within the existing US tobacco use environment.

Perceived Candidacy for Pre-exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men in Paris, France.

Low perception of HIV risk is a challenge to PrEP implementation. We analyzed associations between perceptions of PrEP candidacy, behavioral indications for PrEP, and sexual behaviors. We recruited a sample of 580 MSM from a geosocial-networking smartphone application in Paris, France. A modified Poisson regression model was conducted to examine associations between perceived candidacy for PrEP and behavioral indications for PrEP, and relationships among engagement in group sex, transactional sex, HIV test history, and indications for PrEP. Adjusted risk ratios (aRR) and 95% confidence intervals (CIs) were calculated. For the outcome of perceived candidacy for PrEP, a multinomial logistic regression was performed, and adjusted relative risk ratios (aRRR) were calculated. Multivariate analyses were adjusted for socio-demographics. Respondents who considered themselves PrEP candidates were more likely to meet PrEP eligibility criteria compared to those who did not consider themselves candidates (aRR 1.65; 95% CI 1.34-2.03). Those who had engaged in group or transactional sex were more likely to have behavioral indications for PrEP (aRR 1.27; 95% CI 1.07-1.50, aRR 1.32; 95% CI 1.13-1.56, respectively), whereas HIV test history was not significantly associated with behavioral indications for PrEP. Respondents who had engaged in group sex or transactional sex were more likely to perceive themselves as candidates for PrEP (aRRR 2.24; 95% CI 1.21-4.16, aRRR 2.58; 95% CI 1.09-6.13, respectively), although those never tested for HIV were less likely to perceive themselves as candidates for PrEP (aRRR 0.18; 95% CI 0.03-0.91). The elucidation of candidacy perceptions and risk behaviors is key to furthering the effective implementation of PrEP engagement interventions.

Financial hardship and drug use among men who have sex with men.

BACKGROUND: Little is known about the role of financial hardship as it relates to drug use, especially among men who have sex with men (MSM). As such, this study aimed to investigate potential associations between financial hardship status and drug use among MSM. METHODS: We conducted a cross-sectional survey of 580 MSM in Paris recruited using a popular geosocial-networking smartphone application (GSN apps). Descriptive analyses and multivariate analyses were performed. A modified Poisson model was used to assess associations between financial hardship status and use of drugs (any drugs, tobacco, alcohol, marijuana, inhalant nitrites, and club drugs). RESULTS: In our sample, 45.5% reported that it was somewhat, very, or extremely difficult to meet monthly payments of bills (high financial hardship). In multivariate analyses, a high level of financial hardship was significantly associated with an increased likelihood of reporting use of any substance use (adjusted risk ratio [aRR] = 1.15; 95% CI = 1.05-1.27), as well as use of tobacco (aRR = 1.45; 95% CI = 1.19-1.78), marijuana (aRR = 1.48; 95% CI =1.03-2.13), and inhalant nitrites (aRR = 1.24; 95% CI = 1.03-1.50). CONCLUSIONS: Financial hardship was associated with drug use among MSM, suggesting the need for interventions to reduce the burden of financial hardship in this population.

Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis.

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.

Characteristics of Adults Who Switched From Cigarette Smoking to E-cigarettes.

INTRODUCTION: Because of the rapidly increasing use of electronic cigarettes (e-cigarettes), this study aimed to investigate the individual characteristics and state-level prevalence of U.S. adults who have switched to e-cigarettes from traditional cigarettes. METHODS: Data from the 2012-2013 and 2013-2014 National Adult Tobacco Surveys were analyzed in 2016. Relative percent change in switching was estimated, and the state-specific prevalence of adults who switched to e-cigarettes from traditional cigarettes was calculated and mapped. Multivariate logistic regression was conducted to examine how switching varied by sociodemographic subgroups and region. RESULTS: Overall, the number of individuals who switched from traditional cigarettes to e-cigarettes increased by approximately 100% over the 1-year interval. Significant increases were found among a number of sociodemographics and regions. Multivariate logistic regression analyses showed that young adults and those living in the South and West were more likely to switch to e-cigarettes, compared to former smokers who did not switch. Compared with current dual users, those with higher education and those who were not single were more likely to switch to e-cigarettes. The state with the highest prevalence of switching was New Mexico (7.3%), whereas Connecticut had the lowest prevalence (0.8 %) among former smokers. CONCLUSIONS: There is an increase in the progression from traditional cigarette use to e-cigarette use. Further research is warranted to determine whether this change continues and facilitates cigarette smoking cessation as a possible public health benefit and opportunity to save lives rather than constitutes a potential threat to public health.

It is a painful somatic symptom, not the history of cancer/malignancy that is associated with depression: findings from multiple national surveys.

Medical case management has improved in the past few decades, changing the dynamic interaction between depression and prevalent medical diseases. It is relevant to describe the comorbidity between depression and medical diseases to further improve the effectiveness of case management. We analyzed the data of adults aged 20 years and older, who completed depression screening as a part of the National Health and Nutrition Examination Survey, 2005 to 2012. Depression was ascertained using the Patient Health Questionnaire, a 9-item screening instrument asking about the frequency of depression symptoms over the past 2 weeks. Comorbid diseases were assessed in a self-reported personal interview on doctor-diagnosed health conditions. The associations between depression and medical diseases were limited to the diseases with painful somatic symptoms. Reported from 19.78% of men and 27.84% of women, arthritis was the most prevalent chronic disease, and was the only one consistently associated with depression. The odds ratio of moderate to severe depression was 1.65 (95% confidence interval = 1.12-2.44) for men and 2.11 (1.63-2.99) for women with arthritis compared with their counterparts free of arthritis. Moderate/severe depression was associated with a history of heart disease among men (2.45 [1.19-5.06]) and angina/angina pectoris among women (2.13 [1.07-4.26]). No associations were found between depression and cancer/malignancy, either among men or women. The potential impact of pain management on depression prevention among general population is substantial; more efforts are needed to assess chronic pain to facilitate timely prevention and treatment of depression and comorbid medical conditions.

Analysis of State-Specific Prevalence, Regional Differences, and Correlates of Hookah Use in U.S. Adults, 2012-2013.

OBJECTIVE: To investigate the state-specific prevalence, regional differences, and correlates of hookah use among U.S. adults. METHODS: We analyzed the most recent nationally representative data of adults from the National Adult Tobacco Survey (NATS) 2012-2013 (n = 60192). State-specific prevalence of lifetime and current hookah use was calculated and mapped. Multivariate logistic regression was performed to determine the association between sociodemographic characteristics, regional differences, and hookah use. RESULTS: Among U.S. adults (≥18 years), overall prevalence of lifetime hookah use was 12.3%, while current use was 3.9%. Mapping of state-specific prevalence revealed that the West tended to have higher rates of use, while the South tended to have lower ones. In the adjusted model, we observed that current hookah use was positively associated with younger adults, males, non-Hispanic adults, those with higher education and income statuses, being single, those living in the West, and current cigarette use. CONCLUSION: The prevalence of hookah use varies by state, region, and sociodemographic characteristics among adults. Future research, including longitudinal studies, are needed to identify geographic and sociodemographic characteristics and trends among hookah users, investigate hookah-related health outcomes, and evaluate targeted public health efforts aimed at this emerging threat. IMPLICATIONS: This study investigates state-level prevalence, regional differences, and sociodemographic characteristics of hookah use among U.S. adults, using the most recent NATS. Hookah use was positively associated with younger adults and those living in the West. This study adds to the understanding of the geographic and sociodemographic factors underlying hookah use, which can be used to develop much needed evidence-based regulations and programs that are responsive to the needs of different risk groups.

Association Between Electronic Cigarette Marketing Near Schools and E-cigarette Use Among Youth.

PURPOSE: Electronic cigarettes (e-cigarettes) are now the most popular tobacco product among youth. Little is known about the relationship between exposure to e-cigarette marketing at the point-of-sale and youth e-cigarette use. METHODS: Research staff collected data on e-cigarette availability and promotion in tobacco retailers within a half-mile of 41 schools participating in the 2014 New Jersey Youth Tobacco Survey. These data were linked with participant responses from the New Jersey Youth Tobacco Survey (n = 3,909) and log-Poisson regression models estimated adjusted prevalence ratios for ever and past-month e-cigarette use. RESULTS: Nearly a quarter of high school students in New Jersey have tried e-cigarettes (24.1%) and 12.1% were past-month users. Prevalence was highest among males, non-Hispanic whites, and students who have used other tobacco products. After controlling for covariates and the clustered nature of the data, e-cigarette retailer density around schools was positively associated with ever and past-month use of e-cigarettes (p < .05). E-cigarette advertising volume significantly increased the probability of being a past-month e-cigarette user (adjusted prevalence ratio: 1.03, p = .031). CONCLUSIONS: This study suggests that the point-of-sale environment around schools may contribute to e-cigarette use among youth. Policy efforts to restrict tobacco promotion at the point-of-sale may play a role in reducing the use of e-cigarettes.

Census tract correlates of vape shop locations in New Jersey.

INTRODUCTION: Vape shops are opening across the USA, but little is known about the types of neighborhoods where they are located. This study explores community-level predictors of vape shop locations in New Jersey, USA. METHODS: Vape shops were identified in July 2015 using a validated systematic online search protocol and geocoded using Google Earth Pro. Multivariable logistic regression identified demographic and other predictors of vape shop presence at the census tract level. RESULTS: Tobacco outlet density was consistently associated with higher odds of vape shop presence after adjusting for covariates (p<0.05). However, factors traditionally associated with tobacco retail were negatively associated with vapor outlets. Census tracts with a higher proportion of non-Hispanic black residents had significantly lower odds of having a vape shop (ß=-0.03, p<0.001). DISCUSSION: Vape shops are commonly located in census tracts where tobacco retail is high, but where fewer racial minorities live. The retail environment may communicate social norms regarding vaping and ultimately influence use behaviors of community residents.