Racial Differences in Palliative Care Use in Heart Failure Decedents.

BACKGROUND: Minoritized individuals experience greater heart failure (HF) incidence and mortality rates, yet racial disparities in palliative care (PC) in HF are unknown. METHODS: This retrospective study used electronic medical records to identify adults who were hospitalized at an academic health system and died due to HF between 2012 and 2018. Using multivariable logistic regression, we examined associations between decedents' characteristics and PC consultations (PCCs). RESULTS: Of 1987 decedents, 45.8% (n = 911) received PCCs. Black decedents had 60% greater odds of receiving PCCs (OR = 1.60; 95% CI = 1.21-2.11) than whites. Median time from PCC to death was shorter among white than Black decedents (31.2 vs 51.5 days; P = .001). Mean age at death was younger among Black than white decedents (71.3 [14.8] vs 81.8 [12.3]; P < .001) and decedents of "other" races (71.3 [14.8] vs. 80.3 [10.4]; P = .001). Black decedents were more likely than whites to receive inotropes (54.4% vs 42.3%; P < .001) and to be admitted to hospitals (39.5% vs 29.7%; P < .001) and intensive care units in their last month (30.3% vs 18.3%; P < .001). CONCLUSIONS: Findings suggest greater recognition of palliative-care needs among Black individuals with HF; however, most referrals to PC occur late in the disease trajectory.

Palliative Care for Patients With Heart Failure: Results From a Heart Failure Society of America Survey.

BACKGROUND: Multiple guidelines recommend specialty palliative care (PC) for patients with heart failure (HF), including patients with left ventricular assist devices (LVADs). However, the degree of integration and clinicians' perceptions of PC in HF care remain incompletely characterized. METHODS AND RESULTS: A 36-item survey was sent to 2109 members of the Heart Failure Society of America. Eighty respondents (53% physicians), including 51 respondents from at least 42 medical centers, completed the survey, with the majority practicing in urban (76%) academic medical centers (62%) that implanted LVADs (81%). Among the 42 unique medical centers identified, respondents reported both independent (40%) and integrated (40%) outpatient PC clinic models, whereas 12% reported not having outpatient PC at their institutions. A minority (12%) reported that their institution used triggered PC referrals based on objective clinical data. Of respondents from LVAD sites, the majority reported that a clinician from the PC team was required to see all patients prior to implantation, but there was variability in practices. Among all respondents, the most common reasons for PC referral in HF were poor prognosis, consideration of advanced cardiac therapies or other high-risk procedures and advance-care planning or goals-of-care discussions. The most frequent perceived barriers to PC consultation included lack of PC clinicians, unpredictable HF clinical trajectories and limited understanding of how PC can complement traditional HF care. CONCLUSION: PC integration and clinician perceptions of services vary in HF care. More research and guidance regarding evidence-based models of PC delivery in HF are needed.

Barriers of Acceptance to Hospice Care: a Randomized Vignette-Based Experiment.

BACKGROUND: The per diem financial structure of hospice care may lead agencies to consider patient-level factors when weighing admissions. OBJECTIVE: To investigate if treatment cost, disease complexity, and diagnosis are associated with hospice willingness to accept patients. DESIGN: In this 2019 online survey study, individuals involved in hospice admissions decisions were randomized to view one of six hypothetical patient vignettes: "high-cost, high-complexity," "low-cost, high-complexity," and "low-cost, low-complexity" within two diseases: heart failure and cystic fibrosis. Vignettes included demographics, prognoses, goals, and medications with costs. Respondents indicated their perceived likelihood of acceptance to their hospice; if likelihood was <100%, respondents were asked the barriers to acceptance. We used bivariate tests to examine associations between demographic, clinical, and organizational factors and likelihood of acceptance. PARTICIPANTS: Individuals involved in hospice admissions decisions MAIN MEASURES: Likelihood of acceptance to hospice care KEY RESULTS: N=495 (76% female, 53% age 45-64). Likelihoods of acceptance in cystic fibrosis were 79.8% (high-cost, high-complexity), 92.4% (low-cost, high-complexity), and 91.5% (low-cost, low-complexity), and in heart failure were 65.9% (high-cost, high-complexity), 87.3% (low-cost, high-complexity), and 96.6% (low-cost, low-complexity). For both heart failure and cystic fibrosis, respondents were less likely to accept the high-cost, high-complexity patient than the low-cost, high-complexity patient (65.9% vs. 87.3%, 79.8% vs. 92.4%, both p<0.001). For heart failure, respondents were less likely to accept the low-cost, high-complexity patient than the low-cost, low-complexity patient (87.3% vs. 96.6%, p=0.004). Treatment cost was the most common barrier for 5 of 6 vignettes. CONCLUSIONS: This study suggests that patients receiving expensive and/or complex treatments for palliation may have difficulty accessing hospice.

A Randomized, Multicenter, Evaluator-blind Study to Evaluate the Safety and Effectiveness of VYC-12L Treatment for Skin Quality Improvements.

BACKGROUND: Skin quality may be assessed by degrees of skin smoothness, fine lines, and hydration. VYC-12L is a recently developed hyaluronic acid filler to improve skin quality. OBJECTIVE: This was a randomized, evaluator-blind study assessing safety and effectiveness of intradermal VYC-12L treatment for improving cheek skin smoothness, fine lines, and hydration. METHODS: Participants (≥22 years) with moderate-to-severe investigator-assessed Allergan Cheek Smoothness Scale (ACSS) scores were randomized in 2:1 ratio to receive VYC-12L or control (no treatment with optional treatment). Effectiveness was assessed 1 month after last injection (initial or touch-up) by a responder rate (≥1-grade improvement from baseline on both cheeks) using investigator-rated ACSS and Allergan Fine Lines Scale (AFLS), and tissue dielectric constant probe-measured skin hydration. Safety was evaluated throughout. RESULTS: Participants (VYC-12L, n = 131; control, n = 71) were 86.1% female with a median age of 58.0 years. At month 1, ACSS and AFLS responder rates were statistically significantly higher in the VYC-12L group (57.9%, 58.3%, respectively) than in the untreated controls (4.5%, 5.4%, respectively; p < .001). VYC-12L ACSS and AFLS responder rates remained consistent throughout the 6-month follow-up. Six participants reported treatment-related adverse events; none led to study discontinuation. CONCLUSION: VYC-12L is an effective, well-tolerated treatment for lasting improvement of cheek skin smoothness, fine lines, and hydration.

Rural-Urban Disparities in Mortality From Cirrhosis in the United States From 1999 to 2019.

INTRODUCTION: We examined trends in rural-urban cirrhosis mortality disparities in the United States from decedents aged 25 years and older from 1999 to 2019. METHODS: We calculated cirrhosis age-adjusted mortality rates across 3 population categories: large metropolitan (≥1 million), medium/small metropolitan (50,000-999,999), and rural (<50,000) areas using the US Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research database. RESULTS: We found an almost 20-fold increase in the absolute difference in cirrhosis age-adjusted mortality rates between rural and large metropolitan areas between 1999 and 2019. DISCUSSION: Future research is needed to investigate reasons for this widening rural-urban disparity to improve rural cirrhosis care.

Racial Differences in Firearms Used and Autopsies Following Gun Deaths Exist.

INTRODUCTION: Disparities in gun violence across race are well documented. Studying these disparities is essential to reduce preventable gun deaths. This study evaluates the relationship between sociodemographic factors and firearms used in gun deaths. MATERIALS AND METHODS: This retrospective cohort study of firearm mortalities from 2009 to 2018 used the Mortality Multiple Cause-of-Death Public Use Record from the National Center for Health Statistics. The primary outcome was the type of firearm used and the secondary outcome was autopsy status. Factors of interest include race, ethnicity, gender, marital status, age, education, and place of death. Factors significantly associated with outcomes in univariate analyses were included in separate multivariate logistic regression models for assaults, intentional self-harm, and accidents. RESULTS: A total of 276,127 firearm deaths from 2009 to 2018 were analyzed. Compared to White victims, Black victims were less likely to die from handguns (accident: odds ratio [OR] = 0.70, P < 0.05; self-harm: OR = 0.84, P < 0.001; assault: OR = 0.58, P < 0.001) and rifles, shotguns, or large firearms (accident: OR = 0.30, P < 0.001; self-harm: OR = 0.37, P < 0.001; assault: OR = 0.28, P < 0.001). Black decedents were more likely to undergo autopsy than White decedents (accident: OR = 2.14, P < 0.001; intentional self-harm: OR = 2.02, P < 0.001; assault: OR = 2.02, P < 0.001). Ethnicity, gender, marital status, age, education, and other racial identities were also associated with firearms used and autopsy rates (P < 0.05). CONCLUSIONS: Differences in firearms used and autopsy rates following gun deaths exist by race, ethnicity, gender, marital status, age, and education. Future studies should investigate the relationship between sociodemographic factors and firearms used and autopsy status following gun deaths.

Adherence to Definitions of Labor Arrest Influence on Primary Cesarean Delivery Rate.

OBJECTIVE: The cesarean delivery rate in the United States is 31.9%. One of the leading indications for primary cesarean delivery is labor arrest. A modern understanding of the labor curve supports more time prior to the diagnosis of labor arrest. We conducted this study to examine the impact of adherence to the modern criteria for labor arrest and failed induction on rates of primary cesarean delivery and to identify predictors of meeting these criteria. STUDY DESIGN: We analyzed rates of primary cesarean deliveries overall and primary cesarean deliveries occurring due to arrest of dilation, arrest of descent, and failed induction among the 17,877 live births at a large academic center from 2010 through 2013. Multiple logistic regression modeling identified predictors of meeting the new criteria for these indications based on guidelines published by the 2012 National Institute of Child Health and Human Development. RESULTS: The primary cesarean delivery rate decreased from 23.5 to 21.1% (p = 0.026) from 2010 to 2013. Primary cesarean delivery rate for labor arrest and failed induction decreased from 8.5 to 6.7% (p = 0.005). The percentage of primary cesarean deliveries meeting the 2012 criteria for labor arrest increased from 18.8 to 34.9% (p = 0.002), and the rate of primary cesarean deliveries due to arrest of dilation decreased from 5.1 to 3.4% (p < 0.0005). The percentage of cases meeting the 2012 criteria for arrest of descent increased from 57.8 to 71.0% (p < 0.007), while primary cesarean delivery rate due to arrest of descent remained relatively unchanged, 3.1 to 2.6% (p = 0.330). CONCLUSION: A decrease in the primary cesarean rate was attributable to a decrease in cesarean for arrest of dilation in the setting of a significant increase in meeting the 2012 criteria for arrest of dilation. At the end of the study period, 65.2% of cesareans still did not meet the criteria for arrest of dilation. Greater rates of adherence to these guidelines may yield further reductions in the cesarean rate. KEY POINTS: · Primary cesarean delivery for labor arrest was decreased.. · Meeting criteria for labor arrest increased.. · A hospitalist provider increased odds of meeting criteria..

Evaluating the Contribution of Patient-Provider Communication and Cancer Diagnosis to Racial Disparities in End-of-Life Care Among Medicare Beneficiaries.

BACKGROUND: The quality of end-of-life (EOL) care in the USA remains suboptimal, with significant variations in care by race and across disease subgroups. Patient-provider communication may contribute to racial and disease-specific variations in EOL care outcomes. OBJECTIVE: We examined racial disparities in EOL care, by disease group (cancer vs. non-cancer), and assessed whether racial differences in patient-provider communication accounted for observed disparities. DESIGN: Retrospective cohort study using the 2001-2015 Surveillance, Epidemiology, and End Results - Consumer Assessment of Healthcare Providers and Systems data linked with Medicare claims (SEER-CAHPS). We employed stratified propensity score matching and modified Poisson regression analyses, adjusting for clinical and demographic characteristics PARTICIPANTS: Black and White Medicare beneficiaries 65 years or older with cancer (N=2000) or without cancer (N=11,524). MAIN MEASURES: End-of-life care measures included hospice use, inpatient hospitalizations, intensive care unit (ICU) stays, and emergency department (ED) visits, during the 90 days prior to death. KEY RESULTS: When considering all conditions together (cancer + non-cancer), Black beneficiaries were 26% less likely than their Whites counterparts to enroll in hospice (adjusted risk ratio [ARR]: 0.74, 95%CI: 0.66-0.83). Among beneficiaries without cancer, Black beneficiaries had a 32% lower likelihood of enrolling in hospice (ARR: 0.68, 95%CI: 0.59-0.79). There was no racial difference in hospice enrollment among cancer patients. Black beneficiaries were also at increased risk for ED use (ARR: 1.12, 95%CI: 1.01-1.26). Patient-provider communication did not explain racial disparities in hospice or ED use. There were no racial differences in hospitalizations or ICU admissions. CONCLUSION: We observed racial disparities in hospice use and ED visits in the 90 days prior to death among Medicare beneficiaries; however, hospice disparities were largely driven by patients without cancer. Condition-specific differences in palliative care integration at the end-of-life may partly account for variations in EOL care disparities across disease groups.

Combined nicotine and ethanol age-dependently alter neural and behavioral responses in male rats.

Use of alcohol (EtOH) and nicotine (Nic) typically begins during adolescence. Smoking and drinking often occur together and lead to a higher consumption of alcohol. Although we have shown that Nic+EtOH is reinforcing in self-administration tests in adolescent male rats, whether Nic+EtOH affects other behaviors or neuronal activity in an age-dependent manner is unknown. To address this, adolescent and adult male rats were given intravenous injections of Nic (30 µg/kg)+EtOH (4 mg/kg) and evaluated for locomotor and anxiety-like behaviors. Regional neuronal activity, assessed by cFos mRNA expression, was measured and used to evaluate functional connectivity in limbic regions associated with anxiety and motivation. Nic+EtOH increased locomotor activity and was anxiolytic in adolescents, but not adults. The posterior ventral tegmental area (pVTA), a critical regulator of drug reward, was selectively activated by Nic+EtOH in adults, while activity in its target region, the NAc-shell, was decreased. Drug-induced alterations in functional connectivity were more extensive in adults than adolescents and may act to inhibit behavioral responses to Nic+EtOH that are seen in adolescence. Overall, our findings suggest that brief, low-dose exposure to Nic+EtOH produces marked, age-dependent changes in brain and behavior and that there may be an ongoing maturation of the pVTA during adolescence that allows increased sensitivity to Nic+EtOH's reinforcing, hyperlocomotor, and anxiolytic effects. Furthermore, this work provides a potential mechanism for high rates of co-use of nicotine and alcohol by teenagers: this drug combination is anxiolytic and recruits functional networks that are unique from protective, inhibitory networks recruited in the mature and adult brain.

Defining Skin Quality: Clinical Relevance, Terminology, and Assessment.

BACKGROUND: Flawless skin is one of the most universally desired features, and demand for improvements in skin quality is growing rapidly. Skin quality has been shown to substantially impact emotional health, quality of life, self-perception, and interactions with others. Although skin quality improvements are a common end point in studies of cosmeceuticals, they are rarely assessed in clinical studies of other aesthetic treatments and products. Descriptive terminology for skin quality parameters also varies considerably within the aesthetic field, relying on a range of redundant and occasionally contradictory descriptors. In short, skin quality has not been clearly defined. OBJECTIVE: The goal of this review is to highlight the importance of skin quality to patients and physicians, explore known and unknown factors comprising skin quality, and provide clarity regarding terminology, descriptors, and evaluation tools for assessing skin quality. MATERIALS AND METHODS: A review of the literature on skin quality was performed without limitation on publication date. Relevant articles are presented. RESULTS AND CONCLUSION: We propose a framework of attributes contributing to skin quality rooted in 3 fundamental categories-visible, mechanical, and topographical-with the aim to provide information to help guide clinicians and inform future clinical studies.

Preterm Birth of Infants Prenatally Diagnosed with Congenital Heart Disease, Characteristics, Associations, and Outcomes.

There are limited data on the relation between congenital heart disease (CHD) and preterm birth (PTB). We aimed to estimate the risk of PTB in newborns with CHD, to study associations and risk factors (modifiable and non-modifiable) as well as investigate postnatal outcomes. This was a retrospective cohort study of 336 pregnancies diagnosed with CHD between 2011 and 2016. Groups consisted of those delivered at or after 37 weeks, and those who delivered prior to 37 weeks. Collected data included maternal and fetal characteristics as well postnatal outcomes. Complete data were obtained from 237 singleton pregnancies. The overall proportion of PTB was 23.2% for all CHD, of which 38.2% were spontaneous PTB which was almost unchanged after excluding extracardiac anomalies and pathogenic chromosomal abnormalities. Significant non-modifiable risk factors were pregnancy-related HTN disorders (P < 0.001), fetal growth restriction (P = 0.01), and pathogenic chromosomal abnormalities (P = 0.046). Significant PTB modifiable risk factors included prenatal marijuana use (P = 0.01). Pregnancies delivered at 37-38 weeks had significantly more newborns with birthweight < 2500 g (P < 0.001), required more pre-operative NICU support including intubation (P = 0.049), vasopressors (P = 0.04), prostaglandins (P = 0.003), antibiotics (P = 0.01), and had longer hospital stay (P = 0.001) than those delivered at ≥ 39 weeks. Prenatally diagnosed pregnancies with CHD had higher PTB rate compared to the general population, with spontaneous PTB comprising 38.2% of these preterm deliveries. Most PTB risk factors were non-modifiable, however, significant modifiable factors included marijuana use in pregnancy. Outcomes were favorable in neonates delivered at or beyond 39 weeks.

Fetal Myocardial Function as Assessed by N-Terminal Fragment Brain Natriuretic Protein in Premature Fetuses Exposed to Intra-amniotic Inflammation.

OBJECTIVE: This study aimed to determine the relationship between fetal exposure to intra-amniotic infection/inflammation (IAI) and fetal heart ventricular function as assessed by circulatory levels of N-terminal fragment brain natriuretic protein (NT-proBNP) and the Tei index. STUDY DESIGN: We analyzed 70 samples of paired amniotic fluid (AF) and cord blood retrieved from mothers who delivered preterm at <34 weeks as follows: Yes-IAI (n = 36) and No-IAI (n = 34). IAI was diagnosed by amniocentesis and AF mass spectrometry. Fetal exposure to inflammation was determined through the evaluation of cord blood haptoglobin (Hp) switch-on status and level, and interleukin (IL)-6 levels by Western blotting and enzyme-linked immunosorbent assay, respectively. Fetal heart function was assessed by cord blood NT-proBNP immunoassay and fetal echocardiogram (Tei index). RESULTS: IAI was characterized by significantly higher levels of AF (p < 0.001) and umbilical cord IL-6 (p = 0.004). Cord blood Hp levels and frequency of switch-on status were higher in fetuses exposed to IAI (p < 0.001, both). Fetuses exposed to IAI did not have higher levels of NT-proBNP. Following correction for gestational age and race, neither cord blood NT-proBNP nor the Tei index was significantly different in fetuses with Hp switched-on status (p > 0.05, both). CONCLUSION: Fetal myocardial left ventricular function does not seem to be significantly impaired in fetuses born alive due to IAI if delivery of the fetus occurs immediately following the diagnosis of IAI.

Obstetrical Unit Response to the COVID-19 Pandemic: OUR Study.

OBJECTIVE: This study aimed to describe the response of labor and delivery (L&D) units in the United States to the novel coronavirus disease 2019 (COVID-19) pandemic and determine how institutional characteristics and regional disease prevalence affect viral testing and personal protective equipment (PPE). STUDY DESIGN: A cross-sectional survey was distributed electronically through the Society for Maternal-Fetal Medicine e-mail database (n = 584 distinct practices) and social media between April 14 and 23, 2020. Participants were recruited through "snowballing." A single representative was asked to respond on behalf of each L&D unit. Data were analyzed using Chi-square and Fisher's exact tests. Multivariable regression was performed to explore characteristics associated with universal testing and PPE usage. RESULTS: A total of 301 surveys (estimated 51.5% response rate) was analyzed representing 48 states and two territories. Obstetrical units included academic (31%), community teaching (45%) and nonteaching hospitals (24%). Sixteen percent of respondents were from states with high prevalence, defined as higher "deaths per million" rates compared with the national average. Universal laboratory testing for admissions was reported for 40% (119/297) of units. After adjusting for covariates, universal testing was more common in academic institutions (adjusted odds ratio [aOR] = 1.73, 95% confidence interval [CI]: 1.23-2.42) and high prevalence states (aOR = 2.68, 95% CI: 1.37-5.28). When delivering asymptomatic patients, full PPE (including N95 mask) was recommended for vaginal deliveries in 33% and for cesarean delivery in 38% of responding institutions. N95 mask use during asymptomatic vaginal deliveries remained more likely in high prevalence states (aOR = 2.56, 95% CI: 1.29-5.09) and less likely in hospitals with universal testing (aOR = 0.42, 95% CI: 0.24-0.73). CONCLUSION: Universal laboratory testing for COVID-19 is more common at academic institutions and in states with high disease prevalence. Centers with universal testing were less likely to recommend N95 masks for asymptomatic vaginal deliveries, suggesting that viral testing can play a role in guiding efficient PPE use. KEY POINTS: · Heterogeneity is seen in institutional recommendations for viral testing and PPE.. · Universal laboratory testing for COVID-19 is more common at academic centers.. · N95 mask use during vaginal deliveries is less likely in places with universal testing..

Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation.

Chorioamnionitis, premature rupture of fetal membranes (FMs), and subsequent preterm birth are associated with local infection and inflammation, particularly IL-1ß production. Although bacterial infections are commonly identified, other microorganisms may play a role in the pathogenesis. Because viral pandemics, such as influenza, Ebola, and Zika, are becoming more common, and pregnant women are at increased risk for associated complications, this study evaluated the impact that viral infection had on human FM innate immune responses. This study shows that a herpes viral infection of FMs sensitizes the tissue to low levels of bacterial LPS, giving rise to an exaggerated IL-1ß response. Using an ex vivo human FM explant system and an in vivo mouse model of pregnancy, we report that the mechanism by which this aggravated inflammation arises is through the inhibition of the TAM receptor, MERTK, and activation of the inflammasome. The TAM receptor ligand, growth arrest specific 6, re-establishes the normal FM response to LPS by restoring and augmenting TAM receptor and ligand expression, as well as by preventing the exacerbated IL-1ß processing and secretion. These findings indicate a novel mechanism by which viruses alter normal FM immune responses to bacteria, potentially giving rise to adverse pregnancy outcomes.

Sex-dependent effects of nicotine on the developing brain.

The use of tobacco products represents a major public health concern, especially among women. Epidemiological data have consistently demonstrated that women have less success quitting tobacco use and a higher risk for developing tobacco-related diseases. The deleterious effects of nicotine are not restricted to adulthood, as nicotinic acetylcholine receptors regulate critical aspects of neural development. However, the exact mechanisms underlying the particular sensitivity of women to develop tobacco dependence have not been well elucidated. In this mini-review, we show that gonadal hormone-mediated sexual differentiation of the brain may be an important determinant of sex differences in the effects of nicotine. We highlight direct interactions between sex steroid hormones and ligand-gated ion channels critical for brain maturation, and discuss the extended and profound sexual differentiation of the brain. We emphasize that nicotine exposure during the perinatal and adolescent periods interferes with normal sexual differentiation and can induce long-lasting, sex-dependent alterations in neuronal structure, cognitive and executive function, learning and memory, and reward processing. We stress important age and sex differences in nicotine's effects and emphasize the importance of including these factors in preclinical research that models tobacco dependence. © 2016 Wiley Periodicals, Inc.

Does prenatal stress alter the developing connectome?

Human neurodevelopment requires the organization of neural elements into complex structural and functional networks called the connectome. Emerging data suggest that prenatal exposure to maternal stress plays a role in the wiring, or miswiring, of the developing connectome. Stress-related symptoms are common in women during pregnancy and are risk factors for neurobehavioral disorders ranging from autism spectrum disorder, attention deficit hyperactivity disorder, and addiction, to major depression and schizophrenia. This review focuses on structural and functional connectivity imaging to assess the impact of changes in women's stress-based physiology on the dynamic development of the human connectome in the fetal brain.

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse.

Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.