Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG-Syt1-SV2 plasma membrane nanocluster for synaptic vesicle entry.

The unique nerve terminal targeting of botulinum neurotoxin type A (BoNT/A) is due to its capacity to bind two receptors on the neuronal plasma membrane: polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Whether and how PSGs and SV2 may coordinate other proteins for BoNT/A recruitment and internalization remains unknown. Here, we demonstrate that the targeted endocytosis of BoNT/A into synaptic vesicles (SVs) requires a tripartite surface nanocluster. Live-cell super-resolution imaging and electron microscopy of catalytically inactivated BoNT/A wildtype and receptor-binding-deficient mutants in cultured hippocampal neurons demonstrated that BoNT/A must bind coincidentally to a PSG and SV2 to target synaptic vesicles. We reveal that BoNT/A simultaneously interacts with a preassembled PSG-synaptotagmin-1 (Syt1) complex and SV2 on the neuronal plasma membrane, facilitating Syt1-SV2 nanoclustering that controls endocytic sorting of the toxin into synaptic vesicles. Syt1 CRISPRi knockdown suppressed BoNT/A- and BoNT/E-induced neurointoxication as quantified by SNAP-25 cleavage, suggesting that this tripartite nanocluster may be a unifying entry point for selected botulinum neurotoxins that hijack this for synaptic vesicle targeting.

Effects of extracellular matrix viscoelasticity on cellular behaviour.

Substantial research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, affects fundamental cellular processes, including spreading, growth, proliferation, migration, differentiation and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins are widely used to assess the role of stiffness, and results from such experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo. However, tissues and ECMs are not linearly elastic materials-they exhibit far more complex mechanical behaviours, including viscoelasticity (a time-dependent response to loading or deformation), as well as mechanical plasticity and nonlinear elasticity. Here we review the complex mechanical behaviours of tissues and ECMs, discuss the effect of ECM viscoelasticity on cells, and describe the potential use of viscoelastic biomaterials in regenerative medicine. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and can promote behaviours that are not observed with elastic hydrogels in both two- and three-dimensional culture microenvironments. These findings have provided insights into cell-matrix interactions and how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results suggest design guidelines for the next generation of biomaterials, with the goal of matching tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.

Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models.

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery.

RAD18 opposes transcription-associated genome instability through FANCD2 recruitment.

DNA replication is a vulnerable time for genome stability maintenance. Intrinsic stressors, as well as oncogenic stress, can challenge replication by fostering conflicts with transcription and stabilizing DNA:RNA hybrids. RAD18 is an E3 ubiquitin ligase for PCNA that is involved in coordinating DNA damage tolerance pathways to preserve genome stability during replication. In this study, we show that RAD18 deficient cells have higher levels of transcription-replication conflicts and accumulate DNA:RNA hybrids that induce DNA double strand breaks and replication stress. We find that these effects are driven in part by failure to recruit the Fanconi Anemia protein FANCD2 at difficult to replicate and R-loop prone genomic sites. FANCD2 activation caused by splicing inhibition or aphidicolin treatment is critically dependent on RAD18 activity. Thus, we highlight a RAD18-dependent pathway promoting FANCD2-mediated suppression of R-loops and transcription-replication conflicts.

The end of court-ordered desegregation and U.S. children's health: Quasi-experimental evidence.

School racial segregation significantly impacts racial disparities in U.S. children's health. Recently, school segregation has been increasing, partially due to Supreme Court decisions since 1991 that have made it easier for school districts to be released from court-ordered desegregation. We investigated the association of the end of court-ordered desegregation with child health using the 1997-2018 waves of the National Health Interview Survey (N=8,182 Black, 16,930 White children). We exploited quasi-random variation in the timing of school districts' releases from court orders to estimate effects on general health, body weight, mental health, and asthma, using difference-in-differences and event-study methods (including traditional and heterogeneity-robust estimators). Heterogeneity-robust difference-in-differences analyses show that release was associated with increased school segregation, improved mental health among Black children, and better self-reported health among White children. For heterogeneity-robust event-study analyses, school segregation increased steadily over time after release, with worse self-reported health and higher risk of asthma episodes among Black children 18+ years after release. Black children's mental health temporarily improved in the short term. In contrast, White children had improved self-reported health, mental health, and risk of asthma episodes in some years. Interventions to address the harms of school segregation are important for reducing racial health inequities.

Mediating pathways between neighborhood disadvantage and cardiovascular risk: Quasi-experimental evidence from a Danish refugee dispersal policy.

Research has documented that neighborhood disadvantage is associated with increased cardiovascular disease risk, but it is unclear which mechanistic pathways mediate this association across the life course. Leveraging a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998 and using 30 years of follow-up data from population and health registers, we assessed whether and how individual-level poverty, unstable employment, and poor mental health mediate the relation between neighborhood disadvantage and the risk of hypertension, hyperlipidemia, and type 2 diabetes among Danish refugees (N= 40,811). Linear probability models using the discrete time-survival framework showed that neighborhood disadvantage was associated with increased risk of hypertension (0.05 percentage points [pp] per year [95%CI -0.00, 0.10]); hyperlipidemia (0.03 pp per year [95%CI -0.01, 0.07]), and diabetes (0.01 pp per year (95%CI -0.02, 0.03)). The Baron-Kenny product-of-coefficients method for counterfactual mediation analysis indicated that cumulative income mediated 6%-28% of the disadvantage effect on these outcomes. We find limited evidence of mediation by unstable employment and poor mental health. This study informs our theoretical understanding of the pathways linking neighborhood disadvantage with cardiovascular disease risk and identifies income security as a promising point of intervention in future research.

Advances in Difference-in-differences Methods for Policy Evaluation Research.

Difference-in-differences (DiD) is a powerful, quasi-experimental research design widely used in longitudinal policy evaluations with health outcomes. However, DiD designs face several challenges to ensuring reliable causal inference, such as when policy settings are more complex. Recent economics literature has revealed that DiD estimators may exhibit bias when heterogeneous treatment effects, a common consequence of staggered policy implementation, are present. To deepen our understanding of these advancements in epidemiology, in this methodologic primer, we start by presenting an overview of DiD methods. We then summarize fundamental problems associated with DiD designs with heterogeneous treatment effects and provide guidance on recently proposed heterogeneity-robust DiD estimators, which are increasingly being implemented by epidemiologists. We also extend the discussion to violations of the parallel trends assumption, which has received less attention. Last, we present results from a simulation study that compares the performance of several DiD estimators under different scenarios to enhance understanding and application of these methods.

Medicaid Expansion and Perinatal Health Outcomes: A Quasi-Experimental Study.

OBJECTIVE: There has been little evidence of the impact of preventive services during pregnancy covered under the Affordable Care Act (ACA) on birthing parent and infant outcomes. To address this gap, this study examines the association between Medicaid expansion under the ACA and birthing parent and infant outcomes of low-income pregnant people. METHODS: This study used individual-level data from the 2004-2017 annual waves of the Pregnancy Risk Assessment Monitoring System (PRAMS). PRAMS is a surveillance project of the Centers for Disease Control and Prevention and health departments that annually includes a representative sample of 1,300 to 3,400 births per state, selected from birth certificates. Birthing parents' outcomes of interest included timing of prenatal care, gestational diabetes, hypertensive disorders of pregnancy, cigarette smoking during pregnancy, and postpartum care. Infant outcomes included initiation and duration of breastfeeding, preterm birth, and birth weight. The association between ACA Medicaid expansion and the birthing parent and infant outcomes were examined using difference-in-differences estimation. RESULTS: There was no association between Medicaid expansion and the outcomes examined after correcting for multiple testing. This finding was robust to several sensitivity analyses. CONCLUSIONS FOR PRACTICE: Study findings suggest that expanded access to more complete insurance benefits with limited cost-sharing for pregnant people, a group that already had high rates of insurance coverage, did not impact the birthing parents' and infant health outcomes examined.

Evaluation of the sugar-sweetened beverage tax in Oakland, United States, 2015-2019: A quasi-experimental and cost-effectiveness study.

BACKGROUND: While a 2021 federal commission recommended that the United States government levy a sugar-sweetened beverage (SSB) tax to improve diabetes prevention and control efforts, evidence is limited regarding the longer-term impacts of SSB taxes on SSB purchases, health outcomes, costs, and cost-effectiveness. This study estimates the impact and cost-effectiveness of an SSB tax levied in Oakland, California. METHODS AND FINDINGS: An SSB tax ($0.01/oz) was implemented on July 1, 2017, in Oakland. The main sample of sales data included 11,627 beverage products, 316 stores, and 172,985,767 product-store-month observations. The main analysis, a longitudinal quasi-experimental difference-in-differences approach, compared changes in beverage purchases at stores in Oakland versus Richmond, California (a nontaxed comparator in the same market area) before and 30 months after tax implementation (through December 31, 2019). Additional estimates used synthetic control methods with comparator stores in Los Angeles, California. Estimates were inputted into a closed-cohort microsimulation model to estimate quality-adjusted life years (QALYs) and societal costs (in Oakland) from 6 SSB-associated disease outcomes. In the main analysis, SSB purchases declined by 26.8% (95% CI -39.0 to -14.7, p < 0.001) in Oakland after tax implementation, compared with Richmond. There were no detectable changes in purchases of untaxed beverages or sweet snacks or purchases in border areas surrounding cities. In the synthetic control analysis, declines in SSB purchases were similar to the main analysis (-22.4%, 95% CI -41.7% to -3.0%, p = 0.04). The estimated changes in SSB purchases, when translated into declines in consumption, would be expected to accrue QALYs (94 per 10,000 residents) and significant societal cost savings (>$100,000 per 10,000 residents) over 10 years, with greater gains over a lifetime horizon. Study limitations include a lack of SSB consumption data and use of sales data primarily from chain stores. CONCLUSIONS: An SSB tax levied in Oakland was associated with a substantial decline in volume of SSBs purchased, an association that was sustained more than 2 years after tax implementation. Our study suggests that SSB taxes are effective policy instruments for improving health and generating significant cost savings for society.

High-Throughput Routes to Biomaterials Discovery.

Many existing clinical treatments are limited in their ability to completely restore decreased or lost tissue and organ function, an unenviable situation only further exacerbated by a globally aging population. As a result, the demand for new medical interventions has increased substantially over the past 20 years, with the burgeoning fields of gene therapy, tissue engineering, and regenerative medicine showing promise to offer solutions for full repair or replacement of damaged or aging tissues. Success in these fields, however, inherently relies on biomaterials that are engendered with the ability to provide the necessary biological cues mimicking native extracellular matrixes that support cell fate. Accelerating the development of such "directive" biomaterials requires a shift in current design practices toward those that enable rapid synthesis and characterization of polymeric materials and the coupling of these processes with techniques that enable similarly rapid quantification and optimization of the interactions between these new material systems and target cells and tissues. This manuscript reviews recent advances in combinatorial and high-throughput (HT) technologies applied to polymeric biomaterial synthesis, fabrication, and chemical, physical, and biological screening with targeted end-point applications in the fields of gene therapy, tissue engineering, and regenerative medicine. Limitations of, and future opportunities for, the further application of these research tools and methodologies are also discussed.

Effectiveness of Peer-Support Interventions for Smoking Cessation: A Systematic Review and Meta-analysis.

INTRODUCTION: Peer support has been recommended to promote smoking cessation, but results from prior meta-analyses have not established its efficacy. We conducted a systematic review and meta-analysis to assess current evidence and identify potential modifiers of efficacy. METHODS: Randomized controlled trials of peer-support interventions with a smoking cessation outcome were identified in January 2022 from PubMed and references listed in identified studies. The meta-analysis outcome measure was mean risk ratio (RR, 95% confidence interval [CI]) for abstinence at the longest follow-up timepoint between 3 and 9 months from baseline. Potential modifiers tested were peer smoking status (former, current, or unknown), follow-up timepoint, abstinence measure, and cumulative engagement time between peers and smokers ("dose"). Studies were assessed for risk of bias and certainty of evidence. RESULTS: We identified 16 trials, which varied in abstinence effect size (RR 0.61-3.07), sample size (23-2121), dose (41-207 minutes), and follow-up timepoint (<1-15 months). Across 15 trials with follow-up between 3 and 9 months (N = 8573 participants; 4565 intervention, 4008 control), the pooled Mantel-Haenszel RR was 1.34 (95% CI: 1.11-1.62). Effect sizes were greatest among interventions with formerly smoking peers (RR 1.43, 95% CI 1.17-1.74; five trials). We found positive effects for follow-up timepoints ≥3 months but no effect of intervention dose. The overall quality of evidence was deemed "very low." CONCLUSIONS: Peer-support interventions increased smoking abstinence. There remains a lack of consensus about how to define a peer. Intervention features such as peer smoking status appear to have explanatory power. Additional high-quality and more comparable trials are needed. IMPLICATIONS: This study reviewed the latest evidence from randomized controlled trials and found that peer-support interventions enhance smoking cessation. Efficacy varies with key intervention features such as peer smoking status and follow-up timepoint, which may be used to facilitate development of more effective peer-support interventions. Future trials and reviews would benefit from careful consideration and clear reporting of peer smoking status, length of follow-up, abstinence measures, and intervention dose.

Neighbourhood socioeconomic disadvantage and psychiatric disorders among refugees: a population-based, quasi-experimental study in Denmark.

PURPOSE: Refugees are vulnerable to psychiatric disorders because of risk factors linked to migration. Limited evidence exist on the impact of the neighbourhood in which refugee resettle. We examined whether resettling in a socioeconomically disadvantaged neighbourhood increased refugees' risk of psychiatric disorders. METHODS: This register-based cohort study included 42,067 adults aged 18 years and older who came to Denmark as refugees during 1986-1998. Resettlement policies in those years assigned refugees in a quasi-random fashion to neighbourhoods across the country. A neighbourhood disadvantage index was constructed using neighbourhood-level data on income, education, unemployment, and welfare receipt. Main outcomes were psychiatric diagnoses and psychiatric medication usage ascertained from nationwide patient and prescription drug registers, with up to 30-year follow-up. Associations of neighbourhood disadvantage with post-migration risk of psychiatric disorders were examined using Cox proportional hazards and linear probability models adjusted for individual, family, and municipality characteristics. RESULTS: The cumulative risk of psychiatric diagnoses and medication was 13.7% and 46.1%, respectively. Refugees' risk of psychiatric diagnoses and psychiatric medication usage was higher among individuals assigned to high-disadvantage compared with low-disadvantage neighbourhoods in analyses including fixed effects for assigned municipality (psychiatric diagnoses: hazard ratio (HR) = 1.14, 95% CI 1.04, 1.25; psychiatric medication: HR = 1.05, 95% CI 1.00, 1.11). Consistent results were found using linear probability models. Results for diagnostic categories and subclasses of medications suggested that the associations were driven by neurotic and stress-related disorders and use of anxiolytic medications. CONCLUSION: Resettlement in highly disadvantaged neighbourhoods was associated with an increase in refugees' risk of psychiatric disorders, suggesting that targeted placement of newly arrived refugees could benefit refugee mental health. The results contribute quasi-experimental evidence to support links between neighbourhood characteristics and health.

The role of patient perceptions and hyperfunctional voice disorders in predicting voice therapy attendance.

OBJECTIVES/HYPOTHESIS: Attendance is essential to voice therapy's effectiveness in the treatment of voice and laryngeal disorders. With such high rates of drop-out and non-attendance, it is important to understand the factors that influence this behavior. This study sought to identify potential predictors of attendance to voice therapy at an interdisciplinary voice clinic. STUDY DESIGN: Single-institution retrospective cohort study. METHODS: In this retrospective cohort study, patients evaluated at an interdisciplinary voice clinic who received a referral for voice therapy were identified. Age, gender, voice-related diagnoses, Voice Handicap Index-10 scores, Reflux Symptom Index scores, and measures of patient perceptions (self-rated severity, importance of voice in one's life, and "feelings about voice therapy") were recorded to evaluate associations with attendance to at least one therapy session. Standard statistical analysis and logistic regressions were performed. RESULTS: Of 168 subjects included, 111 (66.1 %) attended at least one session of voice therapy. Patients diagnosed with primary hyperfunctional voice disorders had a significantly higher attendance rate than other groups. Attenders had higher self-ratings of severity and more positive "feelings about voice therapy" compared to non-attenders. Regression models found three significant predictors of therapy attendance: primary diagnosis of hyperfunctional voice disorder, self-rated severity, and "feelings about voice therapy." CONCLUSION: In this cohort, patients with more positive feelings about voice therapy, higher self-rated severity, and a diagnosis of primary hyperfunctional voice disorder were more likely to attend voice therapy.

School racial segregation and long-term cardiovascular health among Black adults in the US: A quasi-experimental study.

BACKGROUND: Cardiovascular disease (CVD) disproportionately affects Black adults in the United States. This is increasingly acknowledged to be due to inequitable distribution of health-promoting resources. One potential contributor is inequities in educational opportunities, although it is unclear what aspects of education are most salient. School racial segregation may affect cardiovascular health by increasing stress, constraining socioeconomic opportunities, and altering health behaviors. We investigated the association between school segregation and Black adults' CVD risk. METHODS AND FINDINGS: We leveraged a natural experiment created by quasi-random (i.e., arbitrary) timing of local court decisions since 1991 that released school districts from court-ordered desegregation. We used the Panel Study of Income Dynamics (PSID) (1991 to 2017), linked with district-level school segregation measures and desegregation court order status. The sample included 1,053 Black participants who ever resided in school districts that were under a court desegregation order in 1991. The exposure was mean school segregation during observed schooling years. Outcomes included several adult CVD risk factors and outcomes. We fitted standard ordinary least squares (OLS) multivariable linear regression models, then conducted instrumental variables (IV) analysis, using the proportion of schooling years spent in districts that had been released from court-ordered desegregation as an instrument. We adjusted for individual- and district-level preexposure confounders, birth year, and state fixed effects. In standard linear models, school segregation was associated with a lower probability of good self-rated health (-0.05 percentage points per SD of the segregation index; 95% CI: -0.08, -0.03; p < 0.001) and a higher probability of binge drinking (0.04 percentage points; 95% CI: 0.002, 0.07; p = 0.04) and heart disease (0.01 percentage points; 95% CI: 0.002, 0.15; p = 0.007). IV analyses also found that school segregation was associated with a lower probability of good self-rated health (-0.09 percentage points; 95% CI: -0.17, -0.02, p = 0.02) and a higher probability of binge drinking (0.17 percentage points; 95% CI: 0.04, 0.30, p = 0.008). For IV estimates, only binge drinking was robust to adjustments for multiple hypothesis testing. Limitations included self-reported outcomes and potential residual confounding and exposure misclassification. CONCLUSIONS: School segregation exposure in childhood may have longstanding impacts on Black adults' cardiovascular health. Future research should replicate these analyses in larger samples and explore potential mechanisms. Given the recent rise in school segregation, this study has implications for policies and programs to address racial inequities in CVD.

Increased lead and glucocorticoid concentrations reduce reproductive success in house sparrows along an urban gradient.

Urbanization is increasing at a rapid pace globally. Understanding the links among environmental characteristics, phenotypes, and fitness enables researchers to predict the impact of changing landscapes on individuals and populations. Although avian reproductive output is typically lower in urban compared with natural areas, the underlying reasons for this discrepancy may lie at the intersection of abiotic and biotic environmental and individual differences. Recent advances in urban ecology highlight the effect of heavy metal contamination on stress physiology. As high levels of glucocorticoid hormones decrease parental investment, these hormones might be the link to decreased reproductive success in areas of high environmental pollution. In this study, we aimed to identify which abiotic stressors are linked to avian reproductive output in urban areas and whether this link is mediated by individual hormone levels. We used fine-scaled estimates (2 m2 spatial resolution) of nighttime light, noise, and urban density to assess their impacts on the physiological condition of adult house sparrows (Passer domesticus). We measured circulating levels of lead and glucocorticoid concentrations in 40 breeding pairs of free-living house sparrows and related these physiological traits to reproductive success. Using structural equation modeling, we found that increased urban density levels linked directly to increased plasma corticosterone and lead concentrations that subsequently led to decreased fledgling mass. Sparrows with increased lead concentrations in plasma also had higher corticosterone levels. Although urban areas may be attractive due to decreased natural predators and available nesting sites, they may act as ecological traps that increase physiological damage and decrease fitness. To illustrate, avian development is strongly explained by parental corticosterone levels, which vary significantly in response to urban density and lead pollution. With fine-scale ecological mapping for a species with small home ranges, we demonstrated the presence and impacts of urban stressors in a small city with high human densities.

Retrospective Review of Reproductive Outcomes Comparing Vaginal Progesterone to Intramuscular Progesterone as Luteal Support in Frozen Embryo Transfer Cycles.

OBJECTIVE: Recent literature suggests that progesterone in oil (PIO) is superior to vaginal progesterone (VP; Prometrium) for endometrial preparation in frozen embryo transfer cycles (FET), improving the live birth rate and reducing the rate of miscarriage. PIO has disadvantages including cost, pain, and stress of administration. The objective of this study was to evaluate whether VP is non-inferior to PIO for medicated FET cycles. METHODS: We conducted a retrospective analysis comparing pregnancy, miscarriage, and live birth rates for PIO versus VP for medicated FET cycles, from 2017 to 2020 at a single fertility clinic. A total of 745 participants were included in the study; 438 received VP, and 307 received PIO. Univariate and multivariate binary and ordinal logistic regression analyses were performed to compare the rates of pregnancy, miscarriage, and live birth between VP and PIO. RESULTS: Our data demonstrated no difference between PIO and VP with respect to the rates of pregnancy (51% vs. 53%), miscarriage (20% vs. 18%), or live birth (31% vs. 34%) (all P > 0.05). For participants taking PIO, the odds of pregnancy were 0.93 [95% CI (0.70, 1.25), P = 0.65] that of participants on VP. CONCLUSION: In our single-centre experience, VP was non-inferior to PIO for endometrial preparation in FET cycles.

Effects of a minimum floor Price law on cigarette use in Oakland, California: A static microsimulation model.

Tobacco minimum floor price laws (MFPLs) are a non-tax price policy that set a price below which tobacco products cannot be sold, thereby raising prices. Despite their growing interest among policy makers, little is known about the effects of local MFPLs on smoking prevalence or smoking intensity. We aimed to project the impact of a local tobacco MFPL on cigarette smoking prevalence and cigarette smoking intensity in Oakland, California, including detailed analysis of several important subpopulations. We used data collected between April 2017 and December 2019 from the California Behavioral Risk Factor Surveillance System and the National Youth Tobacco Survey to construct a static microsimulation model representative of Oakland. We projected the impact of MFPLs ranging from $8.00 to $13.00 per pack. All analyses were conducted between 2019 and 2020. With the introduction of an MFPL and assuming 15% policy evasion, mean price paid per pack was projected to increase by $1.05 to $4.69, cigarette smoking prevalence was projected to drop by 0.3% to 0.8%, and smoking intensity was projected to drop by 0.7% to 2.0% among continuing smokers. Total number of cigarettes smoked per month was projected to drop by 246,000 to 734,000 cigarettes, a 3.0% to 9.0% reduction from the current level (8.2 million cigarettes). The greatest reductions in cigarette smoking prevalence were among those aged 12 to 24-years-old, of non-Hispanic black or other race/ethnicity, and living below the federal poverty level. An MFPL in Oakland may substantially reduce cigarette use and target several important subpopulations.

Projected costs of single-payer healthcare financing in the United States: A systematic review of economic analyses.

BACKGROUND: The United States is the only high-income nation without universal, government-funded or -mandated health insurance employing a unified payment system. The US multi-payer system leaves residents uninsured or underinsured, despite overall healthcare costs far above other nations. Single-payer (often referred to as Medicare for All), a proposed policy solution since 1990, is receiving renewed press attention and popular support. Our review seeks to assess the projected cost impact of a single-payer approach. METHODS AND FINDINGS: We conducted our literature search between June 1 and December 31, 2018, without start date restriction for included studies. We surveyed an expert panel and searched PubMed, Google, Google Scholar, and preexisting lists for formal economic studies of the projected costs of single-payer plans for the US or for individual states. Reviewer pairs extracted data on methods and findings using a template. We quantified changes in total costs standardized to percentage of contemporaneous healthcare spending. Additionally, we quantified cost changes by subtype, such as costs due to increased healthcare utilization and savings due to simplified payment administration, lower drug costs, and other factors. We further examined how modeling assumptions affected results. Our search yielded economic analyses of the cost of 22 single-payer plans over the past 30 years. Exclusions were due to inadequate technical data or assuming a substantial ongoing role for private insurers. We found that 19 (86%) of the analyses predicted net savings (median net result was a savings of 3.46% of total costs) in the first year of program operation and 20 (91%) predicted savings over several years; anticipated growth rates would result in long-term net savings for all plans. The largest source of savings was simplified payment administration (median 8.8%), and the best predictors of net savings were the magnitude of utilization increase, and savings on administration and drug costs (R2 of 0.035, 0.43, and 0.62, respectively). Only drug cost savings remained significant in multivariate analysis. Included studies were heterogeneous in methods, which precluded us from conducting a formal meta-analysis. CONCLUSIONS: In this systematic review, we found a high degree of analytic consensus for the fiscal feasibility of a single-payer approach in the US. Actual costs will depend on plan features and implementation. Future research should refine estimates of the effects of coverage expansion on utilization, evaluate provider administrative costs in varied existing single-payer systems, analyze implementation options, and evaluate US-based single-payer programs, as available.

Cigarette Pack Prices and Sales Following Policy Changes in California, 2011-2018.

Objectives. To estimate the combined effect of California's Tobacco 21 law (enacted June 2016) and $2-per-pack cigarette excise tax increase (enacted April 2017) on cigarette prices and sales, compared with matched comparator states.Methods. We used synthetic control methods to compare cigarette prices and sales after the policies were enacted, relative to what we would have expected without the policy reforms. To estimate the counterfactual, we matched pre-reform covariate and outcome trends between California and control states to construct a "synthetic" California.Results. Compared with the synthetic control in 2018, cigarette prices in California were $1.89 higher ($7.86 vs $5.97; P < .001), and cigarette sales were 16.6% lower (19.9 vs 16.6 packs per capita; P < .001). This reduction in sales equates to 153.9 million fewer packs being sold between 2017 and 2018.Conclusions. California's new cigarette tax was largely passed on to consumers. The new cigarette tax, combined with the Tobacco 21 law, have contributed to a rapid and substantial reduction in cigarette consumption in California.

Peer Mentoring and Automated Text Messages for Smoking Cessation: A Randomized Pilot Trial.

INTRODUCTION: Text-messaging programs for smoking cessation, while efficacious, have high dropout rates. To address this problem, we developed and tested the feasibility and early efficacy of a peer-mentoring intervention for smoking cessation provided by former smokers. METHODS: Adult US smokers were recruited nationally into a randomized pilot trial (N = 200), comparing 6-8 weeks of automated text-messaging support (SmokefreeTXT) and automated text support plus personalized texts from a peer mentor who formerly smoked. The primary outcome was biochemically verified 7-day point-prevalence abstinence at 3 months post-quit date, assessed on an intention-to-treat basis (missing = smoking). Self-reported abstinence, program acceptability, user engagement, and user perceptions were also assessed. RESULTS: Biochemically verified abstinence at 3 months was 7.9% (8/101) in the intervention group and 3.0% (3/99) in the control group (adjusted difference 6.5, 95% CI = 0.7% to 12.3%; p = .03). Self-reported abstinence at 3 months was 23.8% (24/101) in the intervention group versus 13.1% (13/99) in the control group (adjusted difference 12.7, 95% CI = 1.2% to 24.1%; p = .03). The intervention had a positive but insignificant effect on overall satisfaction (78.3% vs. 72.9% control group, p = .55). Having a mentor did not significantly alter duration of interaction with the program nor the proportion unsubscribing, although the intervention group reset their quit date with greater frequency (p < .01) and sent more messages (p < .01). CONCLUSIONS: Peer mentoring combined with automated text messages was feasible and acceptable and increased smoking abstinence compared with automated messages alone. The results highlight the promise of this intervention approach and the need for a full-scale evaluation. IMPLICATIONS: Providing quitting assistance by automated text messaging has been shown to increase smoking abstinence. Yet, dropout rates in text-messaging programs are high. No studies have tested the effectiveness of peer mentors who are former smokers as part of a text-messaging intervention, although they represent a promising way to retain, engage, and support smokers. This randomized pilot trial suggests that peer mentors can complement automated text-messaging programs to promote smoking abstinence.