Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2.

Why individuals with Down syndrome (DS) are more susceptible to SARS-CoV-2-induced neuropathology remains elusive. Choroid plexus (ChP) plays critical roles in barrier function and immune response modulation and expresses the ACE2 receptor and the chromosome 21-encoded TMPRSS2 protease, suggesting its substantial role in establishing SARS-CoV-2 infection in the brain. To explore this, we established brain organoids from DS and isogenic euploid iPSC that consist of a core of functional cortical neurons surrounded by a functional ChP-like epithelium (ChPCOs). DS-ChPCOs recapitulated abnormal DS cortical development and revealed defects in ciliogenesis and epithelial cell polarity in ChP-like epithelium. We then demonstrated that the ChP-like epithelium facilitates infection and replication of SARS-CoV-2 in cortical neurons and that this is increased in DS. Inhibiting TMPRSS2 and furin activity reduced viral replication in DS-ChPCOs to euploid levels. This model enables dissection of the role of ChP in neurotropic virus infection and euploid forebrain development and permits screening of therapeutics for SARS-CoV-2-induced neuropathogenesis.

Individual and regional differences in the effects of school racial segregation on Black students' health.

Background: School racial segregation in the US has risen steadily since the 1990s, propelled by Supreme Court decisions rolling back the legacy of Brown v. Board. Quasi-experimental research has shown this resegregation harms Black students' health. However, whether individual or family characteristics (e.g., higher family incomes) are protective against segregation's health harms-or whether segregation is more damaging in regions of the US with fewer public sector investments-remains unclear. We leverage the quasi-random timing of school districts being released from Brown-era integration plans to examine heterogeneity in the association between resegregation and Black students' health. Methods & findings: We took an instrumental variables approach, using the timing of integration order releases as an instrument for school segregation and analyzing a pre-specified list of theoretically-motivated modifiers in the Panel Study of Income Dynamics. In sensitivity analyses, we fit OLS models that directly adjusted for relevant covariates. Results suggest resegregation may have been particularly harmful in the South, where districts resegregated more quickly after order releases. We find little evidence that the effects of school segregation differed across family income, gender, or age. Conclusion: The end of court-ordered integration threatens the health of Black communities-especially in the US South. Modestly higher incomes do not appear protective against school segregation's harms. Research using larger samples and alternative measures of school segregation-e.g., between districts, instead of within districts-may further our understanding of segregation's health effects, especially in Northern states.

Superior Induced Pluripotent Stem Cell Generation through Phactr3-Driven Mechanomodulation of Both Early and Late Phases of Cell Reprogramming.

Human cell reprogramming traditionally involves time-intensive, multistage, costly tissue culture polystyrene-based cell culture practices that ultimately produce low numbers of reprogrammed cells of variable quality. Previous studies have shown that very soft 2- and 3-dimensional hydrogel substrates/matrices (of stiffnesses ≤ 1 kPa) can drive ~2× improvements in human cell reprogramming outcomes. Unfortunately, these similarly complex multistage protocols lack intrinsic scalability, and, furthermore, the associated underlying molecular mechanisms remain to be fully elucidated, limiting the potential to further maximize reprogramming outcomes. In screening the largest range of polyacrylamide (pAAm) hydrogels of varying stiffness to date (1 kPa to 1.3 MPa), we have found that a medium stiffness gel (~100 kPa) increased the overall number of reprogrammed cells by up to 10-fold (10×), accelerated reprogramming kinetics, improved both early and late phases of reprogramming, and produced induced pluripotent stem cells (iPSCs) having more naïve characteristics and lower remnant transgene expression, compared to the gold standard tissue culture polystyrene practice. Functionalization of these pAAm hydrogels with poly-l-dopamine enabled, for the first-time, continuous, single-step reprogramming of fibroblasts to iPSCs on hydrogel substrates (noting that even the tissue culture polystyrene practice is a 2-stage process). Comparative RNA sequencing analyses coupled with experimental validation revealed that a novel reprogramming regulator, protein phosphatase and actin regulator 3, up-regulated under the gel condition at a very early time point, was responsible for the observed enhanced reprogramming outcomes. This study provides a novel culture protocol and substrate for continuous hydrogel-based cell reprogramming and previously unattained clarity of the underlying mechanisms via which substrate stiffness modulates reprogramming kinetics and iPSC quality outcomes.

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.

A Unique Delusion with Depression in Early Stage of Neurocognitive Disorder Due to Vascular Disease: Considerations for Clinicians.

As global aging becomes more prominent, neurocognitive disorders (NCD) incidence has increased. Patients with NCD usually have an impairment in one or more cognitive domains, such as attention, planning, inhibition, learning, memory, language, visual perception, and spatial or social skills. Studies indicate that 50-80% of these adults will develop neuropsychiatric symptoms (NPS), such as apathy, depression, anxiety, disinhibition, delusions, hallucinations, and aberrant motor behavior. The progression of NCD and subsequent NPS requires tremendous care from trained medical professionals and family members. The behavioral symptoms are often more distressing than cognitive changes, causing caregiver distress/depression, more emergency room visits and hospitalizations, and even earlier institutionalization. This signifies the need for early identification of individuals at higher risk of NPS, understanding the trajectory of their NCD, and exploring treatment modalities. In this case report and review, we present an 82-year-old male admitted to our facility for new-onset symptoms of depression, anxiety, and persecutory delusions. He has no significant past psychiatric history, and his medical history is significant for extensive ischemic vascular disease requiring multiple surgeries and two episodes of cerebrovascular accident (CVA). On further evaluation, the patient was diagnosed with major NCD, vascular subtype. We discuss differential diagnoses and development of NPS from NCD in order to explain the significance of more thorough evaluation by clinicians for early detection and understanding of NCD prognosis.

Oocyte cryopreservation and reciprocal in vitro fertilization in a transgender man on long term testosterone gender-affirming hormone therapy: a case report.

Objective: To report a successful case of oocyte cryopreservation and subsequent in vitro fertilization (IVF) in a transgender male receiving continued testosterone gender-affirming hormone therapy, followed by reciprocal embryo transfer (ET). Design: A case report of a rare case of fertility preservation in a transgender man with concomitant use of testosterone therapy for 4 years before and during ovarian stimulation. Setting: Private fertility clinic with university affiliation. Patients: A 26-year-old transgender man undergoing oocyte cryopreservation before gender-affirming surgery. Interventions: Fertility preservation using oocyte cryopreservation and IVF with reciprocal fresh ET into a cisfemale partner. Main Outcome Measures: Successful oocyte cryopreservation, oocyte thawing, and reciprocal IVF cycle. Results: Oocyte cryopreservation of 29 mature oocytes. Sixteen mature oocytes survived the thaw, and 12 were fertilized with intracytoplasmic sperm injection. A fresh ET of an advanced blastocyst resulted in a clinical pregnancy and live birth. Conclusions: Fertility preservation with oocyte cryopreservation or IVF with embryo cryopreservation is feasible for patients on continued long-term testosterone gender-affirming therapy. Future studies on egg quality and reproductive outcomes are required. Our case report demonstrates a promising outcome in this patient population.

Evaluation of Changes in Prices and Purchases Following Implementation of Sugar-Sweetened Beverage Taxes Across the US.

Importance: Sugar-sweetened beverage (SSB) taxes are promoted as key policies to reduce cardiometabolic diseases and other conditions, but comprehensive analyses of SSB taxes in the US have been difficult because of the absence of sufficiently large data samples and methods limitations. Objective: To estimate changes in SSB prices and purchases following SSB taxes in 5 large US cities. Design, Setting, and Participants: In this cross-sectional study with an augmented synthetic control analysis, changes in prices and purchases of SSBs were estimated following SSB tax implementation in Boulder, Colorado; Philadelphia, Pennsylvania; Oakland, California; Seattle, Washington; and San Francisco, California. Changes in SSB prices (in US dollars) and purchases (volume in ounces) in these cities in the 2 years following tax implementation were estimated and compared with control groups constructed from other cities. Changes in adjacent, untaxed areas were assessed to detect any increase in cross-border purchases. Data used for this analysis spanned from January 1, 2012, to February 29, 2020, and were analyzed between June 1, 2022, and September 29, 2023. Main Outcomes and Measures: The main outcomes were the changes in SSB prices and volume purchased. Results: Using nutritional information, 5500 unique universal product codes were classified as SSBs, according to tax designations. The sample included 26 338 stores-496 located in treated localities, 1340 in bordering localities, and 24 502 in the donor pool. Prices of SSBs increased by an average of 33.1% (95% CI, 14.0% to 52.2%; P < .001) during the 2 years following tax implementation, corresponding to an average price increase of 1.3¢ per oz and a 92% tax pass-through rate from distributors to consumers. SSB purchases declined in total volume by an average of 33.0% (95% CI, -2.2% to -63.8%; P = .04) following tax implementation, corresponding to a -1.00 price elasticity of demand. The observed price increase and corresponding volume decrease immediately followed tax implementation, and both outcomes were sustained in the months thereafter. No evidence of increased cross-border purchases following tax implementation was found. Conclusions and Relevance: In this cross-sectional study, SSB taxes led to substantial, consistent declines in SSB purchases across 5 taxed cities following price increases associated with those taxes. Scaling SSB taxes nationally could yield substantial public health benefits.

Exploring the cell interactome: deciphering relative impacts of cell-cell communication in cell co-culture using a novel microfluidic device.

The human body is made up of approximately 40 trillion cells in close contact, with the cellular density of individual tissues varying from 1 million to 1 billion cells per cubic centimetre. Interactions between different cell types (termed heterotypic) are thus common in vivo. Communication between cells can take the form of direct cell-cell contact mediated by plasma membrane proteins or through paracrine signalling mediated through the release, diffusion, and receipt of soluble factors. There is currently no systematic method to investigate the relative contributions of these mechanisms to cell behaviour. In this paper, we detail the conception, development and validation of a microfluidic device that allows cell-cell contact and paracrine signalling in defined areas and over a variety of biologically relevant length scales, referred to as the interactome-device or 'I-device'. Importantly, by intrinsic device design features, cells in different regions in the device are exposed to four different interaction types, including a) no heterotypic cell interaction, b) only paracrine signalling, c) only cell-cell direct contact, or d) both forms of interaction (paracrine and cell-cell direct contact) together. The device design was validated by both mathematical modelling and experiments. Perfused stem cell culture over the medium term and the formation of direct contact between cells in the culture chambers was confirmed. The I-device offers significant flexibility, being able to be applied to any combination of adherent cells to determine the relative contributions of different communication mechanisms to cellular outcomes.

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.

Deconstructing heterogeneity of replicative senescence in human mesenchymal stem cells at single cell resolution.

Following prolonged cell division, mesenchymal stem cells enter replicative senescence, a state of permanent cell cycle arrest that constrains the use of this cell type in regenerative medicine applications and that in vivo substantially contributes to organismal ageing. Multiple cellular processes such as telomere dysfunction, DNA damage and oncogene activation are implicated in promoting replicative senescence, but whether mesenchymal stem cells enter different pre-senescent and senescent states has remained unclear. To address this knowledge gap, we subjected serially passaged human ESC-derived mesenchymal stem cells (esMSCs) to single cell profiling and single cell RNA-sequencing during their progressive entry into replicative senescence. We found that esMSC transitioned through newly identified pre-senescent cell states before entering into three different senescent cell states. By deconstructing this heterogeneity and temporally ordering these pre-senescent and senescent esMSC subpopulations into developmental trajectories, we identified markers and predicted drivers of these cell states. Regulatory networks that capture connections between genes at each timepoint demonstrated a loss of connectivity, and specific genes altered their gene expression distributions as cells entered senescence. Collectively, this data reconciles previous observations that identified different senescence programs within an individual cell type and should enable the design of novel senotherapeutic regimes that can overcome in vitro MSC expansion constraints or that can perhaps slow organismal ageing.

Transforming undergraduate laboratory courses with interlinked real-world challenges.

Undergraduate laboratory course components often provide training in various techniques without connections to an interlinked real-world scenario. This article emphasizes the benefits of longitudinal integration of research techniques to enhance learning and emphasize societal relevance. An example of a biomedical engineering challenge involving a new pandemic is described.

Adolescent Total and Mental Health-Related Emergency Department Visits During the COVID-19 Pandemic.

Importance: Previous research has assessed changes in pediatric and adolescent health care utilization during the COVID-19 pandemic; however, less is known regarding how the pandemic affected adolescents' use of emergency care, specifically for mental health (MH). Objective: To determine how adolescents (ages 12-17 years), compared with other age groups, sought help in emergency departments (EDs) in general and for MH conditions during the COVID-19 pandemic. Design and Setting: In this cross-sectional study, National Syndromic Surveillance Program data and the Centers for Disease Control and Prevention Mental Health, version 1, query were used to track patterns in weekly adolescent ED visits by region across the 10 US Department of Health and Human Services regions from January 2019 through December 2021. Data analysis was performed in April and May 2023. Main Outcomes and Measures: Total ED visits, MH-related ED visits, and the proportion of total ED visits that were MH related by week-region. Results: Both weekly regional ED visits and MH-related ED visits dropped after the onset of the pandemic. Because total ED visits dropped more than MH-related ED visits, the proportion of MH-related ED visits increased for the adolescent group. Total ED visits only returned to prepandemic weekly levels (2019: mean [range], 7358 [715-25 908] visits) in the middle of 2021 (overall in 2021: mean [range], 6210 [623-25 777] visits). Mental health-related visits also dropped in 2020 but rebounded to prepandemic weekly levels (2019: mean [range], 634 [56-1703] visits) by the end of 2020 (mean [range], 533 [39-1800] visits). Conclusions and Relevance: This cross-sectional study suggests that families' perceptions of the need for emergent MH care were reduced during the pandemic by less than their perception of the need for emergency care overall. Emergency departments should be equipped to provide critical care specifically for adolescents facing MH emergencies.

Testing mediating pathways between school segregation and health: Evidence on peer prejudice and health behaviors.

School racial segregation is increasingly recognized as a threat to US public health: rising segregation in recent decades has been linked to a range of poor health outcomes for Black Americans. Key theorized mediators of these harms remain underexamined, including experiences of interpersonal and institutional racism driving increased stress, and peers' health behaviors influencing students' own. Using cross-sectional survey data on a national sample of adolescents, we investigated associations between school segregation and these two potential mediating pathways, operationalized as adolescents' perceptions of prejudice from fellow students and the health behaviors of their peers (drinking and smoking). We further investigated whether associations were modified by individual race/ethnicity and school racial composition. Pooling across all schools and students, higher levels of school segregation were associated with decreased perceptions of peer prejudice (OR 0.54, 95% CI = 0.34-0.86), but not with peers' health behaviors. However, this masked important differences by respondents' race/ethnicity and school racial/ethnic composition. In predominantly White schools, school segregation was not associated with Black students' perceptions of peers' prejudice, but higher levels of segregation were associated with increased rates of peers' drinking and smoking. In predominantly non-White schools, in contrast-where most Black students are educated-higher levels of school segregation were not associated with perceived peer prejudice nor unhealthier peer behaviors for Black students (in fact, peers' health behaviors improved). And across both school types, higher levels of district segregation were associated with lower odds of reporting peer prejudice among non-Black students of color. Our findings suggest that the paths between school segregation and poor health depend on the type of school children attend in segregated districts. In schools predominantly serving students of color, structural factors upheld by school segregation-i.e., material, educational, disciplinary, or economic disadvantage-likely dominate over peer behaviors as the primary drivers of segregation's health harms.

Developing a Game (Inner Dragon) Within a Leading Smartphone App for Smoking Cessation: Design and Feasibility Evaluation Study.

BACKGROUND: Several stand-alone smartphone apps have used serious games to provide an engaging approach to quitting smoking. So far, the uptake of these games has been modest, and the evidence base for their efficacy in promoting smoking cessation is still evolving. The feasibility of integrating a game into a popular smoking cessation app is unclear. OBJECTIVE: The aim of this paper was to describe the design and iterative development of the Inner Dragon game within Smoke Free, a smartphone app with proven efficacy, and the results of a single-arm feasibility trial as part of a broad program that seeks to assess the effectiveness of the gamified app for smoking cessation. METHODS: In phase 1, the study team undertook a multistep process to design and develop the game, including web-based focus group discussions with end users (n=15). In phase 2, a single-arm study of Smoke Free users who were trying to quit (n=30) was conducted to assess the feasibility and acceptability of the integrated game and to establish the feasibility of the planned procedures for a randomized pilot trial. RESULTS: Phase 1 led to the final design of Inner Dragon, informed by principles from psychology and behavioral economics and incorporating several game mechanics designed to increase user engagement and retention. Inner Dragon users maintain an evolving pet dragon that serves as a virtual avatar for the users' progress in quitting. The phase-2 study established the feasibility of the study methods. The mean number of app sessions completed per user was 13.8 (SD 13.1; median 8; range 1-46), with a mean duration per session of 5.8 (median 1.1; range 0-81.1) minutes. Overall, three-fourths (18/24, 75%) of the participants entered the Inner Dragon game at least once and had a mean of 2.4 (SD 2.4) sessions of game use. The use of Inner Dragon was positively associated with the total number of app sessions (correlation 0.57). The mean satisfaction score of participants who provided ratings (11/24, 46%) was 4.2 (SD 0.6) on a 5-point scale; however, satisfaction ratings for Inner Dragon were only completed by 13% (3/24) of the participants. CONCLUSIONS: Findings supported further development and evaluation of Inner Dragon as a beneficial feature of Smoke Free. The next step of this study is to conduct a randomized pilot trial to determine whether the gamified version of the app increases user engagement over a standard version of the app.

Patterns of US Mental Health-Related Emergency Department Visits During the COVID-19 Pandemic.

Importance: Numerous studies have shown that the prevalence of mental health (MH) conditions worsened during the COVID-19 pandemic. Further research is needed on this phenomenon over a longer time horizon that considers the increasing trend in MH conditions before the pandemic, after the pandemic onset, and after vaccine availability in 2021. Objective: To track how patients sought help in emergency departments (EDs) for non-MH and MH conditions during the pandemic. Design, Setting, and Participants: This cross-sectional study used administrative data on weekly ED visits and a subset of visits for MH from the National Syndromic Surveillance Program from January 1, 2019, to December 31, 2021. Data were reported from the 10 US Department of Health and Human Services (HHS) regions (Boston, New York, Philadelphia, Atlanta, Chicago, Dallas, Kansas City, Denver, San Francisco, and Seattle) for five 11-week periods. Data analysis was performed in April 2023. Main Outcomes and Measures: Weekly trends in total ED visits, mean MH-related ED visits, and proportion of ED visits for MH conditions were investigated to determine changes in each measure after the pandemic onset. Prepandemic baseline levels were established from 2019 data, and time trends of these patterns were examined in the corresponding weeks of 2020 and 2021. A fixed-effects estimation approach with weekly ED region data by year was used. Results: There were 1570 total observations in this study (52 weeks in 2019, 53 weeks in 2020, and 52 weeks in 2021). Statistically significant changes in non-MH and MH-related ED visits were observed across the 10 HHS regions. The mean total number of ED visits decreased by 45 117 (95% CI, -67 499 to -22 735) visits per region per week (39% decrease; P = .003) in the weeks after the pandemic onset compared with corresponding weeks in 2019. The mean number of ED visits for MH conditions (-1938 [95% CI, -2889 to -987]; P = .003) decreased significantly less (23% decrease) than the mean number of total visits after the onset of the pandemic, increasing the mean (SD) proportion of MH-related ED visits from 8% (1%) in 2019 to 9% (2%) in 2020. In 2021, the mean (SD) proportion decreased to 7% (2%), and the mean number of total ED visits rebounded more than that of mean MH-related ED visits. Conclusions and Relevance: In this study, MH-related ED visits demonstrated less elasticity than non-MH visits during the pandemic. These findings highlight the importance of addressing the provision of adequate MH services, both in acute and outpatient settings.

The role of biomechanical factors in models of intervertebral disc degeneration across multiple length scales.

Low back pain is the leading cause of disability, producing a substantial socio-economic burden on healthcare systems worldwide. Intervertebral disc (IVD) degeneration is a primary cause of lower back pain, and while regenerative therapies aimed at full functional recovery of the disc have been developed in recent years, no commercially available, approved devices or therapies for the regeneration of the IVD currently exist. In the development of these new approaches, numerous models for mechanical stimulation and preclinical assessment, including in vitro cell studies using microfluidics, ex vivo organ studies coupled with bioreactors and mechanical testing rigs, and in vivo testing in a variety of large and small animals, have emerged. These approaches have provided different capabilities, certainly improving the preclinical evaluation of these regenerative therapies, but challenges within the research environment, and compromises relating to non-representative mechanical stimulation and unrealistic test conditions, remain to be resolved. In this review, insights into the ideal characteristics of a disc model for the testing of IVD regenerative approaches are first assessed. Key learnings from in vivo, ex vivo, and in vitro IVD models under mechanical loading stimulation to date are presented alongside the merits and limitations of each model based on the physiological resemblance to the human IVD environment (biological and mechanical) as well as the possible feedback and output measurements for each approach. When moving from simplified in vitro models to ex vivo and in vivo approaches, the complexity increases resulting in less controllable models but providing a better representation of the physiological environment. Although cost, time, and ethical constraints are dependent on each approach, they escalate with the model complexity. These constraints are discussed and weighted as part of the characteristics of each model.

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.

Data envelopment analysis to evaluate the efficiency of tobacco treatment programs in the NCI Moonshot Cancer Center Cessation Initiative.

BACKGROUND: The Cancer Center Cessation Initiative (C3I) is a National Cancer Institute (NCI) Cancer Moonshot Program that supports NCI-designated cancer centers developing tobacco treatment programs for oncology patients who smoke. C3I-funded centers implement evidence-based programs that offer various smoking cessation treatment components (e.g., counseling, Quitline referrals, access to medications). While evaluation of implementation outcomes in C3I is guided by evaluation of reach and effectiveness (via RE-AIM), little is known about technical efficiency-i.e., how inputs (e.g., program costs, staff time) influence implementation outcomes (e.g., reach, effectiveness). This study demonstrates the application of data envelopment analysis (DEA) as an implementation science tool to evaluate technical efficiency of C3I programs and advance prioritization of implementation resources. METHODS: DEA is a linear programming technique widely used in economics and engineering for assessing relative performance of production units. Using data from 16 C3I-funded centers reported in 2020, we applied input-oriented DEA to model technical efficiency (i.e., proportion of observed outcomes to benchmarked outcomes for given input levels). The primary models used the constant returns-to-scale specification and featured cost-per-participant, total full-time equivalent (FTE) effort, and tobacco treatment specialist effort as model inputs and reach and effectiveness (quit rates) as outcomes. RESULTS: In the DEA model featuring cost-per-participant (input) and reach/effectiveness (outcomes), average constant returns-to-scale technical efficiency was 25.66 (SD = 24.56). When stratified by program characteristics, technical efficiency was higher among programs in cohort 1 (M = 29.15, SD = 28.65, n = 11) vs. cohort 2 (M = 17.99, SD = 10.16, n = 5), with point-of-care (M = 33.90, SD = 28.63, n = 9) vs. no point-of-care services (M = 15.59, SD = 14.31, n = 7), larger (M = 33.63, SD = 30.38, n = 8) vs. smaller center size (M = 17.70, SD = 15.00, n = 8), and higher (M = 29.65, SD = 30.99, n = 8) vs. lower smoking prevalence (M = 21.67, SD = 17.21, n = 8). CONCLUSION: Most C3I programs assessed were technically inefficient relative to the most efficient center benchmark and may be improved by optimizing the use of inputs (e.g., cost-per-participant) relative to program outcomes (e.g., reach, effectiveness). This study demonstrates the appropriateness and feasibility of using DEA to evaluate the relative performance of evidence-based programs.

Trends in depression risk before and during the COVID-19 pandemic.

Using 11 years of the U.S. Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System survey data set for 2011 to 2021, we track the evolution of depression risk for U.S. states and territories before and during the COVID-19 pandemic. We use these data in conjunction with unemployment and COVID case data by state and by year to describe changes in the prevalence of self-reported diagnosis with a depressive disorder over time and especially after the onset of COVID in 2020 and 2021. We further investigate heterogeneous associations of depression risk by demographic characteristics. Regression analyses of these associations adjust for state-specific and period-specific factors using state and year-fixed effects. First, we find that depression risk had been increasing in the US in years preceding the pandemic. Second, we find no significant average changes in depression risk at the onset of COVID in 2020 relative to previous trends, but estimate a 3% increase in average depression risk in 2021. Importantly, we find meaningful variation in terms of changes in depression risk during the pandemic across demographic subgroups.

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.