A rich and bountiful harvest: Key discoveries in plant cell biology.

The field of plant cell biology has a rich history of discovery, going back to Robert Hooke's discovery of cells themselves. The development of microscopes and preparation techniques has allowed for the visualization of subcellular structures, and the use of protein biochemistry, genetics, and molecular biology has enabled the identification of proteins and mechanisms that regulate key cellular processes. In this review, seven senior plant cell biologists reflect on the development of this research field in the past decades, including the foundational contributions that their teams have made to our rich, current insights into cell biology. Topics covered include signaling and cell morphogenesis, membrane trafficking, cytokinesis, cytoskeletal regulation, and cell wall biology. In addition, these scientists illustrate the pathways to discovery in this exciting research field.

Global collision-risk hotspots of marine traffic and the world's largest fish, the whale shark.

Marine traffic is increasing globally yet collisions with endangered megafauna such as whales, sea turtles, and planktivorous sharks go largely undetected or unreported. Collisions leading to mortality can have population-level consequences for endangered species. Hence, identifying simultaneous space use of megafauna and shipping throughout ranges may reveal as-yet-unknown spatial targets requiring conservation. However, global studies tracking megafauna and shipping occurrences are lacking. Here we combine satellite-tracked movements of the whale shark, Rhincodon typus, and vessel activity to show that 92% of sharks' horizontal space use and nearly 50% of vertical space use overlap with persistent large vessel (>300 gross tons) traffic. Collision-risk estimates correlated with reported whale shark mortality from ship strikes, indicating higher mortality in areas with greatest overlap. Hotspots of potential collision risk were evident in all major oceans, predominantly from overlap with cargo and tanker vessels, and were concentrated in gulf regions, where dense traffic co-occurred with seasonal shark movements. Nearly a third of whale shark hotspots overlapped with the highest collision-risk areas, with the last known locations of tracked sharks coinciding with busier shipping routes more often than expected. Depth-recording tags provided evidence for sinking, likely dead, whale sharks, suggesting substantial "cryptic" lethal ship strikes are possible, which could explain why whale shark population declines continue despite international protection and low fishing-induced mortality. Mitigation measures to reduce ship-strike risk should be considered to conserve this species and other ocean giants that are likely experiencing similar impacts from growing global vessel traffic.

Modeling molecular development of breast cancer in canine mammary tumors.

Understanding the changes in diverse molecular pathways underlying the development of breast tumors is critical for improving diagnosis, treatment, and drug development. Here, we used RNA-profiling of canine mammary tumors (CMTs) coupled with a robust analysis framework to model molecular changes in human breast cancer. Our study leveraged a key advantage of the canine model, the frequent presence of multiple naturally occurring tumors at diagnosis, thus providing samples spanning normal tissue and benign and malignant tumors from each patient. We showed human breast cancer signals, at both expression and mutation level, are evident in CMTs. Profiling multiple tumors per patient enabled by the CMT model allowed us to resolve statistically robust transcription patterns and biological pathways specific to malignant tumors versus those arising in benign tumors or shared with normal tissues. We showed that multiple histological samples per patient is necessary to effectively capture these progression-related signatures, and that carcinoma-specific signatures are predictive of survival for human breast cancer patients. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we provide FREYA, a robust data processing pipeline and statistical analyses framework.

Ethnic differences in metabolic syndrome in high-income countries: A systematic review and meta-analysis.

This review aimed to systematically quantify the differences in Metabolic Syndrome (MetS) prevalence across various ethnic groups in high-income countries by sex, and to evaluate the overall prevalence trends from 1996 to 2022. We conducted a systematic literature review using MEDLINE, Web of Science Core Collection, CINAHL, and the Cochrane Library, focusing on studies about MetS prevalence among ethnic groups in high-income countries. We pooled 23 studies that used NCEP-ATP III criteria and included 147,756 healthy participants aged 18 and above. We calculated pooled prevalence estimates and 95% confidence intervals (CI) using both fixed-effect and random-effect intercept logistic regression models. Data were analysed for 3 periods: 1996-2005, 2006-2009, and 2010-2021. The pooled prevalence of MetS in high-income countries, based on the NCEP-ATP III criteria, was 27.4% over the studied period, showing an increase from 24.2% in 1996-2005 to 31.9% in 2010-2021, with men and women having similar rates. When stratified by ethnicity and sex, ethnic minority women experienced the highest prevalence at 31.7%, while ethnic majority women had the lowest at 22.7%. Notably, MetS was more prevalent in ethnic minority women than men. Among ethnic minorities, women had a higher prevalence of MetS than men, and the difference was highest in Asians (about 15 percentage points). Among women, the prevalence of MetS was highest in Asians (41.2%) and lowest in Blacks/Africans (26.7%). Among men, it was highest in indigenous minority groups (34.3%) and lowest among in Blacks/Africans (19.8%). MetS is increasing at an alarming rate in high-income countries, particularly among ethnic minority women. The burden of MetS could be effectively reduced by tailoring interventions according to ethnic variations and risk profiles.

Perceived Access to Healthcare of Indigenous Peoples in Canada With Rheumatoid Arthritis and Their First-Degree Relatives.

OBJECTIVE: There are complex and interrelated factors that lead to inequitable healthcare delivery in Canada. Many of the factors that underlie these inequities for Canada's geographically dispersed Indigenous peoples remain underexamined. METHODS: A cohort of 831 First Nations (FN) individuals from urban and remote communities were recruited into a longitudinal study of rheumatoid arthritis (RA) risk from 2005 to 2017. Data from each participant's initial enrollment visit were assessed using a survey that captured concerns with healthcare access. RESULTS: We found that remote participants with RA reported poor access compared to remote first-degree relatives (FDRs; P < 0.001); this difference was not observed for urban participants with RA. We observed substantial differences based on sex; female participants perceived access to care to be more difficult than male participants in both urban and remote cohorts (P < 0.001). We also observed that male participants with RA reported poor access to care compared to male FDRs. Importantly, access to care in remote communities appeared to improve over the duration of the study (P = 0.01). In a logistic regression analysis, female sex, remote location, and older age were independent predictors of poor access to care. Predictors of poor access in participants with RA also included female sex, remote location, and older age. CONCLUSION: FN peoples living in remote communities, particularly those with an established RA diagnosis, report more problems accessing health care. Sex-based inequities exist, with FN female individuals reporting greater difficulties in accessing appropriate health care, regardless of RA diagnosis. Addressing these sex-based inequities should be a high priority for improving healthcare delivery.

Population-based study of disease trajectory after radical treatment for high-risk prostate cancer.

OBJECTIVES: To investigate long-term disease trajectories among men with high-risk localized or locally advanced prostate cancer (HRLPC) treated with radical radiotherapy (RT) or radical prostatectomy (RP). MATERIAL AND METHODS: Men diagnosed with HRLPC in 2006-2020, who received primary RT or RP, were identified from the Prostate Cancer data Base Sweden (PCBaSe) 5.0. Follow-up ended on 30 June 2021. Treatment trajectories and risk of death from prostate cancer (PCa) or other causes were assessed by competing risk analyses using cumulative incidence for each event. RESULTS: In total, 8317 men received RT and 4923 men underwent RP. The median (interquartile range) follow-up was 6.2 (3.6-9.5) years. After RT, the 10-year risk of PCa-related death was 0.13 (95% confidence interval [CI] 0.12-0.14) and the risk of death from all causes was 0.32 (95% CI 0.31-0.34). After RP, the 10-year risk of PCa-related death was 0.09 (95% CI 0.08-0.10) and the risk of death from all causes was 0.19 (95% CI 0.18-0.21). The 10-year risks of androgen deprivation therapy (ADT) as secondary treatment were 0.42 (95% CI 0.41-0.44) and 0.21 (95% CI 0.20-0.23) after RT and RP, respectively. Among men who received ADT as secondary treatment, the risk of PCa-related death at 10 years after initiation of ADT was 0.33 (95% CI 030-0.36) after RT and 0.27 (95% CI 0.24-0.30) after RP. CONCLUSION: Approximately one in 10 men with HRLPC who received primary RT or RP had died from PCa 10 years after diagnosis. Approximately one in three men who received secondary ADT, an indication of PCa progression, died from PCa 10 years after the start of ADT. Early identification and aggressive treatment of men with high risk of progression after radical treatment are warranted.

How are socioeconomic inequalities in preterm birth explained by maternal smoking and maternal body mass index: A mediation analysis.

BACKGROUND: Preterm birth affects between 7% and 8% of births in the UK and is a leading cause of infant mortality and childhood disability. Prevalence of preterm birth has been shown to have significant and consistent socioeconomic inequalities. OBJECTIVE: To estimate how much of the association between socioeconomic status (SES) and gestational age at birth is mediated by maternal smoking status and maternal body mass index (BMI). METHODS: Retrospective cohort study of a maternity hospital in the UK. The analysis included all singleton live births between April 2009 and March 2020 to mothers 18 years old and over, between 22 weeks and 43 weeks gestation. We estimate two measures of mediation for four low gestational age categories: (i) The proportion eliminated the percentage of the effect of SES on low gestational age at birth that would be eliminated by removing the mediators, through the Controlled Direct Effects estimated using serial log-binomial regressions; and (ii) The proportion mediated is the percentage of the effect removed by equalising the distribution of the mediators across socioeconomic groups, estimated using Interventional Disparity Measures calculated through Monte Carlo simulations. RESULTS: Overall, 81,219 births were included, with 63.7% low SES. The risk of extremely (0.3% of all births), very (0.7%) and moderately preterm birth (6.3%) was 1.71 (95% Confidence Interval [CI] 1.29, 2.31), 1.43 (95% CI 1.18, 1.73) and 1.26 (95% CI 1.19, 1.34) times higher in the low SES, compared to higher SES respectively. The proportion of this inequality eliminated by removing both maternal smoking and BMI was 43.4% for moderately preterm births. The proportion mediated for smoking was 33.9%, 43.0% and 48.4% respectively. CONCLUSIONS: Smoking during pregnancy is a key mediator of inequalities in preterm birth, representing an area for local action to reduce social inequalities in preterm birth.

Time trends in the use of curative treatment in men 70 years and older with nonmetastatic prostate cancer.

BACKGROUND: Undertreatment of otherwise healthy men in their seventies with prostate cancer has been reported previously. MATERIAL AND METHODS: Using information in a Swedish prostate cancer research database, patterns of management and cancer-specific mortality were compared across age groups in over 70,000 men diagnosed with intermediate- or high-risk nonmetastatic prostate cancer between 2008 and 2020. Crude probabilities of death were estimated non-parametrically. Staging procedures, primary treatment, and cancer death were compared using regression models, adjusting for patient and tumor characteristics. RESULTS: During the study period, the proportion of men treated with curative intent increased in ages 70-74 (intermediate-risk from 45% to 72% and high-risk from 49% to 84%), 75-79 (intermediate-risk from 11% to 52% and high-risk from 12% to 70%), and 80-84 years (intermediate-risk from < 1% to 14% and high-risk from < 1% to 30%). Older age was associated with lower likelihoods of staging investigations and curative treatment, also after adjustment for tumor characteristics and comorbidity. Men treated with curative intent and those initially managed conservatively had lower crude risks of prostate cancer death than men receiving androgen deprivation treatment (ADT). In adjusted analyses, ADT was associated with higher prostate cancer mortality than curative treatment across ages and risk groups. Among men managed conservatively, prostate cancer mortality was higher in ages 70 and above. INTERPRETATION: Use of curative treatment increased substantially in older men with prostate cancer between 2008 and 2020. Our findings suggest reduced age-bias and under-treatment, likely reflecting improved individualized decision-making and adherence to guidelines recommending more active management of older men.

Spin-Restricted Descriptions of Singlet Oxygen Reactions from XMS-CASPT2 Benchmarks.

Reactions of singlet oxygen are numerous, some of which are desired but many are unwanted. Therefore, the ability to correctly predict and interpret this reactivity for complex molecular systems is essential to our understanding of singlet oxygen reactions. DFT is widely used for predicting many reactions but is not suited to degenerate electronic structures; application to isolated singlet oxygen often uses the spin-unrestricted formalism, which results in severe spin contamination. In this work, we demonstrate that spin-restricted DFT can correctly describe the reaction pathway for four prototypical singlet oxygen reactions. By careful benchmarking with XMS-CASPT2, we show that, from the first transition state onward, the degeneracy of the 1Δg state is broken due to differing interactions of the (degenerate) π* orbitals with the organic substrate; this result is well replicated with DFT. These findings demonstrate the utility of using spin-restricted DFT to explore reactions, opening the way to confidently use this computationally efficient method for molecular systems of medium to large organic molecules.

Ambient heat exposure patterns and emergency department visits and hospitalizations among medicare beneficiaries 2008-2019.

OBJECTIVE: To assess the association between ambient heat and all-cause and cause-specific emergency department (ED) visits and acute hospitalizations among Medicare beneficiaries in the conterminous United States. DESIGN: Retrospective cohort study. SETTING: Conterminous US from 2008 and 2019. PARTICIPANTS: 2% random sample of all Medicare fee-for-service beneficiaries eligible for Parts A, B, and D. MAIN OUTCOME MEASURES: All-cause and cause-specific (cardiovascular, renal, and heat-related) ED visits and unplanned hospitalizations were identified using primary ICD-9 or ICD-10 diagnosis codes. We measured the association between ambient temperature - defined as daily mean temperature percentile of summer (June through September) - and the outcomes. Hazard ratios and their associated 95% confidence intervals were estimated using multivariable Cox proportional hazards regression, adjusting for individual level demographics, comorbidities, healthcare utilization factors and zip-code level social factors. RESULTS: Among 809,636 Medicare beneficiaries (58% female, 81% non-Hispanic White, 24% <65), older beneficiaries (aged ≥65) exposed to >95th percentile temperature had a 64% elevated adjusted risk of heat-related ED visits (HR [95% CI], 1.64 [1.46,1.85]) and a 4% higher risk of all-cause acute hospitalization (1.04 [1.01,1.06]) relative to <25th temperature percentile. Younger beneficiaries (aged <65) showed increased risk of heat-related ED visits (2.69 [2.23,3.23]) and all-cause ED visits (1.03 [1.01,1.05]). The associations with heat related events were stronger in males and individuals dually eligible for Medicare and Medicaid. No significant differences were observed by climatic region. We observed no significant relationship between temperature percentile and risk of CV-related ED visits or renal-related ED visits. CONCLUSIONS: Among Medicare beneficiaries from 2008 to 2019, exposure to daily mean temperature ≥ 95th percentile was associated with increased risk of heat-related ED visits, with stronger associations seen among beneficiaries <65, males, and patients with low socioeconomic position. Further longitudinal studies are needed to understand the impact of heat duration, intensity, and frequency on cause-specific hospitalization outcomes.

Social inequalities in child mental health trajectories: a longitudinal study using birth cohort data 12 countries.

BACKGROUND: Social inequalities in child mental health are an important public health concern. Whilst previous studies have examined inequalities at a single time point, very few have used repeated measures outcome data to describe how these inequalities emerge. Our aims were to describe social inequalities in child internalising and externalising problems across multiple countries and to explore how these inequalities change as children age. METHODS: We used longitudinal data from eight birth cohorts containing participants from twelve countries (Australia, Belgium, Denmark, France, Germany, Greece, Italy, Netherlands, Poland, Norway, Spain and the United Kingdom). The number of included children in each cohort ranged from N = 584 (Greece) to N = 73,042 (Norway), with a total sample of N = 149,604. Child socio-economic circumstances (SEC) were measured using self-reported maternal education at birth. Child mental health outcomes were internalising and externalising problems measured using either the Strengths and Difficulties Questionnaire or the Child Behavior Checklist. The number of data collection waves in each cohort ranged from two to seven, with the mean child age ranging from two to eighteen years old. We modelled the slope index of inequality (SII) using sex-stratified multi-level models. RESULTS: For almost all cohorts, at the earliest age of measurement children born into more deprived SECs had higher internalising and externalising scores than children born to less deprived SECs. For example, in Norway at age 2 years, boys born to mothers of lower education had an estimated 0.3 (95% CI 0.3, 0.4) standard deviation higher levels of internalising problems (SII) compared to children born to mothers with high education. The exceptions were for boys in Australia (age 2) and both sexes in Greece (age 6), where we observed minimal social inequalities. In UK, Denmark and Netherlands inequalities decreased as children aged, however for other countries (France, Norway, Australia and Crete) inequalities were heterogeneous depending on child sex and outcome. For all countries except France inequalities remained at the oldest point of measurement. CONCLUSIONS: Social inequalities in internalising and externalising problems were evident across a range of EU countries, with inequalities emerging early and generally persisting throughout childhood.

Building common understanding: seeking consensus and defining social prescribing across contexts - a collective commentary on a Delphi study.

Social prescribing has become a global phenomenon. A Delphi study was recently conducted with 48 social prescribing experts from 26 countries to establish global agreement on the definition of social prescribing. We reflect on the use and utility of the outputs of this work, and where we go from here.

Targeting the Sweet Spot: A Systematic Review With Meta-Analysis of Anterior Versus Posterior Glenohumeral Joint Injections for Adhesive Capsulitis.

OBJECTIVE: To compare clinical outcomes following steroid injections using the anterior and posterior approaches. DESIGN: Systematic review with meta-analysis. SETTING: Embase, Web of Science, and Cochrane Center Register of Controlled Trials were searched for randomized control trials (RCTs) and prospective comparative studies. PATIENTS: Patients with adhesive capsulitis. INTERVENTIONS: Glenohumeral steroid injections using either anterior or posterior approach. MAIN OUTCOME MEASURES: Pain visual analog scale (VAS) and shoulder range of motion (ROM) at 12 weeks, accuracy, and adverse events. Standardized mean difference (SMD) for VAS and weighted mean difference (WMD) for ROMs. RESULTS: We identified 6 RCTs and one prospective comparative study with a total of 468 patients. While there was no difference in pain VAS at 12 weeks between the 2 approaches (SMD, -0.86; 95% CI, -1.76 to 0.04), the anterior approach resulted in greater improvements in external rotation (WMD, 8.08; 95% CI, 0.79-15.38) and abduction (WMD, 6.76; 95% CI, 3.05-10.48) compared with the posterior approach. Subgroup analysis with RCTs that utilized steroid injection with hydrodilatation for both approaches demonstrated greater reduction in pain VAS at 12 weeks with the anterior approach (SMD, -0.52; 95% CI, -0.98 to -0.07). Overall, procedures were well tolerated without major complications. CONCLUSIONS: While pain reduction is similar, the anterior approach may be more beneficial in restoring shoulder external rotation and abduction compared with the posterior approach at 12 weeks. Steroid injection combined with hydrodilatation may further improve pain control when performed with the anterior approach at 12 weeks.

Impact of poverty and adversity on perceived family support in adolescence: findings from the UK Millennium Cohort Study.

Emotional support from family members may have an important effect on adolescent health outcomes, and has been identified as a target for policy to protect against the impacts of poverty and other early life adversities. However, few studies have assessed the extent to which poverty and adversity themselves influence the nature of emotional support that parents can provide to adolescents. We, therefore, aimed to investigate the impact of trajectories of income poverty and family adversities, including parental mental ill health, alcohol misuse and domestic violence across childhood developmental stages on young people's relationships with their families and perceived emotional support received. We analysed longitudinal data on 10,976 children from the nationally representative UK Millennium Cohort study. Exposure trajectories of poverty and family adversities were characterised using group-based multi-trajectory models (age 9 months-14 years). The outcomes were perceived emotional support and quality of family relationships, measured by the three-item Short Social Provisions Scale (SPS-3) and levels of parent-adolescent closeness and conflict, measured at age 14. ORs and 95% CIs were estimated using multivariable logistic regression models, adjusting for potential confounding factors. At age 14, the overall prevalence of low perceived emotional support was 13% (95% CI: 12, 14). Children of mothers with lower socioeconomic status (SES) were more likely to report low emotional support, with a clear social gradient (education-degree plus: 10.3% vs. no qualifications: 15.4%). Compared with children exposed to low levels of poverty and adversity, children in the persistent adversity trajectory groups experienced higher odds of low emotional support and low-quality parent-adolescent relationship; those exposed to both persistent poverty and poor parental mental health were particularly at increased risk of experiencing poor family relationships and low perceived emotional support (adjusted odds ratio 2·2; 95% CI 1·7-2·9). Low perceived emotional support and poor family relationships in adolescence are more prevalent among socially disadvantaged children and adolescents and those experiencing social adversity. Policies to improve levels of family support for UK adolescents should focus on improving modifiable determinants such as child poverty and family mental health.

Distinct trajectories distinguish antigen-specific T cells in peanut-allergic individuals undergoing oral immunotherapy.

BACKGROUND: Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions. OBJECTIVE: This study aimed to determine whether inherent qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT). METHODS: We first performed ex vivo T-cell profiling on peanut-reactive CD154+CD137+ T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4+ T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT. RESULTS: Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6-CRTH2+ and CCR6+CRTH2-). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of TH2A pTeff cells. PnOIT induced elimination of TH2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of TH2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation. CONCLUSION: Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies.

Identification of a Clade-Specific HLA-C*03:02 CTL Epitope GY9 Derived from the HIV-1 p17 Matrix Protein.

Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02 CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope potentially restricted to HLA-C*03:02. Residues E62, T142, and E151 in the HLA-C*03:02 binding groove and positions p3, p6, and p9 on the GY9 epitope are crucial in shaping and stabilizing the epitope binding. Our findings support the growing evidence of the contribution of HLA-C molecules to HIV-1 control and provide a prospect for vaccine strategies.

Temporal Trends in Public Stroke Knowledge, 1995-2021.

BACKGROUND: Outreach campaigns have sought to reduce the burden of stroke by improving knowledge of stroke risk factors (RF) and warning signs (WS). We describe trends in stroke knowledge from 1995 to 2021. METHODS: From 1995 to 2021, 6 separate surveys were conducted in the Greater Cincinnati Northern Kentucky Region. Temporal trends in RF/WS knowledge were analyzed using logistic regression adjusting for Race, sex, age, and education. RESULTS: In 1995, 28.6% of participants (537/1880) could name ≥2 WS, compared with 50.6% (983/1944) in 2021 (trend P<0.0001 after adjustment). In 1995, 44.5% of participants (836/1880) knew ≥2 RF, compared with 56.7% (1103/1944) in 2021 (trend P<0.0001 after adjustment). Although still improved compared with 1995, fewer participants could identify ≥2 RF in 2021 (1103/1944, 56.7%) when compared with 2011 (1287/2036, 63.2%, pairwise P<0.05). This decline in RF knowledge was disproportionately larger in women (odds ratio of 0.67 for knowledge in 2021 compared with 2011 in females, P=0.047 for the interaction between sex and study year). CONCLUSIONS: Although stroke knowledge has overall improved since 1995, there is evidence for lost gains since 2011, particularly in women. Stroke outreach campaigns need ongoing evaluation.

Using Epidemiological Data to Inform Clinical Trial Feasibility Assessments: A Case Study.

BACKGROUND: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. METHODS: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. RESULTS: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0-2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to <6), the number predicted to be eligible for the trial increased to 4%. At the time of trial conclusion, 57% of the enrolled patients qualified only by the modified criteria, and the trial was stopped at an interim analysis that demonstrated efficacy. We estimated that the Wilcoxon rank-sum value for the unadjusted predicted enrollment would not have crossed the threshold for efficacy and the trial not stopped. CONCLUSIONS: Objectively assessing trial inclusion/exclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

Air Pollution and Cardiovascular and Thromboembolic Events in Older Adults With High-Risk Conditions.

Little epidemiologic research has focused on pollution-related risks in medically vulnerable or marginalized groups. Using a nationwide 50% random sample of 2008-2016 Medicare Part D-eligible fee-for-service participants in the United States, we identified a cohort with high-risk conditions for cardiovascular and thromboembolic events (CTEs) and linked individuals with seasonal average zip-code-level concentrations of fine particulate matter (particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5)). We assessed the relationship between seasonal PM2.5 exposure and hospitalization for each of 7 CTE-related causes using history-adjusted marginal structural models with adjustment for individual demographic and neighborhood socioeconomic variables, as well as baseline comorbidity, health behaviors, and health-service measures. We examined effect modification across geographically and demographically defined subgroups. The cohort included 1,934,453 individuals with high-risk conditions (mean age = 77 years; 60% female, 87% White). A 1-µg/m3 increase in PM2.5 exposure was significantly associated with increased risk of 6 out of 7 types of CTE hospitalization. Strong increases were observed for transient ischemic attack (hazard ratio (HR) = 1.039, 95% confidence interval (CI): 1.034, 1.044), venous thromboembolism (HR = 1.031, 95% CI: 1.027, 1.035), and heart failure (HR = 1.019, 95% CI: 1.017, 1.020). Asian Americans were found to be particularly susceptible to thromboembolic effects of PM2.5 (venous thromboembolism: HR = 1.063, 95% CI: 1.021, 1.106), while Native Americans were most vulnerable to cerebrovascular effects (transient ischemic attack: HR = 1.093, 95% CI: 1.030, 1.161).

Trajectories of Child Cognitive and Socioemotional Development and Associations with Adolescent Health in the UK Millennium Cohort Study.

OBJECTIVE: To identify and describe distinct trajectories of cognitive and socioemotional development during childhood and to examine their relationships with adolescent health. STUDY DESIGN: We used group-based multitrajectory modeling applied to longitudinal data on 11 564 children up to age 14 years from the UK Millennium Cohort study to identify trajectories of cognitive and socioemotional development measured using validated instruments. We assessed associations between the derived trajectories and baseline socioeconomic, parental, and school factors using multinomial regression. Logistic regression was used to assess associations between trajectory groups and adolescent health at age 14 and 17 years. RESULTS: Four child development trajectories were identified: "no problems" (76.5%); "late socio-emotional problems" (10.1%); "early cognitive and socioemotional problems" (8.6%); and "persistent cognitive and socioemotional problems" (4.8%). Those in the problem trajectories were more socioeconomically disadvantaged. Compared with the "no problem" trajectory, the "late socioemotional problems" trajectory had increased odds of overweight and mental ill-health at age 14 years of 1.50 (95% CI 1.24-1.81) and 2.51 (2.03-3.10), respectively. For the "persistent problems" group, the OR for overweight was 1.41 (1.04-1.91), and for mental ill-health, 3.01 (2.10-3.30). For both groups, the associations persisted to age 17 years. CONCLUSIONS: In a representative UK cohort, groups of distinct trajectories of cognitive and socioemotional development were identified. Adverse development, if unresolved, can have a negative impact on weight and mental health in adolescence. Socioemotional development was the main driver of the impact on adolescent health and this requires emphasis in child health policy.