Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory Merkel Cell Carcinoma.

Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCRMCC1 that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCRMCC1 (TTCR-MCC1) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFNγ)) with concurrent avelumab. Two patients who received preceding SFRT and IFNγ respectively experienced tumor regression. One experienced regression of 13/14 subcutaneous lesions with 1 'escape' lesion and the other had delayed tumor regression in all lesions after initial progression. Although TTCR-MCC1 cells with an activated phenotype infiltrated tumors including the 'escape' lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT/IFNγ did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows TTCR-MCC1 cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.

Psychological distress and health behaviours in people living with and beyond cancer: a cross-sectional study.

This study aimed to examine whether psychological distress was cross-sectionally associated with meeting World Cancer Research Fund (WCRF) recommendations in people living with and beyond cancer. Participants were adults living with and beyond breast, prostate and colorectal cancer, participating in the baseline wave of the Advancing Survivorship after Cancer Outcomes Trial (ASCOT). Anxiety/depression was assessed using the EQ-5D-5L and dichotomised into any/no problems. WCRF recommendations were assessed via pedometers, 24-h dietary recalls, self-reported alcohol intake (AUDIT-C), and self-reported smoking status. Participants were categorised as meeting WCRF recommendations using the following cut-offs: average daily steps (≥ 10,000/day), average weekly aerobic steps (≥ 15,000/day), fruit and vegetables (≥ 400 g/day), fibre (≥ 30 g/day), red meat (< 500 g/week), processed meat (0 g/day), high calorie food (fat ≤ 33% of total daily energy intake and free sugar ≤ 5% of total daily energy intake), alcohol (≤ 14 units/week) and smoking (non-smoking). A composite health behaviour risk index (CHBRI) was calculated by summing the number of WCRF recommendations met (range: 0-9). Among 1348 participants (mean age = 64 years (SD = 11.4)), 41.5% reported anxiety/depression problems. The mean CHBRI score was 4.4 (SD = 1.4). Anxiety/depression problems were associated with lower odds of meeting WCRF recommendations for average daily steps (odds ratio (OR) = 0.73; 95% CI 0.55, 0.97), but not for any other health behaviour. Psychological distress is associated with lower adherence to WCRF recommendations for physical activity in people living with and beyond cancer. Physical activity may be a mechanism linking psychological distress and poorer outcomes among people living with and beyond cancer, and this should be explored in longitudinal studies.

Azole resistance mechanisms and population structure of the human pathogen Aspergillus fumigatus on retail plant products.

Aspergillus fumigatus is a ubiquitous saprotroph and human-pathogenic fungus that is life-threatening to the immunocompromised. Triazole-resistant A. fumigatus was found in patients without prior treatment with azoles, leading researchers to conclude that resistance had developed in agricultural environments where azoles are used against plant pathogens. Previous studies have documented azole-resistant A. fumigatus across agricultural environments, but few have looked at retail plant products. Our objectives were to determine if azole-resistant A. fumigatus is prevalent in retail plant products produced in the United States (U.S.), as well as to identify the resistance mechanism(s) and population genetic structure of these isolates. Five hundred twenty-five isolates were collected from retail plant products and screened for azole resistance. Twenty-four isolates collected from compost, soil, flower bulbs, and raw peanuts were pan-azole resistant. These isolates had the TR34/L98H, TR46/Y121F/T289A, G448S, and H147Y cyp51A alleles, all known to underly pan-azole resistance, as well as WT alleles, suggesting that non-cyp51A mechanisms contribute to pan-azole resistance in these isolates. Minimum spanning networks showed two lineages containing isolates with TR alleles or the F46Y/M172V/E427K allele, and discriminant analysis of principle components identified three primary clusters. This is consistent with previous studies detecting three clades of A. fumigatus and identifying pan-azole-resistant isolates with TR alleles in a single clade. We found pan-azole resistance in U.S. retail plant products, particularly compost and flower bulbs, which indicates a risk of exposure to these products for susceptible populations and that highly resistant isolates are likely distributed worldwide on these products.IMPORTANCEAspergillus fumigatus has recently been designated as a critical fungal pathogen by the World Health Organization. It is most deadly to people with compromised immune systems, and with the emergence of antifungal resistance to multiple azole drugs, this disease carries a nearly 100% fatality rate without treatment or if isolates are resistant to the drugs used to treat the disease. It is important to determine the relatedness and origins of resistant A. fumigatus isolates in the environment, including plant-based retail products, so that factors promoting the development and propagation of resistant isolates can be identified.

Depressive Symptoms, Socioeconomic Position, and Mortality in Older People Living With and Beyond Cancer.

OBJECTIVE: Evidence shows that higher depressive symptoms are associated with mortality among people living with and beyond cancer (LWBC). However, prior studies have not accounted for a wider range of potential confounders, and no study has explored whether socioeconomic position (SEP) moderates the association. This study aimed to examine the association between depressive symptoms and mortality among people LWBC, and moderation by SEP. METHODS: Participants from the English Longitudinal Study of Aging, diagnosed with cancer and with a measure of depressive symptoms within 4 years after their diagnosis, were included. Elevated depressive symptoms were indicated by a score of ≥3 on the eight-item Center for Epidemiologic Studies Depression Scale. Cox regression models examined associations with all-cause mortality. Competing risk regression examined associations with cancer mortality. RESULTS: In 1352 people LWBC (mean age = 69.6 years), elevated depressive symptoms were associated with a 93% increased risk of all-cause mortality (95% confidence interval = 1.52-2.45) within the first 4 years of follow-up and a 48% increased risk within a 4- to 8-year follow-up (95% confidence interval = 1.02-2.13) after multivariable adjustment. Elevated depressive symptoms were associated with a 38% increased risk of cancer mortality, but not after excluding people who died within 1 year after baseline assessments. There were no interactions between depressive symptoms and SEP. CONCLUSIONS: Elevated depressive symptoms are associated with a greater risk of all-cause mortality among people LWBC within an 8-year follow-up period. Associations between depressive symptoms and cancer mortality might be due to reverse causality.

Associations of self-reported and device-assessed physical activity with fatigue, quality of life, and sleep quality in adults living with and beyond cancer.

BACKGROUND: Greater physical activity is associated with improved outcomes in people living with and beyond cancer. However, most studies in exercise oncology use self-reported measures of physical activity. Few have explored agreement between self-reported and device-based measures of physical activity in people living with and beyond cancer. This study aimed to describe physical activity in adults affected by cancer across self-reported and device-assessed activity, to explore levels of agreement between these measures in terms of their utility for categorizing participants as meeting/not meeting physical activity guidelines, and to explore whether meeting guidelines is associated with fatigue, quality of life, and sleep quality. METHODS: A total of 1348 adults living with and beyond cancer from the Advancing Survivorship Cancer Outcomes Trial completed a survey assessing fatigue, quality of life, sleep quality, and physical activity. The Godin-Shephard Leisure-Time Physical Activity Questionnaire was used to calculate a Leisure Score Index (LSI) and an estimate of moderate-to-vigorous physical activity (MVPA). Average daily steps and weekly aerobic steps were derived from pedometers worn by participants. RESULTS: The percentage of individuals meeting physical activity guidelines was 44.3% using LSI, 49.5% using MVPA, 10.8% using average daily steps, and 28.5% using weekly aerobic steps. Agreement (Cohen's κ) between self-reported and pedometer measures ranged from 0.13 (LSI vs. average daily steps) to 0.60 (LSI vs. MVPA). After adjusting for sociodemographic and health-related covariates, meeting activity guidelines using all measures was associated with not experiencing severe fatigue (odds ratios (ORs): 1.43-1.97). Meeting guidelines using MVPA was associated with no quality-of-life issues (OR = 1.53). Meeting guidelines using both self-reported measures were associated with good sleep quality (ORs: 1.33-1.40). CONCLUSION: Less than half of all adults affected by cancer are meeting physical activity guidelines, regardless of measure. Meeting guidelines is associated with lower fatigue across all measures. Associations with quality of life and sleep differ depending on measure. Future research should consider the impact of physical activity measure on findings, and where possible, use multiple measures.

Fatigue, quality of life and associations with adherence to the World Cancer Research Fund guidelines for health behaviours in 5835 adults living with and beyond breast, prostate and colorectal cancer in England: A cross-sectional study.

BACKGROUND: Many individuals living with and beyond cancer (LWBC) have ongoing quality of life (QoL) issues, including fatigue. The World Cancer Research Fund (WCRF) provides health behaviour recommendations for people LWBC, and there is some evidence linking adherence to these with improved QoL. METHODS: Adults LWBC (specifically breast, colorectal or prostate cancer) completed a survey covering health behaviours (diet, physical activity, alcohol consumption and smoking), fatigue (FACIT-Fatigue Scale, version 4) and a broad measure of QoL (EQ-5D-5L descriptive scale). Participants were categorised as meeting/not meeting WCRF recommendations, using the following cut-offs classified as meeting the guidelines: ≥150 min physical activity/week, fruit and vegetables (≥5 portions/day), fibre (≥30 g fibre per day), free sugar (<5% of total calories from free sugar), fat (<33% total energy), red meat (<500 g/week), processed meat (none), alcohol consumption (<14 units/week) and not a current smoker. Logistic regression analyses explored associations between WCRF adherence and fatigue and QoL issues, controlling for demographic and clinical variables. RESULTS: Among 5835 individuals LWBC (mean age: 67 years, 56% female, 90% white, breast 48%, prostate 32% and colorectal 21%), 22% had severe fatigue and 72% had 1+ issue/s on the EQ-5D-5L. Adhering to physical activity recommendations (odds ratio [OR] = 0.88, confidence interval [CI] = 0.77-0.99), meeting various dietary recommendations (fruit and vegetables OR = 0.79; CI = 0.68-0.91, free sugar OR = 0.85; CI = 0.76-0.96, fat OR = 0.71; CI = 0.62-0.82, red meat OR = 0.65; CI = 0.50-0.85) and not smoking (OR = 0.53, CI = 0.41-0.67) were associated with decreased odds of experiencing severe fatigue. Adhering to physical activity guidelines (OR = 0.71, CI = 0.62-0.82) was also associated with decreased odds of having 1+ QoL issue/s. CONCLUSIONS: Adherence to various WCRF recommendations, particularly the recommendation for physical activity, was associated with less fatigue and better QoL in a large UK cohort of people living with and beyond breast, colorectal or prostate cancer. Multi-component interventions designed to support people LWBC to improve health behaviours, in line with the levels recommended by the WCRF, may also improve QoL.

Toward patient-centered treatment goals for duchenne muscular dystrophy: insights from the "Your Voice" study.

BACKGROUND: Patient-centered research has emerged as critically important for understanding the impact of treatments on key stakeholders. The subjective experience of quality of life (QOL) is increasingly recognized as fundamental to delineating treatment goals. The present study utilized content analysis of qualitative data and quantitative analysis to highlight important domains of disease burden and underlying reasons for their importance, and to characterize goals for new treatments for Duchenne Muscular Dystrophy (DMD). RESULTS: The study sample reflected the perspectives of DMD patients and caregivers representing ambulatory, transitional, and non-ambulatory stages of disability progression (n = 20 per category). Open-ended interviews were content-analyzed and non-parametric statistical tests were used to compare ambulation groups. As patients progressed in disability, the noted DMD burdens reflected some differences in functional areas. While daily functioning and sports/recreation remained the most important priority areas across ambulation groups, "health" became less prominent as the disability progressed from ambulatory to transitional to non-ambulatory phases of disability; whereas relationships became more prominent as one progressed to the non-ambulatory phase from the ambulatory or transitional phases (Kruskall Wallis H = 12.24 and 5.28, p = 0.002 and 0.02, respectively). When asked why their burdens were important to them and how it impacted their or their child's life, self-esteem/confidence was most important for ambulatory patients, and became less prominent for patients in the transitional and non-ambulatory phases of disability (Kruskall Wallis H = 9.46, p = 0.009). In contrast, independence was less important for ambulatory patients, and became increasing prominent for patients in the transitional and non-ambulatory phases of disability (Kruskall Wallis H = 7.35, p = 0.025). Emotional functioning was most prominent for all ambulation groups on their best and worst days. Goals for new DMD treatments focused on functional goals, general QOL goals, and concerns about safety, ease of use, and effectiveness. CONCLUSION: This study provides useful information about treatment goals for DMD from the perspective of patients and their caregivers. It highlights some consistent values across the disability trajectory, as well as introducing an evolution of priorities as the person with DMD becomes more disabled. Results provide a roadmap for patient-centered DMD drug development.

Pericardial Fat, Socioeconomic Status, and Biological Responses to Acute Mental Stress.

OBJECTIVE: Central adiposity is associated with impaired biological responses to mental stress, and socioeconomic status (SES) might moderate this relationship. However, evidence for associations between pericardial fat, a fat depot implicated in the pathogenesis of cardiovascular disease (CVD), with cardiovascular and inflammatory responses to mental stress is lacking, and moderation by SES is unknown. METHODS: The sample was 473 healthy men and women (mean age = 62.8 years) from the Whitehall II study. Cardiovascular and inflammatory responses to laboratory-induced mental stress, consisting of a 5-minute Stroop task and 5-minute mirror tracing task, were assessed. Pericardial fat volume was measured using electron bean computed tomography and adjusted for body surface area. SES was defined by grade of employment within the British civil service (higher/intermediate/lower). RESULTS: Pericardial fat was associated with lower heart rate variability, raised heart rate, plasma interleukin-6, fibrinogen, and C-reactive protein at baseline. Furthermore, greater pericardial fat was associated with lower systolic blood pressure reactivity to mental stress, independent of sociodemographics, smoking status, waist-to-hip ratio, and baseline systolic blood pressure. There were no interactions between pericardial fat and SES for any outcome. CONCLUSIONS: Greater pericardial fat was associated with numerous cardiovascular and inflammatory factors implicated in CVD. It was also related to reduced systolic blood pressure reactivity to acute mental stress, independent of central adiposity and baseline systolic blood pressure. This association did not vary by SES. Reduced systolic blood pressure reactivity to mental stress might contribute to the association between greater pericardial fat and CVD.

Contributions of Friends' Problem Behaviors to Friendship Quality in a Sample of Children with ADHD.

OBJECTIVE: It is often assumed that children with attention-deficit/hyperactivity disorder (ADHD) experience friendship difficulties because of their own problem behaviors. However, friendships are dyadic relationships between two children. This study sought to understand the incremental contributions of friends' problem behaviors to dyadic friendship quality in a clinically diagnosed sample of children with ADHD. METHOD: One hundred and sixty-five dyads consisting of a target child with ADHD and social impairment (age 6-11; 67% male; 72% white) and a reciprocated, real-life friend were recruited. Parents and teachers rated the ADHD symptom severity, externalizing problems, and callous-unemotional (CU) traits of target children and friends. Friendship quality in the dyad was measured with: (a) questionnaires independently completed by target children, their parents, their friends, and the parents of their friends; and (b) observations of child-friend interactions. RESULTS: The severity of ADHD symptoms and externalizing problems (but not CU traits) in target children was associated with more negative friendship quality reported on questionnaires. Adjusting for the corresponding problem behavior in target children, each type of friends' problem behaviors incrementally predicted less positive friendship quality (on questionnaires). Friends' ADHD symptoms and CU traits also incrementally predicted more negative friendship quality (on questionnaires and observations). CONCLUSIONS: Considering problem behaviors in friends of children with ADHD (in addition to those in children with ADHD) may be important for identifying dyads at risk for lower quality friendships. These findings could possibly lead to new directions when designing and evaluating treatments targeting the friendship problems of children with ADHD.

Prospective prediction of developing internalizing disorders in ADHD.

BACKGROUND: Clinical course in attention-deficit/hyperactivity disorder (ADHD) is highly heterogeneous with respect to both core symptoms and associated features and impairment. Onset of comorbid anxiety and mood disorders during later childhood and adolescence is one critical aspect of divergent outcomes in ADHD. Characterizing heterogeneity in onset of anxiety and depression and identifying prospective predictors of these divergent courses may facilitate early identification of the children most at risk. METHODS: A total of 849 children recruited for a case-control study of ADHD development, aged 7-12 years at baseline, completed up to six annual waves of comprehensive clinical and cognitive assessment, including multi-informant behavior ratings, parent semi-structured clinical diagnostic interviews, and measures of executive function (EF). Latent class growth curve analyses (LCGAs) characterized patterns of anxiety and depression over time. Trajectories were predicted from baseline parent-rated child temperament, lab-measured child EF, coded parental criticism, and child-reported self-blame for inter-parental conflict. RESULTS: Latent class growth curve analyses separately identified three trajectories for anxiety and three for depression: persistently high, persistently low, and increasing. Temperamental fear/sadness and irritability were independent predictors that interacted with family characteristics. Baseline parental criticism and self-blame for inter-parental conflict exerted influence but only in the context of low temperamental risk. Better baseline child working memory was associated with delayed onset of depression. CONCLUSIONS: The interaction of baseline child emotional features with EF or family environment predicted divergent courses of both anxiety and depression from middle-childhood to mid-adolescence. Results suggest modifiable risk factors associated with prospective differences in long-term outcomes.

Childhood adversity and cardiometabolic biomarkers in mid-adulthood in the 1958 British birth cohort.

Studies that have examined associations between adverse childhood experiences (ACEs) and cardiometabolic biomarkers in adulthood are limited as they mainly focus on childhood maltreatment. This study aimed to examine the association between a range of prospectively and retrospectively reported ACEs and cardiometabolic biomarkers in mid-adulthood. Multiply-imputed data on 8511 participants from the National Child Development Study (1958 British birth cohort) were used. ACEs were prospectively reported at ages 7, 11 and 16, and retrospectively reported at age 33/44/45. Cardiometabolic outcomes assessed at age 44/45 included glycated haemoglobin (HbA1c), cholesterol (total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)), triglycerides, blood pressure (systolic and diastolic), body mass index, waist circumference and metabolic syndrome. Parental separation/divorce, physical neglect, emotional neglect and psychological abuse were associated with lower HDL cholesterol. Parental offending and physical neglect were associated with higher triglyceride concentrations. Parental offending was also associated with increased HbA1c. Exposure to 2+ (vs. 0) prospective ACEs was associated with lower HDL cholesterol. All these associations were after adjustment for sex and multiple early life factors. To conclude, several individual ACEs are associated with poorer cardiometabolic risk factor profiles in mid-adulthood. Furthermore, exposure to two or more prospective ACEs is associated with lower HDL cholesterol concentrations in mid-adulthood.

The role of partner support for health behaviours in people living with and beyond cancer: A qualitative study.

OBJECTIVE: This study aimed to qualitatively explore how partner support for health behaviours is perceived, received, and utilised in people living with and beyond cancer (LWBC). METHODS: Semi-structured audio interviews were conducted with 24 participants, 15 men and nine women, living with and beyond breast, prostate, and colorectal cancer. Inductive and deductive Thematic Analysis was used to analyse the data. RESULTS: Three key themes with six subthemes were identified relating to partner support for health behaviours: (1) Interdependence (Reciprocity, Overt Control, Influence & Motivation) (2) Concordance (Shared Attitudes & Health Beliefs, Shared Health Behaviour) and (3) Communal Coping (Communal Orientation towards Health and Decision Making, Co-operative Action in Health Behaviour). CONCLUSIONS: Partner support plays a unique and significant role in the health behaviours of people LWBC. Partners play a collaborative role in managing health and facilitating health behaviours, while the high level of concordance in couples may represent a potential barrier to change via the reinforcement of maladaptive health beliefs and behaviours. IMPLICATIONS FOR CANCER SURVIVORS: Overall, findings demonstrate that partners should be considered and included where possible when designing future behaviour change interventions for people LWBC.

Association between depressive symptoms and pericardial fat in healthy older men and women.

Depressive symptoms are associated with increased risk for cardiovascular disease (CVD), and inflammation may contribute to this relationship. Pericardial fat, a highly metabolically active fat depot, is implicated in the pathogenesis of CVD, but its association with depressive symptoms is unclear. This study examined the cross-sectional and longitudinal association between depressive symptoms and pericardial fat over a three-year period. Participants were 543 healthy men and women (mean age = 62.9 years) without history or objective signs of coronary heart disease from the Whitehall II cohort. In men, depressive symptoms were positively associated with pericardial fat at baseline after adjustment for sociodemographics, waist to hip ratio and conventional cardiovascular risk factors. Inflammation, indexed by plasma interleukin 6 concentration, accounted for 17% of this association. Longitudinally, depressive symptoms did not predict pericardial fat three years later in men once baseline levels of pericardial fat were accounted for. No significant associations between depressive symptoms and pericardial fat were found in women. Overall, our findings suggest that greater pericardial fat might be a mechanism by which depressive symptoms are associated with increased risk for CVD in men, and inflammation may also lie on this pathway.

Fatal Bronchopneumonia and Tracheitis in a Green Turtle (Chelonia mydas) Caused by Serratia proteamaculans.

A free-ranging subadult, male green turtle (Chelonia mydas) presented with radiographic evidence of pneumonia and died acutely. On necropsy, the trachea and bronchi were plugged by diphtheritic membranes, comprised of fibrin, necrotic debris, and colonies of bacilli, identified as Serratia proteamaculans. S. proteamaculans, typically considered an opportunistic plant pathogen, has rarely been described as causing disease in animals. This is the first report of S. proteamaculans causing severe necrotizing tracheitis and bronchopneumonia in a reptile.

Exploring the perceived impact of social support on the health behaviours of people living with and beyond cancer during the COVID-19 pandemic: a qualitative study.

PURPOSE: Social support facilitated healthy behaviours in people living with and beyond cancer (LWBC) before the COVID-19 pandemic. Little is known about how social support impacted their health behaviours during the pandemic when social restrictions were imposed. The aim of this study was to qualitatively explore how social support was perceived to impact the health behaviours of people LWBC during the COVID-19 pandemic. METHODS: Semi-structured interviews were conducted via telephone with 24 adults living with and beyond breast, prostate and colorectal cancer. Inductive and deductive framework analysis was used to analyse the data. RESULTS: Five themes developed. These were (1) Companionship and accountability as motivators for physical activity, (2) Social influences on alcohol consumption, (3) Instrumental support in food practices, (4) Informational support as important for behaviour change and (5) Validation of health behaviours from immediate social networks. CONCLUSION: This study described how companionship, social influence, instrumental support, informational support and validation were perceived to impact the health behaviours of people LWBC during the COVID-19 pandemic. Interventions for people LWBC could recommend co-participation in exercise with friends and family; promote the formation of collaborative implementation intentions with family to reduce alcohol consumption; and encourage supportive communication between partners about health behaviours. These interventions would be useful during pandemics and at other times. Government policies to help support clinically extremely vulnerable groups of people LWBC during pandemics should focus on providing access to healthier foods.

A Longitudinal Effectiveness Study of a Child Obesity Electronic Health Record Tool.

BACKGROUND: Primary-care providers, clinic staff, and nurses play an important role in reducing child obesity; yet time restraints and clinical demands compete with effective pediatric weight management and prevention. METHODS: To investigate the potential impact of an electronic health record (EHR) enabled tool to assist primary care teams in addressing child obesity, we conducted a controlled effectiveness study of FitTastic compared with usual care on the BMI pattern of 291 children (2 to 17 years) up to 4 years later. RESULTS: Per χ2 analysis, a greater proportion of children with baseline overweight/obesity in the EHR tool group than the control group had a favorable BMI pattern (32% vs 13%, P = .03). In logistic regression, FitTastic children were more likely than control children to have a favorable BMI pattern at follow-up (OR 3.8, 95% CI 1.1 to 13.2), adjusted for age, gender, race, and parental education. CONCLUSION: Study findings suggest that EHR-enabled tools to assist primary care teams in managing child obesity may be useful for helping to address the weight in children with overweight/obesity, especially in younger children (2 to 5 years). Digital and EHR-enabled technologies may prove useful for partnering health care teams and families in the important tasks of setting positive, family-centered healthy lifestyle behavioral goals and managing child overweight and obesity.

Infant temperament prospectively predicts general psychopathology in childhood.

Recent models of psychopathology suggest the presence of a general factor capturing the shared variance among all symptoms along with specific psychopathology factors (e.g., internalizing and externalizing). However, few studies have examined predictors that may serve as transdiagnostic risk factors for general psychopathology from early development. In the current study we examine, for the first time, whether observed and parent-reported infant temperament dimensions prospectively predict general psychopathology as well as specific psychopathology dimensions (e.g., internalizing and externalizing) across childhood. In a longitudinal cohort (N = 291), temperament dimensions were assessed at 4 months of age. Psychopathology symptoms were assessed at 7, 9, and 12 years of age. A bifactor model was used to estimate general, internalizing, and externalizing psychopathology factors. Across behavioral observations and parent-reports, higher motor activity in infancy significantly predicted greater general psychopathology in mid to late childhood. Moreover, low positive affect was predictive of the internalizing-specific factor. Other temperament dimensions were not related with any of the psychopathology factors after accounting for the general psychopathology factor. The results of this study suggest that infant motor activity may act as an early indicator of transdiagnostic risk. Our findings inform the etiology of general psychopathology and have implications for the early identification for children at risk for psychopathology.

Maternal Emotion Dysregulation Predicts Emotion Socialization Practices and Adolescent Emotion Lability: Conditional Effects of Youth ADHD Symptoms.

Maternal emotional functioning and emotion socialization practices can facilitate or hinder children's emotional development, and youth with symptoms of attention-deficit/hyperactivity disorder (ADHD) are at increased risk for emotion lability. However, little is known about the independent and interactive effects of maternal emotion dysregulation and adolescent ADHD symptoms on maternal emotion socialization and adolescent emotion lability over time. Using secondary data analyses of a longitudinal community sample of youth and their mothers (Nbaseline = 247; 43.7% female), the current study examined direct and indirect effects of maternal emotion dysregulation on adolescent emotion lability via supportive and non-supportive emotion socialization practices as mediators, and the extent to which adolescent ADHD symptoms moderated these longitudinal pathways. Mothers reported on all study constructs. Results showed that non-supportive parenting responses to adolescents' negative emotional expressions partially mediated the association between maternal emotion dysregulation and adolescent emotion lability, and the effect was stronger at higher levels of youth ADHD symptom severity. Results suggest that parent- and youth-level characteristics interact to confer risk for non-supportive emotion socialization practices and adolescent emotion lability. This research contributes uniquely to theory and research on ADHD and emotional functioning across adolescence. Future research should extend this work by utilizing multi-modal assessment.

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.

Genomic comparisons of Escherichia coli ST131 from Australia.

Escherichia coli ST131 is a globally dispersed extraintestinal pathogenic E. coli lineage contributing significantly to hospital and community acquired urinary tract and bloodstream infections. Here we describe a detailed phylogenetic analysis of the whole genome sequences of 284 Australian ST131 E. coli isolates from diverse sources, including clinical, food and companion animals, wildlife and the environment. Our phylogeny and the results of single nucleotide polymorphism (SNP) analysis show the typical ST131 clade distribution with clades A, B and C clearly displayed, but no niche associations were observed. Indeed, interspecies relatedness was a feature of this study. Thirty-five isolates (29 of human and six of wild bird origin) from clade A (32 fimH41, 2 fimH89, 1 fimH141) were observed to differ by an average of 76 SNPs. Forty-five isolates from clade C1 from four sources formed a cluster with an average of 46 SNPs. Within this cluster, human sourced isolates differed by approximately 37 SNPs from isolates sourced from canines, approximately 50 SNPs from isolates from wild birds, and approximately 52 SNPs from isolates from wastewater. Many ST131 carried resistance genes to multiple antibiotic classes and while 41 (14 %) contained the complete class one integron-integrase intI1, 128 (45 %) isolates harboured a truncated intI1 (462-1014 bp), highlighting the ongoing evolution of this element. The module intI1-dfrA17-aadA5-qacEΔ1-sul1-ORF-chrA-padR-IS1600-mphR-mrx-mphA, conferring resistance to trimethoprim, aminoglycosides, quaternary ammonium compounds, sulphonamides, chromate and macrolides, was the most common structure. Most (73 %) Australian ST131 isolates carry at least one extended spectrum ß-lactamase gene, typically blaCTX-M-15 and blaCTX-M-27. Notably, dual parC-1aAB and gyrA-1AB fluoroquinolone resistant mutations, a unique feature of clade C ST131 isolates, were identified in some clade A isolates. The results of this study indicate that the the ST131 population in Australia carries diverse antimicrobial resistance genes and plasmid replicons and indicate cross-species movement of ST131 strains across diverse reservoirs.