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.

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.

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.

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.

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.

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.

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.

DISPERSION OF AEROSOLIZED BACTERIA FROM ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Transmission of tuberculosis typically requires close and prolonged contact with an infected individual. However, several cases of transmission between elephants and from elephants to humans or other animals without direct contact or over long distances have been reported. Elephants have been shown to be capable of producing aerosolized bacterial droplets, suggesting a possible route of transmission that is magnified by the size and force of the elephant respiratory tract. To investigate the dispersion and viability of aerosolized bacteria generated from the elephant respiratory tract, a pre-existing model with a proxy organism was used. A six-stage Andersen sampler was used to detect the proxy organism, a commensal elephant respiratory bacterium, at different locations around an elephant barn at a zoo. The amount of proxy organism detected at various time points and distances from the elephants indicates they are capable of dispersing viable bacterial aerosols further than humans can. The concentration of these aerosols is dependent on proximity to the elephants and does not remain at a high level for prolonged periods of time. These findings support the model of aerosol-mediated transmission of bacteria from elephants and can be used to improve disease management practices and prevent the spread of pathogens from elephants in zoos and other facilities.

Histological Subtypes and Response to PD-1/PD-L1 Blockade in Advanced Urothelial Cancer: A Retrospective Study.

PURPOSE: Urinary tract cancer can be pure urothelial carcinoma, pure nonurothelial carcinoma or variant urothelial carcinoma (defined here as mixed urothelial carcinoma). Little is known regarding outcomes for patients with variant urothelial carcinoma receiving immune checkpoint inhibitors. We hypothesized that variant urothelial carcinoma does not compromise immune checkpoint inhibitor efficacy in patients with advanced urothelial carcinoma. MATERIALS AND METHODS: We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathological, treatment and outcomes data were collected for patients with advanced urothelial carcinoma who received immune checkpoint inhibitors. Patients were divided into pure vs variant urothelial carcinoma subgroups, with variant urothelial carcinoma further divided by type of variant (ie squamous, neuroendocrine etc). We compared overall response rate using univariate and multivariate logistic regression and progression-free survival and overall survival using Kaplan-Meier and univariate and multivariate Cox proportional hazards. RESULTS: Overall 519 patients were identified, with 395, 406 and 403 included in overall response rate, overall survival and progression-free survival analyses, respectively. Overall response rate to immune checkpoint inhibitors between patients with pure vs variant urothelial carcinoma was comparable (28% vs 29%, p=0.90) without significant differences for individual subtypes vs pure urothelial carcinoma. Median overall survival for patients with pure urothelial carcinoma was 11.0 months vs 10.1 months for variant urothelial carcinoma (p=0.60), but only 4.6 months for patients with neuroendocrine features (9 patients, HR 2.75, 95% CI 1.40-5.40 vs pure urothelial carcinoma, p=0.003). Median progression-free survival was 4.1 months for pure vs 5.2 months for variant urothelial carcinoma (p=0.43) and 3.7 months for neuroendocrine features (HR 1.87, 95% CI 0.92-3.79 vs pure urothelial carcinoma, p=0.09). CONCLUSIONS: Overall response rate to immune checkpoint inhibitors was comparable across histological types. However, overall survival was worse for patients with tumors containing neuroendocrine features. Variant urothelial carcinoma should not exclude patients from receiving immune checkpoint inhibitors.

Conference report on contractures in musculoskeletal and neurological conditions.

Limb contractures are debilitating complications associated with various muscle and nervous system disorders. This report summarizes presentations at a conference at the Shirley Ryan AbilityLab in Chicago, Illinois, on April 19-20, 2018, involving researchers and physicians from diverse disciplines who convened to discuss current clinical and preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, cerebral palsy, and other conditions. Presenters described changes in muscle architecture, activation, extracellular matrix, satellite cells, and muscle fiber sarcomeric structure that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint, and neuronal tissues during contracture development with imaging, molecular, and physiologic approaches. Participants identified the requirement for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development.

ACTIVE (Ability Captured Through Interactive Video Evaluation) workspace volume video game to quantify meaningful change in spinal muscular atrophy.

AIM: To evaluate the utility of Ability Captured Through Interactive Video Evaluation (ACTIVE) scaled scores to quantify meaningful change in individuals with spinal muscular atrophy (SMA) types 2 or 3 due to disease progression or treatment. METHOD: ACTIVE is a custom-designed video game that measures workspace volume (WSV). Participants included 62 individuals with SMA (mean age [SD] 10y 9mo [5y], range 2y 9mo-24y) and 362 frequency-matched controls (mean age [SD] 10y 9mo [3y 6mo], range 3y 2mo-24y 9mo). Participants completed ACTIVE, other traditional assessments, and patient-reported outcomes. Responsiveness to change was evaluated by comparing longitudinal data on untreated participants to those receiving Spinraza. RESULTS: ACTIVE was significantly correlated to the Hammersmith Functional Motor Scales Expanded and Revised Upper Limb Module (ρ=0.85 and ρ=0.92 respectively; p<0.001). Relevance to patients and families was established by strong correlations to the Patient Reported Outcomes Measurement Information System self- and parent proxy-measures of upper extremity ability (ρ=0.63 and ρ=0.70 respectively; p<0.001). Responsiveness to change was demonstrated by significant change in scaled scores after treatment (median 15.9 points, Wilcoxon signed-rank test p<0.01). A preliminary minimum clinically important difference is presented. INTERPRETATION: These results suggest that ACTIVE WSV scores are a meaningful assessment with which to quantify change over time in individuals with SMA types 2 and 3. WHAT THIS PAPER ADDS: Ability Captured Through Interactive Video Evaluation (ACTIVE) quantifies upper extremity function in spinal muscular atrophy. ACTIVE's scaled workspace volume strongly correlates to self- and parent-report of function. ACTIVE quantifies meaningful change after treatment.

HABILIDAD CAPTURADA A TRAVÉS DE LA EVALUACIÓN DE VIDEO INTERACTIVA (ACTIVE) DEL VOLUMEN DE TRABAJO DE VIDEOJUEGO PARA CUANTIFICAR UN CAMBIO SIGNIFICATIVO EN LA ATROFIA MUSCULAR ESPINAL: OBJETIVO: Evaluar la utilidad de la Habilidad Capturada a través de la Evaluación de Video Interactiva (ACTIVE) escalada para cuantificar un cambio significativo en individuos con atrofia muscular espinal (SMA) tipos 2 o 3 debido a la progresión de la enfermedad o el tratamiento. METHOD: ACTIVE es un videojuego diseñado a medida que mide el volumen del espacio de trabajo (WSV). Los participantes incluyeron 62 individuos con SMA (edad media [SD] 10 años 9 meses [5 años], rango 2 años 9 meses - 24 años) y 362 controles de frecuencia correspondiente (edad media [SD] 10 años 9 meses [3 años 6 meses], rango 3 años 2 meses - 24 años 9 meses). Los participantes completaron ACTIVE, otras evaluaciones tradicionales y los resultados informados por pacientes. La capacidad de respuesta al cambio se evaluó comparando los datos longitudinales de los participantes no tratados con los que recibieron Spinraza. RESULTADOS: ACTIVE se correlacionó significativamente con las Escalas de Motoras Funcionales de Hammersmith y el Módulo de Miembro Superior Revisado (Rho = 0,85 y 0,92 respectivamente; p<0,001). La relevancia para los pacientes y las familias se estableció mediante fuertes correlaciones con las medidas aproximadas propias y parentales de la capacidad de la extremidad superior (Rho = 0,63 y 0,70 respectivamente; p<0,001). La capacidad de respuesta al cambio se demostró mediante un cambio significativo en las puntuaciones escaladas después del tratamiento (mediana de 15,9 puntos, prueba de rango con signo de Wilcoxon p<0,01). Se presenta una diferencia clínicamente importante preliminar mínima. INTERPRETACIÓN: Estos resultados sugieren que las puntuaciones ACTIVE WSV son una evaluación significativa con la cual se puede cuantificar el cambio a lo largo del tiempo en individuos con SMA tipos 2 y 3.

HABILIDADE CAPTURADA POR MEIO DE AVALIAÇÃO VÍDEO-INTERATIVA (ACTIVE) DO VOLUME ESPAÇO DE TRABALHO DE VÍDEO GAME PARA QUANTIFICAR MUDANÇA SIGNIFICATIVA EM ATROFIA MUSCULAR ESPINHAL: OBJETIVO: Avaliar a utilidade dos escores escalares da Habilidade capturada por avaliação vídeo-interativa (ACTIVE) para quantificar mudança significativa devido à progressão da doença ou tratamento em indivíduos com atrofia muscular espinhal (AME) tipos 2 ou 3. MÉTODO: ACTIVE é um vídeo game projetado individualmente que mensura o volume do espaço de trabalho (VET). Os participantes incluíram 62 indivíduos com AME (média de idade [DP] 10a 9m [5a], variação de 2a 9m-24a) e 362 controles pareados por frequência (média de idade [DP] 10a 9m [3a 6m], variação de 3a 2m-24a 9m). Os participantes completaram o ACTIVE, outras avaliações tradicionais, e resultados relatados por pacientes. A responsividade à mudança foi avaliada comparando dados longitudinais de pacientes não tratados em relação àqueles recebendo Spinraza. RESULTADOS: ACTIVE foi significativamente correlacionado com as Escalas Motoras Funcinais Hammersmith e o Módulo de Membro superior revisado (Rho=0,85 e 0,92 respectivamente; p<0,001). A relevância para pacientes e famílias foi estabelecida por fortes correlações com o Sistema de medida de informação de resultados relatados por pacientes (medidas auto-relatadas e relatadas por pais) da capacidade do membro superior (Rho=0,63 e 0,70 respectivamente; p<0,001). A responsividade à mudança foi demonstrada por mudanca significativa nos escores escalares após o tratamento (mediana 15,9 pontos, teste de Wilcoxon signed-rank p<0,01). Uma medida preliminar de mínima diferença clinicamente importante é apresentada. INTERPRETAÇÃO: Estes resultados sugerem que os escores de VET ACTIVE são uma avaliação significativa com a qual quantificar mudança com o passar do tempo em indivíduos com AME tipos 2 e 3.

Attention bias to reward predicts behavioral problems and moderates early risk to externalizing and attention problems.

The current study had three goals. First, we replicated recent evidence that suggests a concurrent relation between attention bias to reward and externalizing and attention problems at age 7. Second, we extended these findings by examining the relations between attention and behavioral measures of early exuberance (3 years), early effortful control (4 years), and concurrent effortful control (7 years), as well as later behavioral problems (9 years). Third, we evaluated the role of attention to reward in the longitudinal pathways between early exuberance and early effortful control to predict externalizing and attention problems. Results revealed that attention bias to reward was associated concurrently and longitudinally with behavioral problems. Moreover, greater reward bias was concurrently associated with lower levels of parent-reported effortful control. Finally, attention bias to reward moderated the longitudinal relations between early risk factors for behavioral problems (gender, exuberance, and effortful control) and later externalizing and attention problems, such that these early risk factors were most predictive of behavioral problems for males with a large attention bias to reward. These findings suggest that attention bias to reward may act as a moderator of early risk, aiding the identification of children at the highest risk for later behavioral problems.

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.

BACKGROUND: Merkel-cell carcinoma is an aggressive skin cancer that is linked to exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced Merkel-cell carcinoma often responds to chemotherapy, but responses are transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of interest, because these tumors often express PD-L1, and MCPyV-specific T cells express PD-1. METHODS: In this multicenter, phase 2, noncontrolled study, we assigned adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per kilogram of body weight every 3 weeks. The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Efficacy was correlated with tumor viral status, as assessed by serologic and immunohistochemical testing. RESULTS: A total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. CONCLUSIONS: In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.).

Investigation of a developmental pathway from infant anger reactivity to childhood inhibitory control and ADHD symptoms: interactive effects of early maternal caregiving.

BACKGROUND: ADHD is a neurodevelopmental disorder with a complex pathogenesis. Individual differences in temperamental reactivity - in particular, anger reactivity - are predictive of ADHD. The goal of this study was to examine the moderating (maternal caregiving behaviors; MCB) and mediating (inhibitory control) variables of reactivity using a 9-year multimethod prospective longitudinal design. METHODS: Participants included 291 children (135 male; 156 female) who participated in a larger study of temperament and social-emotional development. Anger reactivity was assessed by observation of facial anger during an arm restraint task, and MCB were observed during a series of semi-structured mother-infant tasks, both at 9 months of age. Inhibitory control was assessed by performance on a go/no-go task at 5 years of age. ADHD symptoms were assessed by parent and teacher report questionnaires at 7 and 9 years, respectively. RESULTS: Anger reactivity and poor inhibitory control were predictive of later ADHD symptoms. Results supported a moderated mediation model, in which the indirect effects of anger reactivity on ADHD symptoms through inhibitory control were conditional on quality of early MCB. Inhibitory control mediated the effect of anger reactivity on ADHD symptoms, but only among children exposed to lower-quality MCB. CONCLUSIONS: Infant anger reactivity exerts a direct effect on later ADHD from infancy, suggesting anger reactivity as a very early indicator of ADHD risk. Higher-quality caregiving did not buffer against the direct risk of anger reactivity on ADHD but did buffer against the indirect risk by reducing the negative effect of anger reactivity on inhibitory control. Thus, in the developmental pathway from anger reactivity to ADHD, more sensitive, less intrusive parenting supports the development of protective mechanisms (i.e. inhibitory control) to remediate ADHD risk.

Infant temperament reactivity and early maternal caregiving: independent and interactive links to later childhood attention-deficit/hyperactivity disorder symptoms.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with origins early in life. There is growing evidence that individual differences in temperament reactivity are predictive of ADHD symptoms, yet little is known about the relations between temperament reactivity in early infancy and later ADHD symptoms or the combined effect of reactivity with early environmental factors on ADHD symptom development. Using a 9-year prospective longitudinal design, this study tested the independent and interactive contributions of infant reactivity and maternal caregiving behaviors (MCB) on parent- and teacher-reported childhood ADHD symptoms. METHODS: Participants included 291 children (135 male; 156 female) who participated in a larger study of temperament and social-emotional development. Reactivity was assessed by behavioral observation of negative affect, positive affect, and motor activity during novel stimuli presentations at 4 months of age. MCB were observed during a series of semistructured mother-infant tasks at 9 months of age. Finally, ADHD symptoms were assessed by parent- and teacher-report questionnaires at 7 and 9 years, respectively. RESULTS: Reactivity was predictive of ADHD symptoms, but results were sex specific. For boys, infant motor activity was positively predictive of later ADHD symptoms, but only at lower quality MCB. For girls, infant positive affect was positively predictive of later ADHD symptoms at lower quality MCB, and-unexpectedly-infant positive affect and motor activity were negatively predictive of later ADHD symptoms at higher quality MCB. CONCLUSIONS: These results point to early parenting as a moderating factor to mitigate temperament-related risk for later ADHD, suggesting this as a potential intervention target to mitigate risk for ADHD among reactive infants.

Social threat attentional bias in childhood: Relations to aggression and hostile intent attributions.

The goal of this study was to examine the ways attentional bias to social threat-measured across multiple attentional processes-is related to both child aggression and a well-established cognitive correlate of aggression (namely, hostile intent attributions). A community sample of 211 children (51% male; 9-12 years; 55% Caucasian) participated in our cross-sectional correlational design. Social threat attentional bias was measured through task performance on dot-probe, attentional shifting, and temporal order judgment tasks; each task measured different attentional processes. Aggression was measured by parent- and child-report. Hostile intent attributions were measured through child responses to vignettes involving peer conflict or rejection. Attentional bias to social threat within early phases of attentional processing (i.e., attentional prioritization; stimuli presented for <200 ms in temporal order judgment task) was significantly and positively related to both aggression and hostile intent attributions. Attentional bias to social threat within attentional orienting (stimuli presented for 500 ms in dot-probe task) was positively and significantly related to hostile intent attributions. Attentional bias to social threat within attentional shifting (stimuli presented for multiple seconds) was not significantly related to aggression or hostile intent attributions. Higher levels of aggression and of hostile intent attributions were associated with an attentional bias to social threat within early, but not later, phases of attentional processing. These results suggest specificity in identifying dysfunctional attentional processes that may underlie aggression and aggression-related cognitive biases.

Elementary school classroom physical activity breaks: student, teacher, and facilitator perspectives.

Current physical activity (PA) guidelines recommend that children accumulate at least 60 min of PA each day, and that adults should collaborate across sectors to increase opportunities for PA. Implementing brief classroom PA breaks (CPABs) is one way to help increase daily PA. The primary purpose of this study was to determine perceptions of a 14-wk CPAB program among elementary school children, in the first through fourth grades ( n = 254), at a suburban elementary school, and their teachers ( n = 18). The CPAB program was implemented by university exercise science students, and student and teacher perceptions were assessed through surveys. The children reported that the CPABs were very fun (86%), provided them with a nice break during the school day (88%), were very good for their health (94%), helped them feel more ready to learn (71%), and learn better (50%). The teachers reported that the students really enjoyed the CPABs (100%), that encouraging students to be physically active was either very important (83%) or important (17%), and that they were either very confident (72%) or confident (28%) that they themselves could lead the CPABs. No teacher reported that the CPABs hindered classroom learning. CPABs appear to be enjoyable to both students and teachers, easy to administer, and supportive of learning. Recommendations for improvements within the present collaboration were minimal and could be easily addressed with firmer entrenchment of the program. This collaboration was beneficial and fun for the vast majority involved, and others are urged to implement similar programs.

Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes.

Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58-153 m, whereas two were minimally improved (5-23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges.

The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease.

The molecular genetic basis that leads to Lewy Body (LB) pathology in 15-20% of Alzheimer disease cases (LBV/AD) was largely unknown. Alpha-synuclein (SNCA) and Leucine-rich repeat kinase2 (LRRK2) have been implicated in the pathogenesis of Parkinson's disease (PD), the prototype of LB spectrum disorders. We tested the association of SNCA variants with LB pathology in AD. We then stratified the SNCA association analyses by LRRK2 genotype. We also investigated the expression regulation of SNCA and LRRK2 in relation to LB pathology. We evaluated the differences in SNCA-mRNA and LRRK2-mRNA levels as a function of LB pathology in the temporal cortex (TC) from autopsy-confirmed LBV/AD cases and AD controls. We further investigated the cis-effect of the LB pathology-associated genetic variants within the SNCA and LRRK2 loci on the mRNA expression of these genes. SNCA SNPs rs3857059 and rs2583988 showed significant associations with increased risk for LB pathology. When the analyses were stratified by LRRK2-rs1491923 genotype, the associations became stronger for both SNPs and an association was also observed with rs2619363. Expression analysis demonstrated that SNCA- and LRRK2-mRNA levels were significantly higher in TC from LBV/AD brains compared with AD controls. Furthermore, SNCA-mRNA expression level in the TC was associated with rs3857059; homozygotes for the minor allele showed significant higher expression. LRRK2-transcript levels were increased in carriers of rs1491923 minor allele. Our findings demonstrated that SNCA contributes to LB pathology in AD patients, possibly via interaction with LRRK2, and suggested that expression regulation of these genes may be the molecular basis underlying the observed LB associations.