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Military and law enforcement breachers are exposed to many low-level blasts during their training and occupational experiences in which they detonate explosives to force entry into secured structures. There is a concern that exposure to these repetitive blast events in career breachers could result in cumulative neurological effects. This study aimed to determine concentrations of neurofilament light (NF-L), tau, and amyloid-beta 42 (Aβ42) in serum and in neuronal-derived extracellular vesicles (EVs) in an experienced breacher population, and to examine biomarker associations with neurobehavioral symptoms. Thirty-four participants enrolled in the study: 20 experienced breachers and 14 matched military or civilian law enforcement controls. EV tau concentrations were significantly elevated in experienced breachers (0.3301 ± 0.5225) compared to controls (−0.4279 ± 0.7557; F = 10.43, p = 0.003). No statistically significant changes were observed in EV levels of NF-L or Aβ42 or in serum levels of NF-L, tau, or Aβ42 (p’s > 0.05). Elevated EV tau concentrations correlated with increased Neurobehavioral Symptom Inventory (NSI) score in experienced breachers (r = 0.596, p = 0.015) and predicted higher NSI score (F(1,14) = 7.702, p = 0.015, R2 = 0.355). These findings show that neuronal-derived EV concentrations of tau are significantly elevated and associated with neurobehavioral symptoms in this sample of experienced breachers who have a history of many low-level blast exposures.

OBJECTIVES On the basis of the data from school-aged children, there is consistent evidence that there is a prolonged course of auditory development for perceiving speech embedded in competing background sounds. Furthermore, age-related differences are prolonged and pronounced for a two-talker speech masker compared to a speech-shaped noise masker. However, little is known about the course of development during the toddler and preschool years because it is difficult to collect reliable behavioral data from this age range. The goal of this study was to extend our lower age limit to include toddlers and preschoolers to characterize the developmental trajectory for masked speech detection thresholds across childhood. DESIGN Participants were 2- to 15-year-old children (n = 67) and adults (n = 17), all with normal hearing. Thresholds (71%) were measured for detecting a two-syllable word embedded in one of two maskers: speech-shaped noise or two-talker speech. The masker was presented at 55 dB SPL throughout testing. Stimuli were presented to the left ear via a lightweight headphone. Data were collected using an observer-based testing method in which the participant's behavior was judged by an experimenter using a two-interval, two-alternative testing paradigm. The participant's response to the stimulus was shaped by training him/her to perform a conditioned play-based response to the sound. For children, receptive vocabulary and working memory were measured. Data were fitted with a linear regression model to establish the course of development for each masker condition. Appropriateness of the test method was also evaluated by determining if there were age-related differences in training data, inter-rater reliability, or slope or upper asymptote estimates from pooled psychometric functions across different age groups. RESULTS Child and adult speech detection thresholds were poorer in the two-talker masker than in the speech-shaped noise masker, but different developmental trajectories were seen for the two masker conditions. For the speech-shaped noise masker, threshold improved by about 5 dB across the age span tested, with adult-like performance being reached around 10 years of age. For the two-talker masker condition, thresholds improved by about 7 dB between 2.5 and 15 years. However, the linear fit for this condition failed to achieve adult-like performance because of limited data from teenagers. No significant age-related differences were seen in training data, probe hit rate, or inter-rater reliability. Furthermore, slope and upper asymptote estimates from pooled psychometric functions were similar across different child age groups. CONCLUSIONS Different developmental patterns were seen across the two maskers, with more pronounced child-adult differences and prolonged immaturity during childhood for the two-talker masker relative to the speech-shaped noise masker. Our data do not support the idea that there is rapid improvement of masked speech detection thresholds between 2.5 and 5 years of age. This study also highlights that our observer-based method can be used to collect reliable behavioral data from toddlers and preschoolers-a time period where we know little about auditory development.

Combat military and civilian law enforcement personnel may be exposed to repetitive low-intensity blast events during training and operations. Persons who use explosives to gain entry (i.e., breach) into buildings are known as “breachers” or dynamic entry personnel. Breachers operate under the guidance of established safety protocols, but despite these precautions, breachers who are exposed to low-level blast throughout their careers frequently report performance deficits and symptoms to healthcare providers. Although little is known about the etiology linking blast exposure to clinical symptoms in humans, animal studies demonstrate network-level changes in brain function, alterations in brain morphology, vascular and inflammatory changes, hearing loss, and even alterations in gene expression after repeated blast exposure. To explore whether similar effects occur in humans, we collected a comprehensive data battery from 20 experienced breachers exposed to blast throughout their careers and 14 military and law enforcement controls. This battery included neuropsychological assessments, blood biomarkers, and magnetic resonance imaging measures, including cortical thickness, diffusion tensor imaging of white matter, functional connectivity, and perfusion. To better understand the relationship between repetitive low-level blast exposure and behavioral and imaging differences in humans, we analyzed the data using similarity-driven multi-view linear reconstruction (SiMLR). SiMLR is specifically designed for multiple modality statistical integration using dimensionality-reduction techniques for studies with high-dimensional, yet sparse, data (i.e., low number of subjects and many data per subject). We identify significant group effects in these data spanning brain structure, function, and blood biomarkers.

Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigations of blast-related neurotrauma and operational breaching. In this study, military “breachers” were exposed to controlled, low-level blast during a 10-day explosive breaching course. Using an omics approach, we assessed epigenetic, transcriptional, and inflammatory profile changes in blood from operational breaching trainees, with varying levels of lifetime blast exposure, along with daily self-reported symptoms (with tinnitus, headaches, and sleep disturbances as the most frequently reported). Although acute exposure to blast did not confer epigenetic changes, specifically in DNA methylation, differentially methylated regions (DMRs) with coordinated gene expression changes associated with chronic lifetime cumulative blast exposures were identified. The accumulative effect of blast showed increased methylation of PAX8 antisense transcript with coordinated repression of gene expression, which has been associated with sleep disturbance. DNA methylation analyses conducted in conjunction with reported symptoms of tinnitus in the low vs. high blast incidents groups identified DMRS in KCNE1 and CYP2E1 genes. KCNE1 and CYP2E1 showed the expected inverse correlation between DNA methylation and gene expression, which have been previously implicated in noise related hearing loss. Although no significant transcriptional changes were observed in samples obtained at the onset of the training course relative to chronic cumulative blast, we identified a large number of transcriptional perturbations acutely pre- versus post-blast exposure. Acutely, 67 robustly differentially expressed genes (fold change ≥1.5), including UFC1 and YOD1, ubiquitin-related proteins were identified. Inflammatory analyses of cytokines and chemokines revealed dysregulation of MCP-1, GCSF, HGF, MCSF, and RANTES acutely following blast exposure. These data show the importance of an omics approach, revealing that transcriptional and inflammatory biomarkers capture acute low-level blast overpressure exposure, whereas DNA methylation marks encapsulate chronic long-term symptoms.

Purpose One in 59 children is diagnosed with autism spectrum disorder (ASD). Due to overlapping symptoms between hearing loss and ASD, children who are suspected of having ASD require an audiological evaluation to determine their hearing status for the purpose of differential diagnosis. The purpose of this article is twofold: (a) to increase audiologists' knowledge of ASD by discussing the challenges associated with testing and interpreting clinical data for children with ASD or suspected ASD and (b) to provide visual supports that can be used to facilitate audiological assessment. Method Eight children (ages 4–12 years) were recruited as video model participants. Videos were filmed using scripts that used concise and concrete language while portraying common clinical procedures. Using the video models, corresponding visual schedules were also created. Conclusion Although obtaining reliable hearing data from children with ASD is challenging, incorporating visual supports may facilitate testing. Video models and visual schedules have been created and made freely available for download online under a Creative Commons License (Creative Commons–Attribution-NonCommercial-ShareAlike 4.0 International License). Incorporating visual supports during clinical testing has the potential to reduce the child's and family's stress, as well as to increase the probability of obtaining a reliable and comprehensive audiological evaluation. Future research is warranted to determine the effectiveness and feasibility of implementing these tools in audiology clinics. Supplemental Material https://doi.org/10.23641/asha.10086434

To evaluate the impact of the COVID-19 pandemic on Canadian intensive care unit (ICU) workers.Between June and August 2020, we distributed a cross-sectional online survey of ICU workers evaluating the impact of the pandemic, coping strategies, symptoms of post-traumatic stress disorder (PTSD; Impact of Events Scale-Revised), and psychological distress, anxiety, and depression (Kessler Psychological Distress Scale). We performed regression analyses to determine the predictors of psychological symptoms.We analyzed responses from 455 ICU workers (80% women; 67% from Ontario; 279 nurses, 69 physicians, and 107 other healthcare professionals). Respondents felt that their job put them at great risk of exposure (60%), were concerned about transmitting COVID-19 to family members (76%), felt more stressed at work (67%), and considered leaving their job (37%). Overall, 25% had probable PTSD and 18% had minimal or greater psychological distress. Nurses were more likely to report PTSD symptoms (33%) and psychological distress (23%) than physicians (5% for both) and other health disciplines professionals (19% and 14%). Variables associated with PTSD and psychological distress included female sex (beta-coefficient [B], 1.59; 95% confidence interval [CI], 1.20 to 2.10 and B, 3.79; 95% CI, 1.79 to 5.78, respectively; P0.001 for differences in scores across groups) and perceived increased risk due to PPE shortage or inadequate PPE training (B, 1.87; 95% CI, 1.51 to 2.31 and B, 4.88; 95% CI, 3.34 to 6.43, respectively). Coping strategies included talking to friends/family/colleagues (80%), learning about COVID-19 (78%), and physical exercise (68%). Over half endorsed the following workplace strategies as valuable: hospital-provided scrubs, clear communication and protocols by hospitals, knowing their voice is heard, subsidized parking, and gestures of appreciation from leadership.This survey study shows that ICU workers have been impacted by the COVID-19 pandemic with high levels of stress and psychological burden. Respondents endorsed communication, protocols, and appreciation from leadership as helpful mitigating strategies.RéSUMé: OBJECTIF: Évaluer l’impact de la pandémie de COVID-19 sur les travailleurs canadiens des unités de soins intensifs (USI). MéTHODE: Entre juin et août 2020, nous avons fait parvenir un sondage transversal en ligne aux travailleurs des soins intensifs pour évaluer l’impact de la pandémie, les stratégies d’adaptation et les symptômes de stress post-traumatique (SPT; Échelle révisée de l’impact de l’événement - IES-R), ainsi que la détresse psychologique, l’anxiété et la dépression (Échelle de détresse psychologique de Kessler). Nous avons réalisé des analyses de régression pour déterminer les prédicteurs de symptômes psychologiques. RéSULTATS: Nous avons analysé les réponses de 455 travailleurs des soins intensifs (80 % de femmes; 67 % de l’Ontario; 279 infirmières/infirmiers, 69 médecins et 107 autres professionnels de la santé). Les répondants ont estimé que leur emploi les plaçait face à un risque élevé d’exposition (60 %), craignaient de transmettre la COVID-19 aux membres de leur famille (76 %), se sentaient plus stressés au travail (67 %) et avaient envisagé de quitter leur emploi (37 %). Dans l’ensemble, 25 % souffraient probablement d’un SPT et 18 % présentaient une détresse psychologique minimale ou supérieure. Les infirmières et infirmiers étaient plus susceptibles de rapporter des symptômes de SPT (33 %) et de détresse psychologique (23 %) que les médecins (5 % pour les deux) et les professionnels de la santé des autres disciplines (19 % et 14 %). Les variables associées à un SPT et à la détresse psychologique comprenaient le sexe féminin (coefficient bêta [B], 1,59; intervalle de confiance [IC] à 95 %, 1,20 à 2,10 et B, 3,79; IC 95 %, 1,79 à 5,78, respectivement; P0,001 pour les différences de scores entre les groupes) et la perception d’un risque accru en raison des pénuries d’EPI ou d’une formation inadéquate en EPI (B, 1,87; IC 95 %, 1,51 à 2,31 et B, 4,88; IC 95 %, 3,34 à 6,43, respectivement). Les stratégies d’adaptation comprenaient le fait de parler aux amis, à la famille ou aux collègues (80 %), l’acquisition de connaissances concernant la COVID-19 (78 %) et l’exercice physique (68 %). Plus de la moitié ont estimé que les stratégies de travail suivantes étaient utiles : des uniformes fournis par les hôpitaux, une communication et des protocoles clairs de la part des hôpitaux, le fait de savoir que leur voix est entendue, un stationnement subventionné et des gestes d’appréciation de la part des dirigeants. CONCLUSION: Cette étude montre que les travailleurs des soins intensifs ont été touchés par la pandémie de COVID-19 avec des niveaux élevés de stress et de fardeau psychologique. Les répondants ont déclaré que la communication, les protocoles et les gestes d’appréciation de la direction constituaient des stratégies d’atténuation utiles.

Introduction Insufficient sleep increases pain sensitivity in healthy individuals. Additionally, extending sleep (eg, increasing nocturnal sleep time or adding a mid-day nap) has been shown to restore pain sensitivity to baseline levels in sleep deprived/restricted individuals. Whether sleep extension can reduce pain sensitivity beyond baseline levels in non-sleep restricted/deprived individuals remains unknown. Methods In a sample of 27 healthy, pain-free, normally-sleeping individuals (17 males, mean age ∼24 yrs), we examined the impact of five nights of sleep extension on pain sensitivity. Pain threshold (elapsed time until the participant reported pain) and pain tolerance (total time the participant kept the hand submerged in the cold water) were measured using the Cold Pressor Task. Furthermore, we assessed the extent to which self-reported sleep amount in relation to the minimal subjective sleep requirement for adequate performance (sleep credit) was associated with pain sensitivity changes. Results On average individuals slept almost 2 extra hours per night. Our results indicate that sleep extension increases pain tolerance beyond baseline levels. However, sleep extension did not impact pain threshold. We also found that individuals with a smaller sleep credit (ie, those who habitually obtain less sleep than they feel they need) experienced greater increases in pain tolerance after extending sleep. Conclusions The present findings suggest that sleep extension may increase pain tolerance but not pain threshold in healthy individuals who normally sleep the recommended amount. Our findings also support the idea that sleep credit may be a strong indicator of sleep debt in the context of pain sensitivity.

Rationale: If the risk of ventilator-induced lung injury in acute respiratory distress syndrome (ARDS) is causally determined by driving pressure rather than by Vt, then the effect of ventilation w...

BackgroundOptimal end-of-life care requires identifying patients that are near the end of life. The extent to which attending physicians and trainee physicians agree on the prognoses of their patients is unknown. We investigated agreement between attending and trainee physician on the surprise question: “Would you be surprised if this patient died in the next 12 months?”, a question intended to assess mortality risk and unmet palliative care needs.MethodsThis was a multicentre prospective cohort study of general internal medicine patients at 7 tertiary academic hospitals in Ontario, Canada. General internal medicine attending and senior trainee physician dyads were asked the surprise question for each of the patients for whom they were responsible. Surprise question response agreement was quantified by Cohen’s kappa using Bayesian multilevel modeling to account for clustering by physician dyad. Mortality was recorded at 12 months.ResultsSurprise question responses encompassed 546 patients from 30 attending-trainee physician dyads on academic general internal medicine teams at 7 tertiary academic hospitals in Ontario, Canada. Patients had median age 75 years (IQR 60–85), 260 (48%) were female, and 138 (25%) were dependent for some or all activities of daily living. Trainee and attending physician responses agreed in 406 (75%) patients with adjusted Cohen’s kappa of 0.54 (95% credible interval 0.41 to 0.66). Vital status was confirmed for 417 (76%) patients of whom 160 (38% of 417) had died. Using a response of “No” to predict 12-month mortality had positive likelihood ratios of 1.84 (95% CrI 1.55 to 2.22, trainee physicians) and 1.51 (95% CrI 1.30 to 1.72, attending physicians), and negative likelihood ratios of 0.31 (95% CrI 0.17 to 0.48, trainee physicians) and 0.25 (95% CrI 0.10 to 0.46, attending physicians).ConclusionTrainee and attending physician responses to the surprise question agreed in 54% of cases after correcting for chance agreement. Physicians had similar discriminative accuracy; both groups had better accuracy predicting which patients would survive as opposed to which patients would die. Different opinions of a patient’s prognosis may contribute to confusion for patients and missed opportunities for engagement with palliative care services.

Objectives We aimed to evaluate the personal, professional, and psychological impact of the COVID-19 pandemic on hospital workers and their perceptions about mitigating strategies. Design Cross-sectional web-based survey consisting of (1) a survey of the personal and professional impact of the COVID-19 pandemic and potential mitigation strategies, and (2) two validated psychological instruments (Kessler Psychological Distress Scale [K10] and Impact of Events Scale Revised [IES-R]). Regression analyses were conducted to identify the predictors of workplace stress, psychological distress, and post-traumatic stress. Setting and participants Hospital workers employed at 4 teaching and 8 non-teaching hospitals in Ontario, Canada during the COVID-19 pandemic. Results Among 1875 respondents (84% female, 49% frontline workers), 72% feared falling ill, 64% felt their job placed them at great risk of COVID-19 exposure, and 48% felt little control over the risk of infection. Respondents perceived that others avoided them (61%), reported increased workplace stress (80%), workload (66%) and responsibilities (59%), and 44% considered leaving their job. The psychological questionnaires revealed that 25% had at least some psychological distress on the K10, 50% had IES-R scores suggesting clinical concern for post-traumatic stress, and 38% fulfilled criteria for at least one psychological diagnosis. Female gender and feeling at increased risk due to PPE predicted all adverse psychological outcomes. Respondents favoured clear hospital communication (59%), knowing their voice is heard (55%), expressions of appreciation from leadership (55%), having COVID-19 protocols (52%), and food and beverages provided by the hospital (50%). Conclusions Hospital work during the COVID-19 pandemic has had important personal, professional, and psychological impacts. Respondents identified opportunities to better address information, training, and support needs.

The Cleveland Bay horse is one of the oldest equines in the United Kingdom, with pedigree data going back almost 300 years. The studbook is essentially closed and because of this, there are concerns about loss of genetic variation across generations. The breed is one of five equine breeds listed as critical (

Psychiatrists without specialty forensic training routinely encounter forensic questions and treat justice-involved patients, which underscores the importance of adequate forensic training in general psychiatry residency. Some programs may face challenges providing adequate forensic instruction due to a lack of local forensic psychiatrists or other forensic resources. Novel training approaches are needed to fill this gap. This article describes the development, dissemination, and preliminary impact of two online learning modules designed to teach general psychiatry residents about basic forensic psychiatry principles: confidentiality and the duty to third parties. The modules are based on adult learning theory and synthesize clinically relevant vignettes from historically significant legal cases. We disseminated the modules nationally with built-in pre-tests and post-tests. The module responses demonstrate three significant themes: the modules reached learners across the United States; even advanced residents had relatively low subject matter knowledge prior to module completion; and module completion was associated with a significant improvement in resident learners' knowledge of these two topics. This work shows one potential avenue for filling gaps in forensic education within general psychiatry training, although further studies are needed to appreciate the impact of such educational interventions on clinical practice.

A corpus of stimuli has been collected to support the use of common materials across research laboratories to examine school-aged children's word recognition in speech maskers. The corpus includes (1) 773 monosyllabic words that are known to be in the lexicon of 5- and 6-year-olds and (2) seven masker passages that are based on a first-grade child's writing samples. Materials were recorded by a total of 13 talkers (8 women; 5 men). All talkers recorded two masker passages; 3 talkers (2 women; 1 man) also recorded the target words. The annotated corpus is freely available online for research purposes.

A unique cohort of military personnel exposed to isolated blast was studied to explore acute peripheral cytokine levels, with the aim of identifying blast-specific biomarkers. Several cytokines, including interleukin (IL) 6, IL-10 and tumor necrosis factor alpha (TNFα) have been linked to pre-clinical blast exposure, but remained unstudied in clinical blast exposure. To address this gap, blood samples from 62 military personnel were obtained at baseline, and daily, during a 10-day blast-related training program; changes in the peripheral concentrations of IL-6, IL-10 and TNFα were evaluated using an ultrasensitive assay. Two groups of trainees were matched on age, duration of military service, and previous history of blast exposure(s), resulting in moderate blast cases and no/low blast controls. Blast exposures were measured using helmet sensors that determined the average peak pressure in pounds per square inch (psi). Moderate blast cases had significantly elevated concentrations of IL-6 (F1,60 = 18.81, p

Closed-head concussive injury is one of the most common causes of traumatic brain injury (TBI). Isolated concussions frequently produce acute neurological impairments, and individuals typically recover spontaneously within a short time frame. In contrast, brain injuries resulting from multiple concussions can result in cumulative damage and elevated risk of developing chronic brain pathologies. Increased attention has focused on identification of diagnostic markers that can prognostically serve as indices of brain health after injury, revealing the temporal profile of vulnerability to a second insult. Such markers may demarcate adequate recovery periods before concussed patients can return to required activities. We developed a noninvasive closed-head impact model that captures the hallmark symptoms of concussion in the absence of gross tissue damage. Animals were subjected to single or repeated concussive impact and examined using a battery of neurological, vestibular, sensorimotor, and molecular metrics. A single concussion induced transient, but marked, acute neurological impairment, gait alterations, neuronal death, and increased glial fibrillary acidic protein (GFAP) expression in brain tissue. As expected, repeated concussions exacerbated sensorimotor dysfunction, prolonged gait abnormalities, induced neuroinflammation, and upregulated GFAP and tau. These animals also exhibited chronic functional neurological impairments with sustained astrogliosis and white matter thinning. Acute changes in molecular signatures correlated with behavioral impairments, whereas increased times to regaining consciousness and balance impairments were associated with higher GFAP and neuroinflammation. Overall, behavioral consequences of either single or repeated concussive impact injuries appeared to resolve more quickly than the underlying molecular, metabolic, and neuropathological abnormalities. This observation, which is supported by similar studies in other mTBI models, underscores the critical need to develop more objective prognostic measures for guiding return-to-play decisions.

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.

Aims Epidemiological evidence suggests that adipokines may be associated with the onset of type 2 diabetes, but the evidence to date is limited and inconclusive. This study examined the association between adiponectin and leptin and the subsequent diagnosis of type 2 diabetes in a UK population based cohort of non-diabetic middle-aged men. Methods Baseline serum levels of leptin and adiponectin were measured in 1839 non-diabetic men aged 50–60 years who were participating in the prospective population-based PRIME study. Over a mean follow-up of 14.7 years, new cases of type 2 diabetes were determined from self-reported clinical information with subsequent validation by general practitioners. Results 151 Participants developed type 2 diabetes during follow-up. In Cox regression models adjusted for age, men in the top third of the leptin distribution were at increased risk (hazard ratio (HR) 4.27, 95% CI 2.67–6.83) and men in the top third of the adiponectin distribution at reduced risk (HR 0.24, 95% CI 0.14–0.42) relative to men in the bottom third. However, significance was lost for leptin after additional adjustment for BMI, waist to hip ratio, lifestyle factors and biological risk factors, including C-reactive protein (CRP). Further adjustment for HOMA-IR also resulted in loss of significance for adiponectin. Conclusions This study provides evidence that adipokines are associated with men’s future type 2 diabetes risk but not independently of other risk factors.

Purpose It is challenging to collect reliable behavioral data from toddlers and preschoolers. Consequently, we have significant gaps in our understanding of how auditory development unfolds during this time period. One method that appears to be promising is an observer-based procedure that uses conditioned, play-based responses ( Bonino & Leibold, 2017 ). In order to evaluate the quality of data obtained with this method, this study presented a suprathreshold signal to determine the number of trials 2- to 7-year-old children could complete, as well as the associated hit rate and observer confidence. Method Participants were 23 children (2–7 years old). Children were taught to perform a play-based motor response when they detected the 1000-Hz warble tone signal (at 30 dB SPL). An observer evaluated children's behavior using a 2-interval, 2-alternative testing paradigm. Testing was terminated after 100 trials or earlier, if signs of habituation were observed. Results Data were successfully collected from 22 of the 23 children. Of the 22 children, all but 1 child completed 100 trials. Overall hit rate was high (0.88–1.0; M = 0.94) and improved with listener age. Hit rate was stable across the test session. Strong agreement was seen between the correctness of the response and the observer's confidence in the judgment. Conclusion Results of this study confirm that the 2-interval, observer-based procedure described in this article is a powerful tool for measuring detection and discrimination abilities in young children. Future research will (a) evaluate coder reliability and (b) examine stability of performance across a test session when the signal intensity is manipulated. Supplemental Material https://doi.org/10.23641/asha.8309273

The association between dietary patterns (DP) and prevalence of hearing loss in men enrolled in the Caerphilly Prospective Study was investigated. During 1979–1983, the study recruited 2512 men aged 45–59 years. At baseline, dietary data were collected using a semi-quantitative FFQ, and a 7-d weighed food intake (WI) in a 30 % subsample. Five years later, pure-tone unaided audiometric threshold was assessed at 0·5, 1, 2 and 4 kHz. Principal component analysis (PCA) identified three DP and multiple logistic and ordinal logistic regression models examined the association with hearing loss (defined as pure-tone average of frequencies 0·5, 1, 2 and 4 kHz >25 dB). Traditional, healthy and high-sugar/low-alcohol DP were found with both FFQ and WI data. With the FFQ data, fully adjusted models demonstrated significant inverse association between the healthy DP and hearing loss both as a dichotomous variable (OR=0·83; 95 % CI 0·77, 0·90; PPPP=0·02) and as an ordinal variable (OR=1·17; 95 % CI 1·03, 1·33; P=0·02). A healthy DP was significantly and inversely associated with hearing loss in older men. The role of diet in age-related hearing loss warrants further investigation.

Background Injury causes significant morbidity and mortality that is sometimes attributed to testosterone and violence. We hypothesized that prescribed testosterone might be associated with the subsequent risk of serious injury. Methods We conducted a self-matched individual-patient exposure-crossover analysis comparing injury risks before and after initiation of testosterone. We selected adults treated with testosterone in Ontario, Canada, from October 1, 2012, to October 1, 2017 (enrollment) and continued until October 1, 2018 (follow-up). The primary outcome was defined as an acute traumatic event that required emergency medical care. Results A total of 64,386 patients were treated with testosterone of whom 89% were men with a median age of 52 years. We identified 34,439 serious injuries during the baseline interval before starting testosterone (584 per month) and 7349 serious injuries during the subsequent interval after starting testosterone (565 per month). Rates of injuries were substantially above the population norm in both intervals with no significant increased risk after starting testosterone (relative risk = 1.00; 95% confidence interval: 0.96-1.04, P = 0.850). The unchanged risk extended to diverse patients, was observed for different formulations and applied to all injury mechanisms. In contrast, testosterone treatment was associated with a 48% increased risk of a thromboembolic event (relative risk = 1.48; 95% confidence interval: 1.25-1.74, P Conclusions Testosterone treatment was associated with a substantial baseline risk of serious injury that did not increase further after starting therapy. Physicians prescribing testosterone could consider basic safety reminders to mitigate injury risks.

Aims: As promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations. Methods and results: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)-Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9 mg/dL) compared to central (median 7.9 mg/dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere-Terpstra test P&thinsp

The current study extended limited prior work on polysubstance use among youth in the child welfare system (CWS) by addressing their potentially greater risk of engaging in polysubstance use, the causes of interpersonal variation in use, and changes in use over time, particularly at later points of involvement in the CWS. Using longitudinal data from the National Survey of Child and Adolescent Well-Being (n = 1,178), a series of time-invariant and time-varying demographic and contextual factors were explored to assess their role both overall and at unique points of involvement in the CWS. A series of unconditional and conditional curve-of-factor models were estimated and results indicated that time-invariant characteristics of ethnicity and gender were not related to polysubstance use. Time-variant characteristics of age and placement were associated with polysubstance use and highlighted the dynamic nature of age as a risk factor. Out-of-home placement was protective against later substance use for youth who had been removed from contexts with their original caretaker where there were higher levels of reported violence. Our results suggest that in the child welfare population, the modeling of multiple substances rather than a single substance in isolation is more informative because it yields information on the confluence of behaviors that tend to occur and evolve together.

Autoimmune profiling in rats revealed the antioxidant enzyme, peroxiredoxin 6 (PRDX6), as a target for autoantibodies evoked in response to traumatic brain injury (TBI). Consistent with this proposal, immunohistochemical analysis of rat cerebral cortex demonstrated that PRDX6 is highly expressed in the perivascular space, presumably contained within astrocytic foot processes. Accordingly, an immunosorbent electrochemiluminescence assay was developed for investigating PRDX6 in human samples. PRDX6 was found to be measurable in human blood and highly expressed in human cerebral cortex and platelets. Circulating levels of PRDX6 were elevated fourfold over control values 4 to 24 h following mild-to-moderate TBI. These findings suggest that PRDX6 may serve as a biomarker for TBI and that autoimmune profiling is a viable strategy for the discovery of novel TBI biomarkers.

We report results from the second annual screening round (T1) of Manchester’s ‘Lung Health Check’ pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.

This study examined the factor structure of the Self-Compassion Scale (SCS) using secondary data drawn from 20 samples (N = 11,685)-7 English and 13 non-English-including 10 community, 6 student, 1 mixed community/student, 1 meditator, and 2 clinical samples. Self-compassion is theorized to represent a system with 6 constituent components: self-kindness, common humanity, mindfulness and reduced self-judgment, isolation and overidentification. There has been controversy as to whether a total score on the SCS or if separate scores representing compassionate versus uncompassionate self-responding should be used. The current study examined the factor structure of the SCS using confirmatory factor analyses (CFA) and Exploratory Structural Equation Modeling (ESEM) to examine 5 distinct models: 1-factor, 2-factor correlated, 6-factor correlated, single-bifactor (1 general self-compassion factor and 6 group factors), and 2-bifactor models (2 correlated general factors each with 3 group factors representing compassionate or uncompassionate self-responding). Results indicated that a 1- and 2-factor solution to the SCS had inadequate fit in every sample examined using both CFA and ESEM, whereas fit was excellent using ESEM for the 6-factor correlated, single-bifactor and correlated 2-bifactor models. However, factor loadings for the correlated 2-bifactor models indicated that 2 separate factors were not well specified. A general factor explained 95% of the reliable item variance in the single-bifactor model. Results support use of the SCS to examine 6 subscale scores (representing the constituent components of self-compassion) or a total score (representing overall self-compassion), but not separate scores representing compassionate and uncompassionate self-responding. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men. Methods: In our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes. Findings: Individual participant-level data were analysed from 980793 adults. During 9 center dot 8 million person-years of follow-up, among participants aged between 35 and 89 years, 19686 (25 center dot 6%) of 76965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2 center dot 10, 95% CI 1 center dot 97-2 center dot 24) and tripled risk among women (3 center dot 00, 2 center dot 71-3 center dot 33; x(2) test for heterogeneity p

SUMMARY: MR imaging of high-altitude cerebral edema shows reversible WM edema, especially in the corpus callosum and subcortical WM. Recent studies have revealed hemosiderin deposition in WM long after high-altitude cerebral edema has resolved, providing a high-altitude cerebral edema “footprint.” We wished to determine whether these microbleeds are present acutely and also describe the evolution of all MR imaging findings. In 8 patients with severe high-altitude cerebral edema, we obtained 26 studies: 18 with 3T and 8 with 1.5T scanners, during the acute stage, recovery, and follow-up in 7 patients and acutely in 1 patient. Imaging confirmed reversible cytotoxic and vasogenic WM edema that unexpectedly worsened the first week during clinical improvement before resolving. The 3T SWI, but not 1.5T imaging, showed extensive microbleeds extending beyond areas of edema seen acutely, which persisted and with time coalesced. These findings support cytotoxic and vasogenic edema leading to capillary failure/leakage in the pathophysiology of high-altitude cerebral edema and provide imaging correlation to the clinical course.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55–74 years, were invited to ‘lung health checks’ (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Objectives To investigate the effects of caffeine on psychomotor vigilance and sleepiness during sleep restriction and following subsequent recovery sleep. Methods Participants were N = 48 healthy good sleepers. All participants underwent five nights of sleep satiation (time-in-bed [TIB]: 10 hours), followed by five nights of sleep restriction (TIB: 5 hours), and three nights of recovery sleep (TIB: 8 hours) in a sleep laboratory. Caffeine (200 mg) or placebo was administered in the form of chewing gum at 08:00 am and 12:00 pm each day during the sleep restriction phase. Participants completed hourly 10-minute psychomotor vigilance tests and a modified Maintenance of Wakefulness Test approximately every 4 hours during the sleep restriction and recovery phases. Results Caffeine maintained objective alertness compared to placebo across the first 3 days of sleep restriction, but this effect was no longer evident by the fourth day. A similar pattern of results was found for Maintenance of Wakefulness Test sleep latencies, such that those in the caffeine group (compared to placebo) did not show maintenance of wakefulness relative to baseline after the second night of restriction. Compared to placebo, participants in the caffeine condition displayed slower return to baseline in alertness and wakefulness across the recovery sleep period. Finally, the caffeine group showed greater N3 sleep duration during recovery. Conclusions Caffeine appears to have limited efficacy for maintaining alertness and wakefulness across 5 days of sleep restriction. Perhaps more importantly, there may be recovery costs associated with caffeine use following conditions of prolonged sleep loss.

Importance People who immigrate face unique health literacy, communication, and system navigation challenges, and they may have diverse preferences that influence end-of-life care. Objective To examine end-of-life care provided to immigrants to Canada in the last 6 months of their life. Design, Setting, and Participants This population-based cohort study (April 1, 2004, to March 31, 2015) included 967 013 decedents in Ontario, Canada, using validated linkages between health and immigration databases to identify immigrant (since 1985) and long-standing resident cohorts. Exposures All decedents who immigrated to Canada between 1985 and 2015 were classified as recent immigrants, with subgroup analyses assessing the association of time since immigration, and region of birth, with end-of-life care. Main Outcomes and Measures Location of death and intensity of care received in the last 6 months of life. Analysis included modified Poisson regression with generalized estimating equations, adjusting for age, sex, socioeconomic position, causes of death, urban and rural residence, and preexisting comorbidities. Results Among 967 013 decedents of whom 47 514 (5%) immigrated since 1985, sex, socioeconomic status, urban (vs rural) residence, and causes of death were similar, while long-standing residents were older than immigrant decedents (median [interquartile range] age, 75 [58-84] vs 80 [68-87] years). Recent immigrant decedents were overall more likely to die in intensive care (15.6% vs 10.0%; difference, 5.6%; 95% CI, 5.2%-5.9%) after adjusting for differences in age, sex, income, geography, and cause of death (relative risk, 1.30; 95% CI, 1.27-1.32). In their last 6 months of life, recent immigrant decedents experienced more intensive care admissions (24.9% vs 19.2%; difference, 5.7%; 95% CI, 5.3%-6.1%), hospital admissions (72.1% vs 68.2%; difference, 3.9%; 95% CI, 3.5%-4.3%), mechanical ventilation (21.5% vs 13.6%; difference, 7.9%; 95% CI, 7.5%-8.3%), dialysis (5.5% vs 3.4%; difference, 2.1%; 95% CI, 1.9%-2.3%), percutaneous feeding tube placement (5.5% vs 3.0%; difference, 2.5%; 95% CI, 2.3%-2.8%), and tracheostomy (2.3% vs 1.1%; difference, 1.2%; 95% CI, 1.1%-1.4%). Relative risk of dying in intensive care for recent immigrants compared with long-standing residents varied according to recent immigrant region of birth from 0.84 (95% CI, 0.74-0.95) among those born in Northern and Western Europe to 1.96 (95% CI, 1.89-2.05) among those born in South Asia. Conclusions and Relevance Among decedents in Ontario, Canada, recent immigrants were significantly more likely to receive aggressive care and to die in an intensive care unit compared with other residents. Further research is needed to understand the mechanisms behind this association.

To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls.Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]).Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite.Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings.

Discrimination statistics describe the ability of a survival model to assign higher risks to individuals who experience earlier events: examples are Harrell's C-index and Royston and Sauerbrei's D, which we call the D-index. Prognostic covariates whose distributions are controlled by the study design (e.g. age and sex) influence discrimination and can make it difficult to compare model discrimination between studies. Although covariate adjustment is a standard procedure for quantifying disease-risk factor associations, there are no covariate adjustment methods for discrimination statistics in censored survival data.To develop extensions of the C-index and D-index that describe the prognostic ability of a model adjusted for one or more covariate(s).We define a covariate-adjusted C-index and D-index for censored survival data, propose several estimators, and investigate their performance in simulation studies and in data from a large individual participant data meta-analysis, the Emerging Risk Factors Collaboration.The proposed methods perform well in simulations. In the Emerging Risk Factors Collaboration data, the age-adjusted C-index and D-index were substantially smaller than unadjusted values. The study-specific standard deviation of baseline age was strongly associated with the unadjusted C-index and D-index but not significantly associated with the age-adjusted indices.The proposed estimators improve meta-analysis comparisons, are easy to implement and give a more meaningful clinical interpretation.? 2014 The Author. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Developmental models of the etiology of alcohol problems have proposed several pathways for how childhood cognitive deficits relate to later alcohol problems. Deviance proneness models purport that underlying behavioral disregulation manifests in part as cognitive deficits and poor academic performance in childhood and later as alcohol problems in adulthood (see Gorenstein & Newman, 1980; Sher, 1991; Zucker, Chermack, & Curran, 2000). Alternative models have proposed more direct paths—that high intelligence and academic success can lead to both increased likelihood of being a lifetime drinker by placing individuals in heavier drinking environments (e.g., college) as well as decreased likelihood of developing alcohol problems via better opportunities in adulthood that may buffer against problems (see Johnson, Hicks, McGue, & Iacono, 2009). Conversely, pressure to maintain academic achievement may result in distress (e.g., Stoeber & Rambow, 2007), which in turn can lead to alcohol use and problems (Crum et al., 2006; Schulenberg, Bachman, O’Malley, & Johnston, 1994). It is also possible that multiple processes are involved, with both behavioral undercontrol and contextual factors contributing to the link between early cognitive deficits and later alcohol involvement. General population sample studies have demonstrated that relatively higher IQs are typically found among low-to-moderate drinkers compared with abstainers and heavy drinkers (see Anstey, Windsor, Rodgers, Jorm, & Christensen, 2005; Muller et al., 2013 for reviews). In longitudinal studies, higher childhood IQ has been positively associated with alcohol use and higher consumption levels in early and later adulthood (Johnson et al., 2008; Kanazawa & Hellberg, 2010). For example, in a U.S. national sample of young adults assessed over a 5-year interval, higher verbal IQ predicted increased risk for subsequent drinking and decreased risk for problems among drinkers even after covarying for socioeconomic status (Windle & Blane, 1989). This is consistent with a prospective study of a general Scottish sample that found higher verbal IQ at 11 years was associated with alcohol problems 40 years later after covarying for socioeconomic position (Batty, Deary, & Macintyre, 2006). Taken together, these studies suggest that higher IQ, and in particular verbal IQ, is predictive of increased likelihood of being a lifetime drinker and decreased likelihood of alcohol-related problems later in life, and that these associations are not accounted for by sociodemographic correlates of higher verbal abilities. Academic achievement is also a potential childhood cognitive predictor of subsequent alcohol involvement. Support for poor academic achievement associated with subsequent alcohol use and problems also has been found in longitudinal studies and general samples with varying ranges of follow-up (see, e.g., Duncan, Duncan, Biglan & Ary, 1998; Hawkins, Catalano, & Miller, 1992; Schulenberg et al., 1994). For example, Hayatbakhsh et al. (2011) demonstrated that poorer school performance at age 14 years predicted alcohol problems 21 years later in a general sample of Australian students, although already at age 14 over 60% of the sample indicated drinking in the past week. Studies that examine academic achievement in younger samples are needed to help clarify if poor academic achievement is a predictor of subsequent alcohol involvement or just a consequence of early alcohol use. In this study, we present longitudinal data from a birth cohort sample who were assessed at age 11 years on measures of cognitive and academic ability (prior to the typical age of onset of alcohol use) and then approximately 25 years later on lifetime alcohol use and alcohol use disorder (AUD) symptoms. The sample is from the island of Mauritius (a middle-income eastern African nation), allowing for the examination of these relationships in a non-western society that values education and academic performance (the population has an 89% literacy rate and public primary and secondary education are free; CIA Factbook, 2014; SACMEQ, 2012), but where childhood cognitive performance is not linked to heavy drinking environments as it often is in Western societies (e.g., college; Slutske et al., 2004). However, as in Western societies, both intelligence and school success in Mauritius may enable individuals to obtain financial and personal resources that increase the likelihood and opportunities for social drinking, even if buffering against risk for alcohol problems (see Johnson et al., 2009; Muller et al., 2013). Such contextual factors may affect relationships between childhood cognitive performance and subsequent alcohol involvement; thus, examining these associations in novel societies such as Mauritius will help determine the generalizability of the developmental models that have been generated using data primarily from Western societies (see Luczak et al., 2014). Given our prior findings with this sample that found gender and an index of psychosocial adversity (based on familial, housing, and environmental variables) were associated with IQ (Liu, Raine, Venables, & Mednick, 2003; Lynn, Raine, Venables, Mednick, & Irwing, 2005), and that being Muslim was protective for lifetime drinking but not for alcohol problems among drinkers (Luczak et al., 2014), we recognize the importance of including gender, psychosocial adversity, and Muslim religion when examining the link between cognition and alcohol use in this sample.

To assess whether educational class, an index of socioeconomic position, improves the accuracy of the SCORE cardiovascular disease (CVD) risk prediction equation.In a pooled analysis of 68 455 40-64-year-old men and women, free from coronary heart disease at baseline, from 47 prospective population-based cohorts from Nordic countries (Finland, Denmark, Sweden), the UK (Northern Ireland, Scotland), Central Europe (France, Germany, Italy) and Eastern Europe (Lithuania, Poland) and Russia, we assessed improvements in discrimination and in risk classification (net reclassification improvement (NRI)) when education was added to models including the SCORE risk equation.The lowest educational class was associated with higher CVD mortality in men (pooled age-adjusted HR=1.64, 95% CI 1.42 to 1.90) and women (HR=1.31, 1.02 to 1.68). In men, the HRs ranged from 1.3 (Central Europe) to 2.1 (Eastern Europe and Russia). After adjustment for the SCORE risk, the association remained statistically significant overall, in the UK and Eastern Europe and Russia. Education significantly improved discrimination in all European regions and classification in Nordic countries (clinical NRI=5.3%) and in Eastern Europe and Russia (NRI=24.7%). In women, after SCORE risk adjustment, the association was not statistically significant, but the reduced number of deaths plays a major role, and the addition of education led to improvements in discrimination and classification in the Nordic countries only.We recommend the inclusion of education in SCORE CVD risk equation in men, particularly in Nordic and East European countries, to improve social equity in primary prevention. Weaker evidence for women warrants the need for further investigations.

A social multiplier effect is a social interaction in which the behavior of a person in a social network varies with the normative behavior of others in the network, also known as an endogenous interaction. Policies and intervention efforts can harness social multiplier effects because, in theory, interventions on a subset of individuals will have “spillover effects” on other individuals in the network. This study investigates potential social multiplier effects for violence in middle schools, and whether there is evidence for a social multiplier effect transmitted from girls to boys. Three years of longitudinal data (2003–2005) from Project Northland Chicago were used to investigate this question, with a sample consisting of youth in Grades 6 through 8 in 61 Chicago Public Schools (N = 4,233 at Grade 6, N = 3,771 at Grade 7, and N = 3,793 at Grade 8). The sample was 49.3 % female, and primarily African American (41.9 %) and Latino/a (28.7 %), with smaller proportions of whites (12.9 %), Asians (5.2 %) and other ethnicities. Results from two sets of regression models estimating the effects of 20th (low), 50th (average), and 80th (high) percentile scores for girls and boys on levels of violence in each gender group revealed evidence for social multiplier effects. Specifically, boys and girls were both influenced by social multiplier effects within their own gender group, and boys were also affected by normative violence scores among girls, typically those of the best-behaved (20th percentile) girls. The finding that girls may have positive social influence on boys’ levels of violent behavior extends prior findings of beneficial social effects of girls on boys in the domains of education and risky driving. Further, this social normative effect presents a potential opportunity to improve school-based intervention efforts for reducing violence among youth by leveraging girls as carriers of a social multiplier effect for reduced violence in the middle school environmental context, particularly among boys, who are at greater risk.

Background Genetic factors predispose individuals to attention-deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3 . In this study, we functionally analyzed noncoding variants in this gene as likely pathological contributors. Methods In silico, in vitro, and in vivo approaches were used to identify and characterize evolutionary conserved elements within the ADGRL3 linkage region (~207 Kb). Family-based genetic analyses of 838 individuals (372 affected and 466 unaffected patients) identified ADHD-associated single nucleotide polymorphisms harbored in some of these conserved elements. Luciferase assays and zebrafish green fluorescent protein transgenesis tested conserved elements for transcriptional enhancer activity. Electromobility shift assays were used to verify transcription factor–binding disruption by ADHD risk alleles. Results An ultraconserved element was discovered (evolutionary conserved region 47) that functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in evolutionary conserved region 47, formed by rs17226398, rs56038622, and rs2271338, reduced enhancer activity by 40% in neuroblastoma and astrocytoma cells ( p Bonferroni ADGRL3 expression. The rs2271338 risk allele disrupts binding of YY1 transcription factor, an important factor in the development and function of the central nervous system. Expression quantitative trait loci analysis of postmortem human brain tissues revealed an association between rs2271338 and reduced ADGRL3 expression in the thalamus. Conclusions These results uncover the first functional evidence of common noncoding variants with potential implications for the pathology of ADHD.

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT

cardiovascular disease: Emerging opportunities for prevention?☆ Yolande Esquirol ⁎, John Yarnell , Jean Ferrieres , Alun Evans , Jean-Bernard Ruidavets , Aline Wagner , Jean Dallongeville , Dominique Arveiler , Pierre Ducimetiere , Philippe Amouyel , Annie Bingham , Frank Kee d and on behalf of the Prime study a Inserm, UMR1027, Toulouse, F-31073, France b Universite de Toulouse III, UMR1027, Toulouse, F-31073, France c CHU Toulouse, SMPE, F-31059, France d UK Clinical Research Collaboration Centre of Excellence for Public Health, Queen's University Belfast, Belfast, UK e CHU Toulouse, Department of Cardiology B, F-31059, France f Strasbourg MONICA Project, Department of Epidemiology and Public Health, EA 3430, Strasbourg University, 67085 Strasbourg cedex, France g Lille MONICA Project, Inserm UMR744, Lille, France h Institut Pasteur de Lille, Lille, France i Lille Nord de France University, Lille, France j Inserm-Paris XI University, Paul Brousse Hospital, Villejuif, France

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the

This study examined the measurement structure of Child Behavior Checklist internalizing and externalizing syndrome scales in 1,146 eleven-year-old children from a birth cohort in Mauritius. We tested for measurement invariance at configural, metric, and scalar levels by gender and religioethnicity (Creole, Hindu, Muslim). A pared-down model representing five primary factors and two secondary factors met all three forms of invariance, supporting the validity of their use for group comparisons among Mauritian children. As rated by their parents, girls were higher than boys on Somatic Complaints and lower on Aggressive Behavior, Attention Problems, and Externalizing. Creoles were higher than Muslims and Hindus on all seven factors. Hindus were higher than Muslims on Somatic Complaints and lower on Aggressive Behavior. To our knowledge, this is the first study to demonstrate strict invariance of a Child Behavior Checklist-based internalizing and externalizing factor structure among subgroups within a society.

Objective To test the applicability of the sex-specific 2008 Framingham general cardiovascular risk equation for coronary heart disease (CHD) and stroke in European middle-aged men from Ireland and France. Methods In the PRIME study, 9638 healthy middle-aged men recruited in France and Ireland were surveyed for 10 years for the occurrence of first CHD and stroke events. The original Framingham equation, the partially calibrated Framingham equation (using the PRIME baseline survival at 10 years), and the completely calibrated Framingham equation (additionally using risk factor means calculated in PRIME) were assessed. Model fit (expected versus observed events) and discrimination ability were assessed using a modified Hosmer–Lemeshow Chi-square statistic and Harrell's c-index respectively. Results The original (uncalibrated) Framingham equation overestimated by 1.94-fold the risk of CHD and stroke combined in PRIME, and by 2.23 and 1.42-fold in PRIME-France and PRIME-Ireland respectively. Adequate fit was found after complete calibration. However, discrimination ability of the Framingham equation was poor as shown by Harrell's c-index lower than 0.70. Conclusion The (completely) calibrated 2008 Framingham equation predicted accurate number of CHD and stroke events but discriminated poorly individuals at higher from those at lower event risk in a European population of middle-aged men.

Many school-based interventions have been aimed at alcohol use prevention among youth, but with limited effectiveness.1,2 One potential avenue for making school-based drinking interventions more effective is through the use of social multipliers. A social-multiplier effect is produced when policies take advantage of the tendency of individual behaviors to vary with the behavior of the reference group.3 For example, recent research in the area of obesity suggests that young people’s social networks may be used as social multipliers, so that the benefits of obesity prevention activities can be extended beyond the direct target of the intervention.4,5 This approach of targeting social networks is likely to be cost-effective because scarce resources could be spent on reaching influential persons and changing their behaviors, rather than spreading efforts more thinly across all students. For example, a given funding level may be sufficient if it fully involves only 10% of students, whereas it might be insufficient if spread over 100% of students. In the former case, there might be a smaller number of influential -dents (eg, peer leaders) that could diffuse prevention messages and norms.6,7 However, identifying influential students is key to this strategy. In this paper, we start with the assumption that identifying overlapping friendship networks is too complex and time-consuming to be used as part of a broadly implemented intervention. Instead, we focus on the distribution of drinking behavior within grade levels at schools. Our primary goal is to address the questions: Which points in the drinking distribution, within school and grade, are important in the “contagion” of drinking over time? Are students who are extreme in drinking behavior more influential who are average or normal with regard to drinking more influential? Alcohol use, the focus of our investigation, is an important problem to address at younger ages because early-onset drinking is associated with problem drinking behaviors later in life. It is a well-replicated finding that the younger a person starts drinking, the greater the risk for alcohol-related problems.8,9 These problems include impaired brain development and intellect, alcohol-related cirrhosis, and alcohol dependence.5,9,10 Alcohol use also has immediate consequences for adolescents, including increased risk for traffic crashes, crime, unintentional injury, disease, risky sexual behavior, academic problems, depression, homicide, and suicide.11,12 Drinking is also a social behavior. Although some reasons to drink are intrapersonal, such as personality type and social skills,11 many influences to drink are social, including prevalence of drinking in the home, in the community, and among peers.12 Major social influences among adolescents are family members, peers, school colleagues and personnel, and media models.13–15 Adolescents are thought to observe, bond to, and in turn model the social behaviors of those who are influential. Peers are thought to be the most significant social-risk factor in adolescent experimentation with alcohol and drugs—more important than the influence from parents.13,16 For example, Keefe17 documented that as youths age, parental influence on sub -stance use decreases, but peer influence remains strong and consistent. Peer influence on substance use is thought to occur through several avenues. In terms of socialization, adolescents may adjust their behaviors based on attitudes and behaviors of others in the surrounding environment.18 There is also evidence for a false consensus effect among adolescents in which adolescents overestimate peer acceptance for drugs or alcohol as a social norm,19,20 with some studies showing that perceived use among peers is more influential for behavior than actual use.21 Finally, in terms of self-selection, adolescents may choose to associate with peers who are similar to them and who readily have drugs or alcohol available.22 Fortunately, focusing on the distribution of drinking behavior among grades within schools not only sidesteps the effort needed to identify peer networks, but also allows us to avoid selection problems because grade-level peers are assigned rather than selected. Our research questions were as follow. First, who has more influence on the alcohol consumption of classmates: students who are extreme for drinking, or students who are average or normal with regard to drinking? Second, do these effects differ by gender, or according to whether peers’ cognitions (intentions) versus actual behaviors are used as the marker of drinking? Last, is there evidence that either extreme or average drinking behaviors or intentions actually change the distribution of drinking behaviors in this age-group over time, highlighting their role as social multipliers for drinking? One hypothesis is that students in a grade or in a school gauge their behavior against that of higher-risk students, with the idea that anything up to that level is “okay.” On the other hand, students may gauge their behavior on the grade average. If the former hypothesis is true, scarce resources could be concentrated on the extreme students, which would lead to a social-multiplier effect because everyone else will be influenced.

Inhibitory signaling through Tyr985 of the leptin receptor contributes to the attenuation of anorectic leptin action in obese animals. Leptin receptor (LEPR-B) Tyr985Leu homozygote mutant mice (termed l/l) were previously generated to study Tyr985's contributions to inhibition of LEPR-B signaling; young female l/l mice display a lean, leptin-sensitive phenotype, while young male l/l are not significantly different from wild-type. We report here that testosterone (but not estrogen) determines the sex-specificity of the l/l phenotype. This provides additional insight into the cellular mechanism by which gonadal hormones determine central sensitivity to leptin, and may help elucidate the long-noted sex differences in leptin sensitivity. Additionally, we observed that Tyr985 signaling protects against a diet-dependent switch that exacerbates obesity with high fat feeding, such that the enhanced leptin sensitivity of l/l mice on a normal diet leads to increased adiposity in the face of chronic high-fat diet.

Obesity is primarily due to food intake in excess of the body's energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT2CR) is a target for the treatment of human obesity. Mechanistically, 5-HT2CRs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT2CRs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT2CR agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT2CR expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT2CR expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT2CRCRE line to clarify the function of subset of 5-HT2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT2C receptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT2CR neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

Adrenal activity can be assessed in the equine species by analysis of feces for corticosterone metabolites. During a potentially aversive situation, corticotrophin releasing hormone (CRH) is released from the hypothalamus in the brain. This stimulates the release of adrenocorticotrophic hormone (ACTH) from the pituitary gland, which in turn stimulates release of glucocorticoids from the adrenal gland. In horses the glucocorticoid corticosterone is responsible for several adaptations needed to support equine flight behaviour and subsequent removal from the aversive situation. Corticosterone metabolites can be detected in the feces of horses and assessment offers a non-invasive option to evaluate long term patterns of adrenal activity. Fecal assessment offers advantages over other techniques that monitor adrenal activity including blood plasma and saliva analysis. The non-invasive nature of the method avoids sampling stress which can confound results. It also allows the opportunity for repeated sampling over time and is ideal for studies in free ranging horses. This protocol describes the enzyme linked immunoassay (EIA) used to assess feces for corticosterone, in addition to the associated biochemical validation.

BACKGROUND: Behavioral factors are important in disease incidence and mortality and may explain associations between mortality and various psychological traits.PURPOSE: These analyses investigated the impact of behavioral factors on the associations between depression, hostility and cardiovascular disease(CVD) incidence, CVD mortality, and all-cause mortality.METHODS: Data from the PRIME Study (N = 6953 men) were analyzed using Cox proportional hazards models, following adjustment for demographic and biological CVD risk factors, and other psychological traits, including social support.RESULTS: Following initial adjustment, both depression and hostility were significantly associated with both mortality outcomes (smallest SHR = 1.24, p CONCLUSIONS: These findings demonstrate well-known associations between depression, hostility, and mortality and suggest the potential importance of behaviors in explaining these relationships.

This paper establishes foundational knowledge on development of polysubstance use among adolescents in the U.S. child welfare system (CWS).Data on U.S. CWS adolescents from the National Study of Child and Adolescent Well-Being were examined for rates of alcohol, marijuana, and hard drug use; and change in use over time.Past 30-day absolute use was highest for alcohol, but daily/near-daily use highest for marijuana. Marijuana use increased at later time points. A correlated growth model suggested covariation in use of the substances. A curve-of-factors model suggested that higher-order factors explain most variation in substance use, except at the last time point. Those with lower use changed the most across time.Subsequent research among CWS adolescents in the U.S. should consider substances jointly. Prevention should focus on marijuana, and later periods of adolescence and CWS involvement. Youth not thought of as at great risk upon entering the CWS may be most vulnerable.

Objective The goal of this study was to establish the developmental trajectories for children's open-set recognition of monosyllabic words in each of two maskers: two-talker speech and speech-shaped noise. Design Listeners were 56 children (5 to 16 years) and 16 adults, all with normal hearing. Thresholds for 50% correct recognition of monosyllabic words were measured in a two-talker speech or a speech-shaped noise masker in the sound field using an open-set task. Target words were presented at a fixed level of 65 dB SPL throughout testing, while the masker level was adapted. A repeated-measures design was used to compare the performance of three age groups of children (5 to 7 years, 8 to 12 years, and 13 to 16 years) and a group of adults. The pattern of age-related changes during childhood was also compared between the two masker conditions. Results Listeners in all four age groups performed more poorly in the two-talker speech than the speech-shaped noise masker, but the developmental trajectories differed for the two masker conditions. For the speech-shaped noise masker, children's performance improved with age until about 10 years of age, with little systematic child-adult differences thereafter. In contrast, for the two-talker speech masker, children's thresholds gradually improved between 5 and 13 years of age, followed by an abrupt improvement in performance to adult-like levels. Children's thresholds in the two masker conditions were uncorrelated. Conclusions Younger children require a more advantageous signal-to-noise ratio than older children and adults to achieve 50% correct word recognition in both masker conditions. However, children's ability to recognize words appears to take longer to mature and follows a different developmental trajectory for the two-talker speech masker than the speech-shaped noise masker. These findings highlight the importance of considering both age and masker type when evaluating children's masked speech perception abilities.

The primary goal of this study was to compare infants' susceptibility to making produced by a two-talker speech and a speech-shaped noise masker. It is well documented that school-age children experience more difficulty recognizing speech embedded in two-talker speech than spectrally matched noise, a result attributed to immaturity in the ability to segregate target from masker speech, and/or to selectively attend to the target while disregarding the perceptually similar speech masker. However, findings from infant psychophysical studies suggest that infants are susceptible to auditory masking even when target and competing sounds are acoustically distinct.Listeners were infants (8 to10 months), children (8 to 10 years), and adults (18 to 33 years). The task was an observer-based, single-interval disyllabic word detection, in the presence of either a speech-shaped noise or a two-talker masker. The masker played continuously at 55 dB SPL, and the target level was adapted to estimate threshold.As observed previously for closed-set consonant and word identification as well as open-set word and sentence recognition, school-age children experienced relatively more masking than adults in the two-talker than the speech-shaped noise masker. The novel result of this study was that infants' speech detection thresholds were about 24 dB higher than those of adults in both maskers. While response bias differed between listener groups, it did not differ reliably between maskers.It is often assumed that speech perception in a speech masker places greater demands on a listener's ability to segregate and selectively attend to the target than a noise masker. This assumption is based on results showing larger child/adult differences for speech perception in a speech masker composed of a small number of talkers than in spectrally matched noise. The observation that infants experience equal masking for speech and noise maskers suggests that infants experience informational masking in both maskers and raises the possibility that the cues which make the steady noise a relatively ineffective masker for children are learned.

To investigate the association between periodontitis and mortality from all causes in a prospective study in a homogenous group of 60- to 70-year-old West European men.A representative sample of 1400 dentate men, (mean age 63.8, SD 3.0 years), drawn from the population of Northern Ireland, had a comprehensive periodontal examination between 2001 and 2003. Men were divided into thirds on the basis of their mean periodontal attachment loss (PAL). The primary endpoint, death from any cause, was analysed using Kaplan-Meier survival plots and Cox's proportional hazards model.In total, 152 (10.9%) of the men died during a mean follow-up of 8.9 (SD 0.7) years; 37 (7.9%) men in the third with the lowest PAL (1.8 mm) died compared with 73 (15.7%) in the third with the highest PAL (2.6 mm). The unadjusted hazard ratio (HR) for death in the men with the highest level of PAL compared with those with the lowest PAL was 2.11 (95% CI 1.42-3.14), p 0.0001. After adjustment for confounding variables (age, smoking, hypertension, BMI, diabetes, cholesterol, education, marital status and previous history of a cardiovascular event) the HR was 1.57 (1.04-2.36), p = 0.03.The European men in this prospective cohort study with the most severe loss of periodontal attachment were at an increased risk of death compared with those with the lowest loss of periodontal attachment.