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Mental health and HIV risk behavior have been studied with ecological momentary assessment (EMA), but this approach has not been combined with tracking of activity space (where people go and what they encounter there) in people with HIV and their social relations, who may be HIV+ or HIV-. Activity space represents a modifiable risk or protective factor for behavior related to health status and quality of life, in both clinical and nonclinical populations. We conducted an observational study with 286 participants (243 HIV+ and 43 HIV-), roughly matched for socioeconomic status and neighborhood of residence via three waves of snowball sampling. Each participant carried a smartphone for up to 4 weeks, making 5 randomly prompted entries and 1 end-of-day entry each day, plus self-initiated event-contingent entries for sexual activity and drug use. Responses to randomly prompted items provided subjective evaluations of the safety of the participant's current social and physical environment (the place they were and the people they were with). GPS-based location tracking-coupled with publicly available statistic indicating neighborhood-level physical disorder and socioeconomic disadvantage-provided an indicator of each participant's exposure to objective psychosocial hazard. We examined possible relationships of these objective and subjective environmental exposures with risky sexual and intravenous drug-use behavior, knowledge and utilization of antiretroviral treatment and prophylaxis, and momentary mental health (mood and stress, which relate to risky behavior and overall well-being). We found that both risky behavior and mental health were more related to participants' subjective evaluations of their activity space than to objective measures of neighborhood-level disorder, suggesting that, even within an objectively hazardous neighborhood, people who find a niche they perceive as socially and physically safe may engage in less risky behavior and have better well-being.Trial registration Clinicaltrials.gov Identifier NCT01571752., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The prevalence and associated overdose death rates from opioid use disorder (OUD) have dramatically increased in the last decade. Despite more available treatments than 20 years ago, treatment access and high discontinuation rates are challenges, as are personalized medication dosing and making timely treatment changes when treatments fail. In other fields such as depression, brief measures to address these tasks combined with an action plan-so-called measurement-based care (MBC)-have been associated with better outcomes. This workgroup aimed to determine whether brief measures can be identified for using MBC for optimizing dosing or informing treatment decisions in OUD., Methods: The National Institute on Drug Abuse Center for the Clinical Trials Network (NIDA CCTN) in 2022 convened a small workgroup to develop consensus about clinically usable measures to improve the quality of treatment delivery with MBC methods for OUD. Two clinical tasks were addressed: (1) to identify the optimal dose of medications for OUD for each patient and (2) to estimate the effectiveness of a treatment for a particular patient once implemented, in a more granular fashion than the binary categories of early or sustained remission or no remission found in The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)., Discussion: Five parameters were recommended to personalize medication dose adjustment: withdrawal symptoms, opioid use, magnitude (severity and duration) of the subjective effects when opioids are used, craving, and side effects. A brief rating of each OUD-specific parameter to adjust dosing and a global assessment or verbal question for side-effects was viewed as sufficient. Whether these ratings produce better outcomes (e.g., treatment engagement and retention) in practice deserves study. There was consensus that core signs and symptoms of OUD based on some of the 5 DSM-5 domains (e.g., craving, withdrawal) should be the basis for assessing treatment outcome. No existing brief measure was found to meet all the consensus recommendations. Next steps would be to select, adapt or develop de novo items/brief scales to inform clinical decision-making about dose and treatment effectiveness. Psychometric testing, assessment of acceptability and whether the use of such scales produces better symptom control, quality of life (QoL), daily function or better prognosis as compared to treatment as usual deserves investigation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The type of major duodenal papilla could be associated with difficult biliary cannulation at first endoscopic retrograde cholangiopancreatography (ERCP) in adults., Methods: This retrospective cross-sectional study included patients undergoing ERCP for the first time by an expert endoscopist. We defined the type of papilla according to the endoscopic classification of Haraldsson in type 1-4. The outcome of interest was difficult biliary cannulation, defined according to the European Society of Gastroenterology. To assess the association of interest, we calculated crude and adjusted prevalence ratios (PRc and PRa, respectively) and their respective 95% confidence intervals (CI) using Poisson regression with robust variance models, employing bootstrap methods. For the adjusted model we included the variables age, sex, and indication for ERCP, according to an epidemiological approach., Results: We included 230 patients. The most frequent type of papilla was type 1 (43.5%), and 101 (43.9%) of the patients presented difficult biliary cannulation. The results were consistent between the crude and adjusted analyses. After adjusting for age, sex, and ERCP indication, the prevalence of difficult biliary cannulation was highest in patients with papilla type 3 (PRa 3.66, 95%CI 2.49-5.84), followed by patients with papilla type 4 (PRa 3.21, 95%CI 1.82-5.75), and patients with papilla type 2 (PRa 1.95, 95%CI 1.15-3.20) compared to patients with papilla type 1., Conclusion: In adults undergoing ERCP for the first time, patients with papilla type 3 had a greater prevalence of difficult biliary cannulation than patients with papilla type 1., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Background: Previous studies have shown that environment and health can influence drug use trajectories and the effects of substance use disorder (SUD) treatments. We hypothesized that trajectories of drug use-related problems, based on changes in DSM-5 symptoms, would vary by type(s) of drugs used, health factors, and neighborhood characteristics., Methods: We assessed mental and physical health, stress, social instability, neighborhood characteristics (disorderliness and home value), and DSM-5 symptom counts at two study visits, 12 months apart, in a community sample (baseline N  = 735) in Baltimore, MD. Three prominent categories of drug-use trajectory were identified with K-means cluster analysis of symptom counts: Persistent (4 or more symptoms at both visits or at Visit 2), Improved (decrease from 4 or more symptoms at Visit 1 to 3 or fewer symptoms at Visit 2), and Low-Stable (3 or fewer symptoms at both visits). Baseline health and neighborhood measures were tested as predictors of trajectory in mediation and moderation models., Results: Among people with current opioid- and/or stimulant-use, odds of an Improved trajectory were (1) decreased with neighborhood disorder and social instability, or (2) increased with home value and social instability. Odds of a Low-Stable trajectory were decreased by social instability and stress but increased in those who were older or self-identified as white., Conclusions: Trajectories of drug use-related problems are influenced by sociodemographic variables, neighborhood factors, and health. Assessing DSM-5 symptom counts as an outcome measure may be valuable in monitoring or predicting long-term trajectories and treatment effectiveness.

Background: Social media sites, dating apps, and information search sites have been used to reach individuals at high risk for HIV infection. However, it is not clear which platform is the most efficient in promoting home HIV self-testing, given that the users of various platforms may have different characteristics that impact their readiness for HIV testing., Objective: This study aimed to compare the relative effectiveness of social media sites, dating apps, and information search sites in promoting HIV self-testing among minority men who have sex with men (MSM) at an increased risk of HIV infection. Test kit order rates were used as a proxy to evaluate promotion effectiveness. In addition, we assessed differences in characteristics between participants who ordered and did not order an HIV test kit., Methods: Culturally appropriate advertisements were placed on popular sites of three different platforms: social media sites (Facebook, Instagram), dating apps (Grindr, Jack'D), and information search sites (Google, Bing). Advertisements targeted young (18-30 years old) and minority (Black or Latinx) MSM at risk of HIV exposure. Recruitment occurred in 2 waves, with each wave running advertisements on 1 platform of each type over the same period. Participants completed a baseline survey assessing sexual or injection use behavior, substance use including alcohol, psychological readiness to test, attitudes toward HIV testing and treatment, and HIV-related stigma. Participants received an electronic code to order a free home-based HIV self-test kit. Follow-up assessments were conducted to assess HIV self-test kit use and uptake of pre-exposure prophylaxis (PrEP) at 14 and 60 days post enrollment., Results: In total, 271 participants were enrolled, and 254 were included in the final analysis. Among these 254 participants, 177 (69.7%) ordered a home HIV self-test kit. Most of the self-test kits were ordered by participants enrolled from dating apps. Due to waves with low enrollment, between wave statistical comparisons were not feasible. Within wave comparison revealed that Jack'D showed higher order rates (3.29 kits/day) compared to Instagram (0.34 kits/day) and Bing (0 kits/day). There were no associations among self-test kit ordering and HIV-related stigma, perceptions about HIV testing and treatment, and mistrust of medical organizations., Conclusions: Our findings show that using popular dating apps might be an efficient way to promote HIV self-testing. Stigma, perceptions about HIV testing and treatment, or mistrust of medical organizations may not affect order rates of HIV test kits promoted on the internet., Trial Registration: ClinicalTrials.gov NCT04155502; https://clinicaltrials.gov/ct2/show/NCT04155502., International Registered Report Identifier (irrid): RR2-10.2196/20417., (©Chrysovalantis Stafylis, Gabriella Vavala, Qiao Wang, Bethany McLeman, Shea M Lemley, Sean D Young, Haiyi Xie, Abigail G Matthews, Neal Oden, Leslie Revoredo, Dikla Shmueli-Blumberg, Emily G Hichborn, Erin McKelle, Landhing M Moran, Petra Jacobs, Lisa A Marsch, Jeffrey D Klausner. Originally published in JMIR Formative Research (https://formative.jmir.org), 23.09.2022.)

Background and Aim: There is no gold-standard and considerable heterogeneity in outcome measures used to evaluate treatments for opioid use disorder (OUD) along the opioid treatment cascade. The aim of this study was to develop the US National Institute on Drug Abuse (NIDA) National Drug Abuse Treatment Clinical Trials Network (CTN) opioid use disorder core outcomes set (OUD-COS)., Design: Four-round, e-Delphi expert panel consensus study and plenary research group discussion and targeted consultation., Setting: United States., Participants: A panel of 25 members including clinical practitioners, clinical researchers and administrative staff from the CTN, the network's affiliated clinical and community sites and the NIDA Centre for the CTN., Measurements: From a pool of 24 candidate items in four domains (biomedical/disease status; behaviors, symptoms and functioning; opioid treatment cascade; and morbidity and mortality), the panel completed an on-line questionnaire to rank items with defined specification on a 9-point scale for importance, with a standard 70% consensus criterion., Findings: After the fourth round of the questionnaire and subsequent discussion, consensus was reached for five outcomes: two patient-reported (global impression of improvement and incident non-fatal overdose); one clinician-reported (illicit/non-medical drug toxicology); and two from administrative records (duration of treatment and fatal opioid poisoning)., Conclusions: An e-Delphi consensus study has produced the US National Institute on Drug Abuse (NIDA) National Drug Abuse Treatment Clinical Trials Network opioid use disorder core outcomes set (version 1) for opioid use disorder treatment efficacy and effectiveness research., (© 2022 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Anhedonia is usually defined as partial or total loss of the capacity for pleasure. People with anhedonia in the context of major depressive disorder may have an unexpected capacity for event-related mood brightening, observable when mood is assessed dynamically (with smartphone-based ecological momentary assessment [EMA]) rather than only statically via questionnaire. We used EMA to monitor mood and pleasant events for 4 weeks in 54 people being treated with opioid agonist medication for opioid-use disorder (OUD), which is also associated with anhedonia, said to manifest especially as loss of pleasure from nondrug reward. We compared OUD patients' EMA reports with those of 47 demographically similar controls. Background positive mood was lower in OUD patients than in controls, as we hypothesized (Cohen ds = .85 to 1.32, 95% CIs [.66, 1.55]), although, contrary to our hypothesis, background negative mood was also lower (ds = .82 to .85, 95% CIs [.73, .94]). As hypothesized, instances of nondrug pleasure were as frequent in OUD patients as in controls-and were not rated much less pleasurable (d = .18, 95% CI [-.03, .35]). Event-related mood brightening occurred in both abstinent and nonabstinent OUD patients (ds = .18 to .37, CIs [-.01, .57]) and controls (ds = .04 to .60, CIs [-.17, .79]), brightening before each event began earlier for controls than OUD patients, but faded similarly postevent across groups. Our findings add to the evidence that anhedonia does not rule out reactive mood brightening, which, for people with OUD being treated on opioid agonist medication, can be elicited by nondrug activities. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The persistence of HIV-1 associated neurocognitive disorders (HAND) in the post-cART era, afflicting between 40 and 70% of HIV-1 seropositive individuals, supports a critical need for the development of adjunctive therapeutic treatments. Selective estrogen receptor β agonists, including S-Equol (SE), have been implicated as potential therapeutic targets for the treatment of neurocognitive disorders. In the present study, the therapeutic efficacy of 0.2 mg SE for the treatment of HAND was assessed to address two key questions in the HIV-1 transgenic (Tg) rat. First, does SE exhibit robust therapeutic efficacy when treatment is initiated relatively early (i.e., between 2 and 3 months of age) in the course of viral protein exposure? Second, does the therapeutic utility of SE generalize across multiple neurocognitive domains? Treatment with SE enhanced preattentive processes and stimulus-response learning to the level of controls in all (i.e., 100%) HIV-1 Tg animals. For sustained and selective attention, statistically significant effects were not observed in the overall analyses (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). However, given our a priori hypothesis, subsequent analyses were conducted, revealing enhanced sustained and selective attention, approximating controls, in a subset (i.e., 50%, n = 5 and 80%, n = 8, respectively) of HIV-1 Tg animals treated with SE. Thus, the therapeutic efficacy of SE is greater when treatment is initiated relatively early in the course of viral protein exposure and generalizes across neurocognitive domains, supporting an adjunctive therapeutic for HAND in the post-cART era. Graphical Abstract HIV-1 transgenic (Tg) and control animals were treated with either 0.2 mg S-Equol (SE) or placebo between 2 and 3 months of age (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). Neurocognitive assessments, tapping preattentive processes, stimulus response learning, sustained attention and selective attention, were conducted to evaluate the utility of SE as a therapeutic for HIV-1 associated neurocognitive disorders (HAND). Planned comparisons between HIV-1 Tg and control animals treated with placebo were utilized to establish a genotype effect, revealing prominent neurocognitive impairments (NCI) in the HIV-1 Tg rat across all domains. Furthermore, to establish the utility of SE, HIV-1 Tg animals treated with SE were compared to control animals treated with placebo. Treatment with 0.2 mg SE ameliorated NCI, to levels that were indistinguishable from controls, in at least a subset (i.e., 50-100%) of HIV-1 Tg animals. Thus, SE supports an efficacious, adjunctive therapeutic for HAND.

Background: Individual trajectories of drug use and drug-related problems are highly heterogeneous. There is no standard taxonomy of these trajectories, but one could be developed by defining natural categories based on changes in symptoms of substance-use disorders over time., Methods: Our study was conducted in a community sample in Baltimore, Maryland. At baseline, all participants were using opioids and/or cocaine, but none were in treatment. Drug use and symptomatology were assessed again at 12 months (N = 115)., Results: We defined Quitters as participants who had not used for at least 30 days at follow-up (17%). For the remaining participants, we performed longitudinal cluster analysis on DSM symptom-counts, identifying three trajectory clusters: newly or persistently Symptomatic (40%) participants, Chippers (21.5%) with few symptoms, and Converted Chippers (21.5%) with improved symptom counts. Logistic regression showed that profiles of Quitters did not resemble Chippers, but instead resembled Symptomatic participants, having high probability of disorderly home neighborhood, nonwhite race, and negative mood. Quitters tended to have two protective factors: initiating opioid-agonist treatment during the study (r effect  = 0.25, CL95 0.02-0.48) and lack of polydrug use (r effect  = 0.25, CL95 0.004-0.49). Converted Chippers tended to be white, with orderly home neighborhoods and less negative mood (r effects 0.24 to 0.31, CL95 0.01-0.54)., Conclusions: Changes in DSM symptomology provided a meaningful measure of individual trajectories. Quitters shared psychosocial characteristics with Symptomatic participants, but not with participants who continued to use with few symptoms. This suggests that Quitters abstained out of necessity, not because their problems were less severe., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Due to the sustained prevalence of human immunodeficiency virus (HIV)-1 associated neurocognitive disorders (HAND) in the post-combination antiretroviral therapy (cART) era, as well as the increased prevalence of older HIV-1 seropositive individuals, there is a critical need to develop adjunctive therapeutics targeted at preserving and/or restoring neurocognitive function. To address this knowledge gap, the present study examined the utility of S-Equol (SE), a phytoestrogen produced by gut microbiota, as an innovative therapeutic strategy. A signal detection operant task with varying signal durations (1,000, 500, 100 ms) was utilized to assess sustained attention in HIV-1 transgenic (Tg) and control animals. During the signal detection pretest assessment, HIV-1 Tg animals displayed profound deficits in stimulus-response learning and sustained attention relative to control animals. Subsequently, between 6 and 8 months of age, HIV-1 Tg and control animals were treated with a daily oral dose of either placebo or SE (0.05, 0.1, 0.2 mg) and a posttest assessment was conducted in the signal detection operant task with varying signal durations. In HIV-1 Tg animals, a linear decrease in the number of misses at 100 ms was observed as SE dose increased, suggesting a dose response with the most effective dose at 0.2 mg SE, approximating controls. Comparison of the number of misses across signal durations at the pretest and posttest revealed a preservation of neurocognitive function in HIV-1 Tg animals treated with 0.2 mg SE; an effect that was in sharp contrast to the neurocognitive decline observed in HIV-1 Tg animals treated with placebo. The results support the utility of 0.2 mg SE as a potential efficacious neuroprotective and/or neurorestorative therapeutic for sustained attention, in the absence of any adverse peripheral effects, in the HIV-1 Tg rat. Thus, the present study highlights the critical need for further in vivo studies to elucidate the full potential and generalizability of phytoestrogen treatment for HAND.

Many patients with opioid use disorder do not have successful outcomes during treatment but the underlying reasons are not well understood. An OPRD1 variant (rs678849) was previously associated with methadone and buprenorphine efficacy in African-Americans with opioid use disorder. The objective of this study was to determine if the effect of rs678849 on opioid use disorder treatment outcome could be replicated in an independent population. Participants were recruited from African-American patients who had participated in previous studies of methadone or buprenorphine treatment at the outpatient treatment research clinic of the NIDA Intramural Research Program in Baltimore, MD, USA between 2000 and 2017. Rs678849 was genotyped retrospectively, and genotypes were compared with urine drug screen results from the previous studies for opioids other than the one prescribed for treatment. Genotypes were available for 24 methadone patients and 55 buprenorphine patients. After controlling for demographics, the effect of rs678849 genotype was significant in the buprenorphine treatment group (RR = 1.69, 95% confidence interval (CI) 1.59-1.79, p = 0.021). Buprenorphine patients with the C/C genotype were more likely to have opioid-positive drug screens than individuals with the C/T or T/T genotypes, replicating the original pharmacogenetic finding. The effect of genotype was not significant in the methadone group (p = 0.087). Thus, the genotype at rs678849 is associated with buprenorphine efficacy in African-Americans being treated for opioid use disorder. This replication suggests that rs678849 genotype may be a valuable pharmacogenetic marker for deciding which opioid use disorder medication to prescribe in this population.

Temporal processing deficits have been implicated as a potential elemental dimension of higher-level cognitive processes, commonly observed in neurocognitive disorders. Despite the popularization of prepulse inhibition (PPI) in recent years, many current protocols promote using a percent of control measure, thereby precluding the assessment of temporal processing. The present study used cross-modal PPI and gap prepulse inhibition (gap-PPI) to demonstrate the benefits of employing a range of interstimulus intervals (ISIs) to delineate effects of sensory modality, psychostimulant exposure, and age. Assessment of sensory modality, psychostimulant exposure, and age reveals the utility of an approach varying the interstimulus interval (ISI) to establish the shape of the ISI function, including increases (sharper curve inflections) or decreases (flattening of the response amplitude curve) in startle amplitude. Additionally, shifts in peak response inhibition, suggestive of a differential sensitivity to the manipulation of ISI, are often revealed. Thus, the systematic manipulation of ISI affords a critical opportunity to evaluate temporal processing, which may reveal the underlying neural mechanisms involved in neurocognitive disorders.

Motivational alterations, such as apathy, in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry. We used the HIV-1 transgenic (Tg) rat to assess effect of long-term HIV-1 protein exposure on motivated behavior using sucrose (1-30%, w/v) and cocaine (0.01-1.0 mg/kg/infusion) maintained responding with fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. For sucrose-reinforced responding, HIV-1 Tg rats displayed no change in EC 50 relative to controls, suggesting no change in sucrose reinforcement but had a downward shifted concentration-response curves, suggesting a decrease in response vigor. Cocaine-maintained responding was attenuated in HIV-1 Tg rats (FR1 0.33 mg/kg/infusion and PR 1.0 mg/kg/infusion). Dose-response tests (PR) revealed that HIV-1 Tg animals responded significantly less than F344 control rats and failed to earn significantly more infusions of cocaine as the unit dose increased. When choosing between cocaine and sucrose, control rats initially chose sucrose but with time shifted to a cocaine preference. In contrast, HIV-1 disrupted choice behaviors. DAT function was altered in the striatum of HIV-1 Tg rats; however, prior cocaine self-administration produced a unique effect on dopamine homeostasis in the HIV-1 Tg striatum. These findings of altered goal directed behaviors may determine neurobiological mechanisms of apathy in HIV-1+ patients.

Background: In a recent clinical trial (NCT00295308), we demonstrated that clonidine decreased the association between opioid craving and moderate levels of stress and affect in patients receiving buprenorphine-based opioid agonist therapy., Objectives: To examine the relationship between illicit opioid use and craving and affect during the evaluation of clonidine as an adjunct medication in buprenorphine treatment for opioid use disorder. Secondarily, to examine whether those relationships are driven by within- or between-participant factors., Methods: This was a secondary data analysis from our original trial. Participants (N = 108, female: n = 23, male n = 85) receiving buprenorphine were randomized to receive adjunct clonidine or placebo. Participants used portable electronic devices to rate stress, mood, and craving via ecological momentary assessment (EMA) four times randomly each day. To associate the EMA data with illicit opioid use, each EMA report was linked to participants' next urine drug screen (thrice weekly). We used generalized linear mixed models to examine the interaction between treatment group and illicit opioid use, as well as to decompose the analysis into within- and between-participant effects., Results: Craving for opioids and cocaine was increased when participants were using illicit opioids; this effect was greater in the clonidine group. For affect, mood was poorer during periods preceding opioid-positive urines than opioid-negative urines for clonidine-treated participants, whereas there was no difference for placebo participants., Conclusion: This secondary analysis provides evidence that for participants maintained on opioid agonist therapy, clonidine minimized the behavioral impact of moderate levels of negative affect and craving.

Background: Responses to stress and drug craving differ between men and women. Differences in the momentary experience of stress in relation to craving are less well-understood., Objectives: Using ecological momentary assessment (EMA), we examined sex differences in real-time in two areas: (1) causes and contexts associated with stress, and (2) the extent to which stress and drug cues are associated with craving., Methods: Outpatients on opioid-agonist treatment (135 males, 47 females) reported stress, craving, and behavior on smartphones for 16 weeks. They initiated an entry each time they felt more stressed than usual (stress event) and made randomly prompted entries 3 times/day. In stress-event entries, they identified the causes and context (location, activity, companions), and rated stress and craving severity., Results: The causes reported for stress events did not differ significantly by sex. Women reported arguing and being in a store more often during stress events, and men reported working more often during stress events, compared to base rates (assessed via random prompts). Women showed a greater increase in opioid craving as a function of stress (p < 0.0001) and had higher stress ratings in the presence of both stress and drug cues relative to men (p < 0.01). Similar effects were found for cocaine craving in men (p < 0.0001)., Conclusion: EMA methods provide evidence based on real-time activities and moods that opioid-dependent men and women experience similar contexts and causes for stress but differ in stress- and cue-induced craving. These findings support sex-based tailoring of treatment, but because not all participants conformed to the overall pattern of sex differences, any such tailoring should also consider person-level differences.

Objective: In a clinical trial examining daily clonidine as an adjunct to buprenorphine treatment for opioid dependence, we found that clonidine increased opioid abstinence and decoupled stress from craving. From a personalized-medicine perspective, the next step is to identify people for whom clonidine would be beneficial. To that end, using data from the same clinical trial, we examined the associations of daily-life activities with treatment success., Methods: Outpatients (N = 118) received clonidine (0.3 mg/d) or placebo during 18 weeks of buprenorphine treatment. Participants carried a smartphone that randomly prompted them 4 times per day to report their moods and activities. Using generalized linear mixed models, we assessed the likelihoods of different types of daily activity as a function of clonidine versus placebo, days of longest continuous opioid abstinence, and their interaction., Results: Participants in the buprenorphine-only (buprenorphine plus placebo) control group who engaged in more responsibilities (work and child/elder care) had longer streaks of abstinence, whereas those who engaged in more unstructured-time activities had shorter streaks of abstinence. Conversely, for participants in the buprenorphine-plus-clonidine group, longer streaks of abstinence were associated with higher frequencies of activities associated with "unstructured" time., Conclusions: The study replicates findings that engaging in responsibilities is related to positive treatment outcomes in standard opioid agonist therapy. The pattern of results also suggests that clonidine helped participants engage in unstructured-time activities with less risk of craving or use than they might otherwise have had.

Objectives: People with substance use problems living in neighborhoods with high levels of disorder are disproportionately likely to experience trauma and develop PTSD symptoms. We sought to evaluate the relationships between objective neighborhood disorder, perceptions of neighborhood, and the use of maladaptive coping behaviors among both non-substance-using and substance-using participants with and without PTSD symptoms., Methods: Participants (255 non-drug users [NDUs], 168 marijuana and/or alcohol users [MAUs], and 273 opioid and/or stimulant users) completed the Addiction Severity Index, PTSD Checklist-Civilian Version, The COPE Inventory, and the Perceived Neighborhood Scale. The Neighborhood Inventory for Environmental Typology (NIfETy) was used to objectively assess neighborhood disorder at participants' home addresses. Regression modeling was used to assess within-group predictors of PTSD and test for mediation in the relationships between PTSD, perceptions of neighborhood, and coping behaviors., Results: In NDUs, lower sense of community partially mediated the relationship between PTSD symptoms and using mental disengagement to cope. In MAUs, higher levels of perceived crime partially mediated the individual relationships between PTSD symptoms and using mental disengagement, focusing on and venting emotions, and using substances to cope. Opioid and/or stimulant users with PTSD symptoms reported using higher levels of mental disengagement, focusing on and venting emotions, and substances to cope and perceived a higher degree of crime; no mediation was inferred., Conclusion: Perceptions of community and crime may be more predictive of PTSD symptoms than objectively measured neighborhood disorder. These perceptions partially mediate the relationship between maladaptive coping behaviors and PTSD symptoms.

Background: Concerns exist regarding the adequacy of the pediatric subspecialty workforce in the United States. Data on practice patterns and job characteristics are necessary to help develop policies to ensure availability., Methods: We performed survey data analysis of all pediatric subspecialists enrolled in Maintenance of Certification in 2013 and 2014, assessing demographic information, characteristics of current positions, plans for retirement, and satisfaction with allocation of professional and clinical responsibilities. Four logistic regression models examined the independent association of demographic variables collected along with variables of practice ownership and academic appointment with the outcome variables of pediatric subspecialists reporting match of desired with current actual professional duties, match of desired with current actual clinical responsibilities, current part-time employment, and expected age of retirement <65 years of age., Results: Data from 5100 subspecialists were analyzed (response rate 87.2%). Most (83%; N = 4251) reported their current allocation of professional time was what they desired in their current position; similarly, 93% ( N = 4755) reported likewise for clinical responsibilities. Differences by gender and years in subspecialty were evident, with women much more likely to work part time than men (odds ratio 6.22); those >20 years in practice were less likely to retire before the age of 65 compared with those <10 years in practice (odds ratio 0.33)., Conclusions: This study is the largest to date of practicing pediatric subspecialists. Variation in work patterns found between genders, with time in practice, and between subspecialties suggests that future research should focus on these issues., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Approximately 50 % of HIV-1 seropositive individuals develop HIV-1 associated neurocognitive disorders (HAND), which commonly include alterations in executive functions, such as inhibition, set shifting, and complex problem solving. Executive function deficits in HIV-1 are fairly well characterized, however, relatively few studies have explored the elemental dimensions of neurocognitive impairment in HIV-1. Deficits in temporal processing, caused by HIV-1, may underlie the symptoms of impairment in higher level cognitive processes. Translational measures of temporal processing, including cross-modal prepulse inhibition (PPI), gap-prepulse inhibition (gap-PPI), and gap threshold detection, were studied in mature (ovariectomized) female HIV-1 transgenic (Tg) rats, which express 7 of the 9 HIV-1 genes constitutively throughout development. Cross-modal PPI revealed a relative insensitivity to the manipulation of interstimulus interval (ISI) in HIV-1 Tg animals in comparison to control animals, extending previously reported temporal processing deficits in HIV-1 Tg rats to a more advanced age, suggesting the permanence of temporal processing deficits. In gap-PPI, HIV-1 Tg animals exhibited a relative insensitivity to the manipulation of ISI in comparison to control animals. In gap-threshold detection, HIV-1 Tg animals displayed a profound differential sensitivity to the manipulation of gap duration. Presence of the HIV-1 transgene was diagnosed with 91.1 % accuracy using gap threshold detection measures. Understanding the generality and permanence of temporal processing deficits in the HIV-1 Tg rat is vital to modeling neurocognitive deficits observed in HAND and provides a key target for the development of a diagnostic screening tool.

Aripiprazole blocks psychostimulant seeking in a rat model of relapse. However, in humans, it may increase ongoing use. We tested aripiprazole specifically for relapse prevention. Methadone-maintained outpatients who were abstinent from cocaine in weeks 11-12 were randomized to double-blind aripiprazole (15 mg daily) or placebo in weeks 13-27 after 12 weeks of contingency management. Participants reported craving through ecological momentary assessment. We stopped the trial because very few (18/41) participants fulfilled the abstinence criterion. The results suggested that aripiprazole delayed lapse [hazard ratio (HR)=0.45, 95% confidence interval (CI)=0.14-1.42, P=0.17] and relapse (HR=0.31, 95% CI=0.07-1.27, P=0.10), but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group (Fisher's exact P=0.026), although the frequency of craving was similar in the aripiprazole and placebo groups (1.89 vs. 1.16%, reffect=0.43, 95% CI=-0.08-0.76). The results suggest that in recently abstinent cocaine users, aripiprazole might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle.

Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1-6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI.

Objectives: Following pediatric moderate-to-severe traumatic brain injury (msTBI), few predictors have been identified that can reliably identify which individuals are at risk for long-term cognitive difficulties. This study sought to determine the relative contribution of detailed descriptors of injury severity as well as demographic and psychosocial factors to long-term cognitive outcomes after pediatric msTBI., Methods: Participants included 8- to 19-year-olds, 46 with msTBI and 53 uninjured healthy controls (HC). Assessments were conducted in the post-acute and chronic stages of recovery. Medical record review provided details regarding acute injury severity. Parents also completed a measure of premorbid functioning and behavioral problems. The outcome of interest was four neurocognitive measures sensitive to msTBI combined to create an index of cognitive performance., Results: Results indicated that none of the detailed descriptors of acute injury severity predicted cognitive performance. Only the occurrence of injury, parental education, and premorbid academic competence predicted post-acute cognitive functioning. Long-term cognitive outcomes were best predicted by post-acute cognitive functioning., Discussion: The findings suggest that premorbid factors influence cognitive outcomes nearly as much as the occurrence of a msTBI. Furthermore, of youth with msTBI who initially recover to a level of moderate disability or better, a brief cognitive battery administered within several months after injury can best predict which individuals will experience poor long-term cognitive outcomes and require additional services.

Background and Objectives: A near vacuum exists for credible information regarding specialty-specific demography, including gender, years since training completion, current employer, academic affiliation, and hours worked in specific tasks. Understanding the current status and changes to the medical workforce and its work patterns is essential to assessing whether the supply and distribution meets the needs of patients, institutions, society, and educational programs., Methods: A self-administered electronic survey sent to all pediatricians at the time of their enrollment in the Maintenance of Certification program in 2013-2014. The survey focused on exploring trends associated with career choice, career paths, time spent in professional activities, and current practice characteristics. Logistic regression and χ(2) analyses were conducted., Results: The response rate was 87.2% (N = 15 351). Of those who completed the survey, 9253 (64%) self-identified as general pediatricians. An increased likelihood of working part-time was seen among women (odds ratio [OR]: 12.21), those without an academic appointment (OR: 1.32), and those not working in a private/independent practice (OR: 1.15). Overall, 89% (n = 8214) of respondents stated that their current allocation of professional time was approximately what they wanted. Those more likely to be involved in quality improvement in the past year did not work in independent/private practices (OR: 1.78) and worked full-time (OR: 1.16)., Conclusions: Understanding the current nature of the pediatric workforce is a first step in providing data to guide future workforce planning and the training experiences required to maintain and shape the workforce to meet the current and future needs of children., (Copyright © 2016 by the American Academy of Pediatrics.)

Objectives: The issues of importance in selecting a first job for new pediatric subspecialists, and their ability to find positions that match their professional and clinical goals, are unknown. The objectives were to (1) describe current employment patterns, practice characteristics, factors influencing choice of first position, and future work goals of new pediatric subspecialists; and (2) examine the relationship of these variables with the actual professional time allocation and clinical responsibilities compared with the desired first job., Methods: The authors surveyed 3010 individuals sitting for ≥1 of the 14 subspecialty certification exams. The main outcomes were (1) most important factors in choosing employment; (2) ability to gain employment in positions that matched their goals; and (3) variation in employment characteristics among men versus women, time since completion of training, and part-time versus full-time status., Results: Response rate was 97%. Lifestyle/spousal or family considerations was the factor identified as most important in the choice of first position after fellowship training for half of respondents (50%; n = 1277). There was a median of 75% of actual time spent in direct and/or consultative inpatient or outpatient care, with 5% in medical education, 5% in administration, and 5% in research. A majority (74%; n = 1825) reported this proportion to be approximately what they wanted. Most respondents (89%; n = 2194) reported that their allocation of patient care responsibilities (ie, inpatient versus outpatient) was approximately what they wanted., Conclusion: A large majority of pediatric subspecialists found initial positions matching their goals for professional responsibilities and clinical care., (Copyright © 2016 by the American Academy of Pediatrics.)

Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are observed in neurodevelopmental and neuropsychiatric disorders. Despite the large PPI literature, the majority of studies characteristically employ tests with one interstimulus interval (ISI), of one modality, at one age. In the context of the auditory startle response (ASR), the present study examined (1) the profile for the ontogeny of PPI through adulthood in Long-Evans hooded rats with a reasonably comprehensive ISI function, (2) whether the ontogenetic profile for PPI is sensitive to modality of the prepulse stimulus, as a within-session variable, and (3) whether the maturation of PPI differs for males and females. Despite the basic effect of more pronounced PPI in adult relative to preweanling animals, each sensory modality displayed a unique ontogenetic profile for PPI, without any compelling evidence for major differences between males and females, in accordance with the known temporal course of peripheral and central maturational profiles of sensory systems in the rat. The context for assessing auditory PPI (auditory and tactile vs. auditory and visual prepulses) influenced the overall startle response, i.e., a shift in the height of the entire profile, but did not significantly impact the auditory PPI profile per se. The translational relevance of preclinical sensorimotor assessments to patients with neurodevelopmental and/or neuropsychiatric disorders depends partly on an understanding of the ontogeny of sensorimotor gating in different sensory systems, and can be strengthened with the use of a reasonably comprehensive number of ISIs to provide relatively precise and defined response functions., (© 2015 Wiley Periodicals, Inc.)

Background: Several studies have recently demonstrated that the immune responses against malaria is governed by different factors, including the genetic components of the host. The IL-4 gene appears to be a strong candidate factor because of its role in the regulation of the Th2 response. The present study investigated the role of IL-4 polymorphisms in the development of IgG antibodies against PvAMA-1 and the IL-4 levels in individuals infected with Plasmodium vivax in a malaria endemic area in the Brazilian Amazon., Methods: The study sample included 83 patients who were diagnosed with P. vivax infection using thick smear and confirmed by nested-PCR. The IL-4 -590C>T and IL-4 -33C>T polymorphisms were genotyped by PCR-RFLP, and the intron 3 VNTR was genotyped by PCR. A standardised ELISA protocol was used to measure the total IgG against PvAMA-1. The cytokine/chemokine levels were measured using a Milliplex multiplex assay (Millipore). All of the subjects were genotyped with 48 ancestry informative markers to determine the proportions of African, European and Amerindian ancestry using STRUCTURE software., Results: Of the 83 patients, 60 (73%) produced IgG antibodies against PvAMA-1. A significant decrease in the percentage of respondents was observed among the primo-infected individuals. No significant differences were observed in the frequencies of genotypes and haplotypes among individuals who were positive or negative for IgG antibodies against PvAMA-1. Furthermore, no significant correlation was observed between the IL-4 polymorphisms, antibody levels, IL-4 levels, and parasitemia., Conclusions: This study indicated that the polymorphisms identified in the IL-4 gene are not likely to play a role in the regulation of the antibody response against PvAMA-1 and IL-4 production in vivax malaria., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Studies have demonstrated a dramatic increase in the number of new nurse practitioners (NPs) overall completing NP education each year. However, NPs who provide specialized care to children have not experienced increases in their pipeline at all. This has resulted in shortages of neonatal nurse practitioners (NNPs)., Purpose: The aim of this study was to gain a greater understanding of the NNP pipeline and potential for increasing the number of new NNPs graduating each year., Methods: Telephone survey of all NNP educational programs., Discussion: Approximately one fourth of all NNP education programs had closed over the past several years. This is despite a strong job market, planned increases in hiring NNPs, and a seemingly growing shortage of NNPs., Conclusion: Problems with the NNP pipeline are not due to a lack of capacity of existing programs, but rather to difficulties in increasing the enrollment demand., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In contrast to family nurse practitioners and other adult nurse practitioners, the percentage of new pediatric nurse practitioners (PNPs) graduating each year has not increased., Purpose: The aim of this study was to determine whether the marginal increase in the pipeline for PNPs is related to a limit in the capacity of educational programs or whether unfilled student openings exist., Methods: Self-administered survey of program directors at all recognized PNP educational programs in the United States., Results: Approximately 10% of PNP programs in the United States were either closed, put on hold, or did not have new graduates in the last 3 years. Even with these closures, over 25% of active programs did not fill all available positions for the class entering in 2012., Conclusion: Despite evidence that demonstrates plans by employers to hire a greater number of PNPs in a variety of clinical venues including pediatric hospitals, primary care and subspecialty pediatric practices, the PNP pipeline has remained relatively stagnant. More than one third of program directors do not believe that their PNP program is currently at capacity, indicating that underutilized capacity to educate PNPs is a hindrance to meeting the current and future demands for these professionals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Objectives: Concern is often expressed about the satisfaction of new physicians and the potential match of their workplace goals with available positions. We studied the interface of desired professional activities with actual initial positions., Methods: Survey study of all general pediatricians taking the 2012 General Pediatrics Certifying Examination., Results: Of the 5210 who sat for the General Pediatrics Certifying Examination, 5163 (>99%) completed the survey. Of the total respondents, 45% self- identified as general pediatricians (N = 2327). Of those who completed training <2 years ago (N = 1365), most were currently engaged in clinical care (87%; N = 1190). The most important factor, cited most frequently by both men and women, in the choice of their first job was lifestyle and spousal or family considerations. Most (83%; N = 977) reported that the allocation of time for specific duties in their current position was consistent with their goals, with no differences between men and women. Most had no desire for inpatient activity., Conclusions: Despite concerns about young general pediatricians being able to find positions that meet their career goals, most were in jobs that approximated their desired allocation of professional time and focus of clinical work., (Copyright © 2015 by the American Academy of Pediatrics.)

Background: The proportion of the newly graduated pediatric workforce that becomes hospitalists has been increasing slightly over the past decade. However, it is unknown what proportion of those who accept hospitalist positions as their first job intend to remain in the field longer term. This is important to workforce projections regarding the magnitude of those who will function in this role., Methods: The American Board of Pediatrics incorporated a structured questionnaire within the online application process to the General Pediatrics certification application. Respondents identified as residents or chief residents who selected "hospitalist position" as their immediate postresidency plan were the focus this study. We compared survey responses by gender and location of the medical school attended., Results: Since the initiation of the general pediatrics certification examination application survey, 6335 completed the questionnaire. 79% (n=5001) were either in residency training or were a chief resident. Of those, 8% (n=376) reported they planned to work as a pediatric hospitalist immediately after completing residency. Fewer than half (43%; n=161) reported this to be their long-term career plan. This finding varied by both medical school type and by gender., Conclusions: The majority of pediatric residents and chief residents who take hospitalist positions immediately after training do not intend for hospital practice to be the long-term focus of their careers. As the field of hospital medicine continues to develop, understanding career trajectories can help inform current and future efforts regarding the potential for different mechanisms for training and certification., (Copyright © 2015 by the American Academy of Pediatrics.)

Introduction: The objective of this study was to determine the prevalence and etiological profile of enteropathogens in children from a daycare center., Methods: From October 2010 to February 2011 stool samples from 100 children enrolled in a government daycare center in the municipality of São José do Rio Preto, in the state of São Paulo, were collected and analyzed., Results: A total of 246 bacteria were isolated in 99% of the fecal samples; 129 were in the diarrheal group and 117 in the non-diarrheal group. Seventy-three strains of Escherichia coli were isolated, 19 of Enterobacter, one of Alcaligenes and one of Proteus. There were 14 cases of mixed colonization with Enterobacter and E. coli. Norovirus and Astrovirus were detected in children with clinical signs suggestive of diarrhea. These viruses were detected exclusively among children residing in urban areas. All fecal samples were negative for the presence of the rotavirus species A and C. The presence of Giardia lamblia, Entamoeba coli, Endolimax nana and hookworm was observed. A significant association was found between food consumption outside home and daycare center and the presence of intestinal parasites., Conclusions: For children of this daycare center, intestinal infection due to pathogens does not seem to have contributed to the occurrence of diarrhea or other intestinal symptoms. The observed differences may be due to the wide diversity of geographical, social and economic characteristics and the climate of Brazil, all of which have been reported as critical factors in the modulation of the frequency of different enteropathogens.

Objective: Little is known regarding the predictors of social deficits that occur following childhood traumatic brain injury (TBI). The current study sought to investigate social problem solving (SPS) and its relationship to social adjustment after TBI., Methods: Participants included 8-13 year old children, 25 with severe TBI, 57 with complicated mild-to-moderate TBI and 61 with orthopaedic injuries (OI). Children responded to scenarios involving negative social situations by selecting from a fixed set of choices their causal attribution for the event, their emotional reaction to the event and how they would behave in response. Parent ratings of social behaviours and classmate friendship nominations and sociometric ratings were obtained for a sub-set of all participants., Results: Children with severe TBI were less likely than children with OI to indicate they would attribute external blame or respond by avoiding the antagonist; they were more likely to indicate they would feel sad and request adult intervention. Although several SPS variables had indirect effects on the relationship between TBI and social adjustment, clinical significance was limited., Conclusions: The findings suggest that, while children with TBI display atypical SPS skills, SPS cannot be used in isolation to accurately predict social adjustment.

Pediatric AIDS caused by human immunodeficiency virus type 1 (HIV-1) remains one of the leading worldwide causes of childhood morbidity and mortality. HIV-1 proteins, such as Tat and gp120, are believed to play a crucial role in the neurotoxicity of pediatric HIV-1 infection. Detrimental effects on development, behavior, and neuroanatomy follow neonatal exposure to the HIV-1 viral toxins Tat1-72 and gp120. The present study investigated the neurobehavioral effects induced by the HIV-1 neurotoxic protein Tat1-86, which encodes the first and second exons of the Tat protein. In addition, the potential effects of HIV-1 toxic proteins Tat1-86 and gp120 on inflammatory pathways were examined in neonatal brains. Vehicle, 25 μg Tat1-86 or 100 ng gp120 was injected into the hippocampus of male Sprague-Dawley pups on postnatal day 1 (PD1). Tat1-86 induced developmental neurotoxic effects, as witnessed by delays in eye opening, delays in early reflex development and alterations in prepulse inhibition (PPI) and between-session habituation of locomotor activity. Overall, the neurotoxic profile of Tat1-86 appeared more profound in the developing nervous system in vivo relative to that seen with the first exon encoded Tat1-72 (Fitting et al., 2008b), as noted on measures of eye opening, righting reflex, and PPI. Neither the direct PD1 CNS injection of the viral HIV-1 protein variant Tat1-86, nor the HIV-1 envelope protein gp120, at doses sufficient to induce neurotoxicity, necessarily induced significant expression of the inflammatory cytokine IL-1β or inflammatory factors NF-κβ and I-κβ. The findings agree well with clinical observations that indicate delays in developmental milestones of pediatric HIV-1 patients, and suggest that activation of inflammatory pathways is not an obligatory response to viral protein-induced neurotoxicity that is detectable with behavioral assessments. Moreover, the amino acids encoded by the second tat exon may have unique actions on the developing hippocampus., (Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.)

Nearly half of all HIV-1-positive individuals on combination antiretroviral therapy (cART) are afflicted with HIV-1-associated neurocognitive disorders (HAND). The most prevalent cognitive deficits observed in the cART era are those of attention and executive function. Presently, we sought to model deficits in attention and core components of executive function (inhibition, flexibility, and set-shifting) observed in HAND using the HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes. Ovariectomized female Fischer HIV-1 Tg and non-transgenic control rats (ns = 39-43) were tested in a series of operant tasks: signal detection, discrimination learning, reversal learning, and extradimensional set-shifting. The HIV-1 Tg animals attained the criterion of three sessions at 70% accuracy at a significantly slower rate than the control animals on all tasks with the exception of the extradimensional set-shifting task. Of the animals that met the criteria, there was no significant difference in percent accuracy in any task. However, the HIV-1 Tg rats showed a lower overall response rate in signal detection and discrimination learning. A discriminant function analysis classified the animals by genotype with 90.4% accuracy based on select measures of their performance. The functional consequences of chronic low-level expression of the HIV-1 proteins on attention, as well as inhibition and flexibility as core components of executive function, are apparent under conditions which resemble the brain proinflammatory immune responses and suppression of infection in HIV-1+ individuals under cART. Deficits in attention and core components of executive function may reflect an underlying impairment in temporal processing in HAND.

Objective: In vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension., Approach and Result: Male wild type and KCa3.1-/-/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1-/-/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype., Conclusion: Despite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension.

Background: The demand for hiring pediatric nurse practitioners (PNPs) is strong. However, the number of newly educated PNPs has remained relatively flat during the past several years. Understanding the rationale and timing for the decision to pursue this profession is essential to having a positive impact on increasing the future workforce., Methods: A mail survey of all new PNPs certified between January 2009 and July 2011 (N = 1040) was conducted., Results: The response rate was 79.9%. Nearly half of all respondents (45%, N = 314) reported that they work in outpatient general pediatrics, 26% (N = 184) in outpatient subspecialty pediatrics, and 22% (N = 152) in inpatient settings. More than one third (36%, N = 253) spend most of their time in a private practice. Forty percent (N = 307) reported that they decided to pursue education as an advanced practice nurse while in practice as a registered nurse (RN), and 38% (N = 289) made the decision before pursuing RN education., Conclusions: Efforts to increase the PNP pipeline will need to be directed both to students during their RN education and to creating opportunities for current RNs to pursue advanced practice nurse education that is focused on children., (Copyright © 2014 National Association of Pediatric Nurse Practitioners. Published by Mosby, Inc. All rights reserved.)

HIV-1-associated neurocognitive disorders (HAND) afflict up to 50 % of HIV-1+ individuals, despite the effectiveness of combination antiretroviral therapy (CART) in reducing the prevalence of more severe neurocognitive impairment. Alterations in brainstem auditory evoked potentials (BAEP), a measure of temporal processing, are one of the earliest neurological abnormalities of HIV-1-positive individuals. Prepulse inhibition (PPI) of the auditory startle response (ASR), a measure of sensorimotor gating, was studied in HIV-1 transgenic (Tg) rats, which express 7 of the 9 HIV-1 genes. Ovariectomized female Fischer HIV-1 Tg and control rats (ns = 41-42) were tested for PPI at three test periods, with at least 2 months separating each test period, using auditory and visual prepulses, an auditory startle stimulus, and interstimulus intervals (ISI) ranging from 0 to 4000 msec. Auditory and visual prepulse trial blocks were presented in counterbalanced order. For both auditory and visual prepulses, HIV-1 Tg animals exhibited a flatter ISI function, which did not sharpen with age, as it did in controls. Over time, auditory prepulses precipitated a temporal shift in peak inhibition in HIV-1 Tg animals relative to controls, whereas with visual prepulses, both groups displayed peak inhibition at the 40 msec ISI. A lack of perceptual sharpening with age and a relative insensitivity to the temporal dimension of sensorimotor gating are evident in the HIV-1 Tg rat prior to clinical signs of wasting. Deficits in sensorimotor gating may not only provide an early subtle diagnostic marker of HAND, but may also afford a key target for development of potential therapeutics.

Aim: To determine if the duration of general practitioner (GP) consultations, or the proportional distribution of item numbers associated with longer consultations, with children has changed in association with the demographic changes in Australia., Method: Secondary data analysis of Medicare claims from 1996 to 2010, which were stratified by patient age and visit type as designated by billing item number, and of the Bettering the Evaluation of Care and Health (BEACH) database was conducted. The Medicare data that were analysed were changes in overall proportion and absolute numbers of longer consultations for children from 1996 to 2010, while the BEACH data that were analysed were changes in the average duration of visits for children and the proportion of visits by children for chronic conditions., Results: Despite the increase in the population of children, and the increasing numbers of children with chronic illness, the absolute number of longer consultations for children has decreased over the time period studied. Further, the proportion of all longer consultations that are being provided to children has diminished. For those consultations that do occur, the GPs are not spending any more time with children in 2010 than they did in consultations in 2000., Conclusions: There have been significant changes in the patterns of longer consultations provided to children by GPs. Efforts to ensure that children receive primary care for chronic conditions and preventive care must now take on a greater urgency for the health-care system., (© The Authors and Commonwealth of Australia. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Clinical studies have provided evidence that the progression of HIV-1-associated neurocognitive disorders (HAND) involves alterations in dopamine (DA) systems. Drugs of abuse that act on the brain DA system, such as cocaine (Coc), may exacerbate HIV-1 infection and consequent behavioral and neurological manifestations. In the present study, we used the HIV-1 transgenic (Tg) rat, which constitutively expresses 7 of the 9 HIV-1 genes, to assess potential DA system alterations in three behavioral assays: prepulse inhibition (PPI) of the auditory startle response (ASR), novelty and habituation/retention, and sensitization to Coc across repeated administration. Adult female Sprague-Dawley rats were tested in each experiment. The HIV-1 Tg animals were hyperreactive to auditory startle stimuli and displayed a leftward shift in the temporal window for maximal PPI, suggesting an alteration in sensorimotor gating. All animals displayed an initial robust locomotor response to a novel environment which dissipated with repeated testing; however, the HIV-1 Tg rats, relative to controls, consistently showed a weaker novelty response across monthly-spaced assessments. The HIV-1 Tg animals also showed decreased intrasession habituation of motor activity across 3-day periods that emerged across monthly-spaced locomotor activity sessions; a pattern consistent with impaired long-term episodic memory. Furthermore, the HIV-1 Tg group displayed differential cocaine-induced sensitization, observed both in initiation across the 10-day cocaine treatment, and in expression following a cocaine rechallenge after a 7-day abstinence. Collectively, the present data implicate that the non-infectious HIV-1 Tg rat, which resembles the complete suppression of infection in HIV-1 positive individuals under CART, displays sustained, if not permanent, alterations in the brain DA system., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: The purposes of this study were to measure a safe zone and a path for ultra-minimally invasive sonographically guided carpal tunnel release with a 1-mm incision in healthy volunteers and then test the procedure in cadavers., Methods: First, a previously reported sonographic zone was defined as the space between the median nerve and the closest ulnar vascular structure. Axially, the safest theoretical cutting point for carpal tunnel release was set by bisecting this zone. Magnetic resonance imaging was used for axially determining the limits of the sectors (origin at the cutting point) that did not enclose structures at risk (arteries and nerves) and coronally for determining whether our release path could require directions that could potentially compromise safety (origin at the pisiform's proximal pole). Second, in cadavers, we performed ultra-minimally invasive sonographically guided carpal tunnel release from an intracarpal position through a 1-mm antebrachial approach. Efficacy (deepest fibrous layer release rate), safety (absence of neurovascular or tendon injury), and damage to any anatomy superficial to transverse carpal ligament were assessed by dissection., Results: All 11 of our volunteers (22 wrists) had safe axial sectors located volar and radially of at least 80.4º (considered safe). Release path directions were theoretically safe (almost parallel to the longitudinal axis of the forearm). In 10 cadaver wrists, ultra-minimally invasive sonographically guided carpal tunnel release was effective (100% release rate) and safe without signs of intrusion into the superficial anatomy., Conclusions: Ultra-minimally invasive sonographically guided carpal tunnel release in a safe sonographic zone may be feasible The technique preserves the superficial anatomy and diminishes the damage of a surgical approach.

Background and Objective: Changes to the structure and nature of resident duty hour assignments can create compensatory workforce needs in hospital or outpatient settings to ensure appropriate patient care. The objective of this study was to understand what, if any, adjustments children's hospitals have made in staffing and assignments of specific duties during the past 2 years as a result of residency duty hour changes, and what changes are anticipated in the upcoming 2 years., Methods: Mail survey to chief executive officers and chief operating officers of 114 freestanding children's hospitals or children's hospitals within a larger hospital., Results: Response rate was 65.4%. Respondents from more than half of hospitals (57%, N = 36) reported increasing the overall full-time equivalent (FTE) of hospitalists in response to the 2011 resident work hour changes. Forty-eight percent (N = 30) increased the overall FTE of pediatric nurse practitioners (PNPs), and 42% (N = 27) increased the FTE of neonatal nurse practitioners (NNPs). Most hospitals plan to increase the number of hospitalists (69%, N = 44), PNPs (59%, N = 37), or pediatric attending physicians (56%, N = 35) over the next 2 years. Forty-three percent (N = 27) of hospitals plan to increase the number of NNPs over the next 2 years, and a quarter plan to increase physician assistants (25%, N = 16) or pediatric house staff (24%, N = 15)., Conclusions: Changes in work hours for pediatric residents appear to have an impact on workforce planning within pediatric hospitals. Decreases in available resident work hours will create an increasing demand, primarily for nonresident physicians, PNPs, and NNPs.

Objectives: Mild traumatic brain injury (TBI) and injury-related outcomes such as postconcussive symptoms (PCS) may influence health-related quality of life (HRQOL) in children., Methods: We evaluated HRQOL in 186 8- to 15-year-old children with mild TBI and 99 children with orthopedic injuries (OI). Parents rated the frequency and severity of PCS at an initial assessment within 2-weeks postinjury and rated HRQOL at 3- and 12-months postinjury., Results: The mild TBI and OI groups did not differ in psychosocial HRQOL, but the mild TBI group showed lower physical HRQOL at the 12-month follow-up. Somatic PCS were a significant predictor of physical HRQOL over time, and both cognitive and somatic PCS were significant predictors of psychosocial HRQOL over time. Children with higher PCS at the initial assessment had lower HRQOL scores at later time points., Conclusions: Effective management of PCS may be associated with improvements in HRQOL following pediatric mild TBI.

Since the introduction of combination antiretroviral therapy (cART) in the mid-90s, the most severe forms of HIV-1-associated neurocognitive disorders (HAND) have diminished. However, milder forms of HAND remain prevalent. Basic and clinical studies implicate alterations in the dopaminergic (DAergic) system in HIV-1 infection. We used the Fischer 344 HIV-1 transgenic (HIV-1 Tg) rat, which expresses 7 of the 9 HIV-1 genes, to examine potential DAergic alterations. Animals were studied beginning at 35 days of age to assess early-onset DAergic alterations, well before any documented neurological symptoms or clinical signs of "wasting". At 48 hr intervals, animals were administered a single dose of methamphetamine (METH) (0, 0.5, 1, 2.5 and 5 mg/kg/ml s.c.) and tested for the auditory startle response (ASR) and prepulse inhibition (PPI), using an auditory prepulse [85 dB(A) broad-band noise stimulus] and an auditory startle stimulus [100 dB(A) broad-band noise stimulus] in a sound-attenuating chamber with a continuous 70 dB(A) white noise background. The protocol used a 5-min acclimation period, 6 startle trials, and 36 PPI trials [ISIs of 0, 8, 40, 80, 120, and 4000 ms, 6-trial blocks, Latin square design]. As the dose of METH increased, PPI of the startle response decreased. The HIV-1 Tg rats displayed a greater dose-dependency to the METH-induced disruption of PPI compared to non-transgenic controls. Western blot analysis of midbrain extracts revealed lower tyrosine hydroxylase (TH) protein levels and higher monoamine oxidase A (MAO-A) protein levels in HIV-1 Tg rats treated with METH compared to non-transgenic controls. Early-detected cognitive alterations in the preattentive process of sensorimotor gating may have significant predictive utility regarding the progression of DAergic alterations in HIV-1 infection.

Objectives: To assess whether postconcussive symptoms (PCS) can be used to discriminate injury severity among children with mild traumatic brain injury (TBI)., Participants: One hundred eighty-six children with mild TBI, divided into high and low injury severity depending on whether the injury was associated with a loss of consciousness (LOC), and a comparison group of 99 children with orthopedic injuries (OI), all aged 8 to 15 years at the time of injury., Main Measures: Parent-rated frequency and severity of PCS at initial assessment within 2 weeks postinjury and again at 3 and 12 months postinjury., Results: Ratings of PCS obtained at the initial and 3-month assessments differentiated children with mild TBI from OI, although only ratings at the initial assessment discriminated among all 3 groups. Somatic PCS accounted for most of the discriminatory power., Conclusions: Overall, the accuracy of group classification was relatively modest, with a large proportion of misclassifications of children in the mild-TBI groups. Although children with mild TBI have more PCS than children with OI, PCS do not permit sufficiently accurate discrimination of mild TBI and injury severity to warrant diagnostic decisions at this time.

One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants' startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the auditory startle response (ASR), habituation, and prepulse inhibition (PPI) in the offspring. Nulliparous Long-Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC) from gestation day (GD) 8-20 (1×/day-GD8-14, 2×/day-GD15-20). COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18-20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg). When reassessed in adulthood (D90-100), a linear dose-response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval and induced significant sex-dependent changes in response latency. Idazoxan, an α(2)-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses.

The epsilon4 allele of the apolipoprotein E (APOE) gene has been linked to negative outcomes among adults with traumatic brain injury (TBI) across the spectrum of severity, with preliminary evidence suggesting a similar pattern among children. This study investigated the relationship of the APOE epsilon4 allele to outcomes in children with mild TBI. Participants in this prospective, longitudinal study included 99 children with mild TBI between the ages of 8 and 15 recruited from consecutive admissions to Emergency Departments at two large children's hospitals. Outcomes were assessed acutely in the Emergency Department and at follow-ups at 2 weeks, 3 months, and 12 months post-injury. Among the 99 participants, 28 had at least one epsilon4 allele. Children with and without an epsilon4 allele did not differ demographically. Children with an epsilon4 allele were significantly more likely than those without an epsilon4 allele to have a Glasgow Coma Scale score of less than 15, but the groups did not differ on any other measures of injury severity. Those with an epsilon4 allele exhibited better performance than children without an epsilon4 allele on a test of constructional skill, but the groups did not differ on any other neuropsychological tests. Children with and without an epsilon4 allele also did not differ on measures of post-concussive symptoms. Overall, the findings suggest that the APOE epsilon4 allele is not consistently related to the outcomes of mild TBI in children.

HIV infection is often associated with frontal systems pathology and related deficits in the strategic encoding and retrieval aspects of episodic memory. However, no prior HIV studies have explicitly examined source memory, which refers to recall of information regarding the context in which a declarative memory was formed. Source memory is heavily reliant on frontal systems and strategic cognitive processes and is singly dissociable from the content of the memory (i.e., item memory), which is more dependent on medial temporal systems and automatic processes. The present study examined item and source memory in 60 individuals with HIV infection and 35 demographically similar seronegative participants. The primary finding of interest was a significant HIV effect on source (but not item) memory for complex visual stimuli. Follow-up correlational analyses showed a significant association between visual source memory errors and impairment on measures of executive functions, working memory, and higher-level list learning encoding strategies. These findings extend the hypothesized profile of strategic encoding and retrieval deficits in HIV to the construct of source memory, which may be differentially affected relative to item memory for complex visual stimuli.

The construct of prospective memory (ProM), or "remembering to remember," is hypothesized to play a critical role in normal activities of daily living and has increasingly been the focus of clinical research over the past 10 years. However, the assessment of ProM as part of routine clinical care is presently hampered by the paucity of psychometrically sound, validated ProM tests available in the neuropsychological literature. The Memory for Intentions Screening Test (MIST; Raskin, 2004) is a user-friendly, comprehensive measure of ProM that demonstrates preliminary evidence of construct validity. Extending this research, this study evaluated the psychometric characteristics of the MIST in a sample of 67 healthy adults. Despite a mildly restricted range of scores, results revealed excellent inter-rater reliability, adequate split-half reliability, and satisfactory inter-relationships between the MIST summary score, subscales, and error types. Analysis of demographic correlates showed that the MIST was independently associated with both age and education, but not with sex or ethnicity. These findings broadly support the psychometric properties of the MIST, specifically its reliability and expected relationships with demographic characteristics. Recommendations are provided regarding future research to enhance the clinical usefulness of the MIST.