Addressing HIV stigma in healthcare, community, and legislative settings in Central and Eastern Europe.

INTRODUCTION: Surging HIV prevalence across countries of Central and Eastern Europe (CEE) is largely a result of poor HIV care engagement and a lack of comprehensive support for key populations. This is fostered by widespread stigma across healthcare, community, and legislative settings. DISCUSSION: Throughout CEE, HIV stigma and intersectional stigma are serious obstacles to providing adequate medical care to people living with HIV. Anticipated and enacted (experienced) stigma from healthcare professionals, and fears of breaches in confidentiality, deter individuals from having an HIV test and engaging in HIV care. Furthermore, negative connotations surrounding HIV infection can lead to discrimination from family, friends, colleagues, and the public, leading to internalized stigma and depression. Key populations that have higher HIV prevalence, such as men who have sex with men, people who inject drugs, transgender individuals, and sex workers, experience additional stigma and discrimination based on their behaviour and identities. This contributes to the concentrated HIV epidemics seen in these populations in many CEE countries. The stigma is exacerbated by punitive legislation that criminalizes HIV transmission and penalizes sexual orientation, drug use, gender identities, and sex work. Despite high levels of HIV stigma and intersectional stigma, there are many evidence-based interventions that have reduced stigma in other parts of the world. Here, we discuss the interventions that are currently being enacted in various countries of CEE, and we suggest additional effective, evidence-based interventions that will tackle stigma and lead to increased HIV care engagement and higher rates of viral suppression. We cover the promotion of the undetectable = untransmittable (U = U) message, stigma-reduction education and training for healthcare professionals, patient-centric approaches for testing and treatment, and advocacy for non-discriminatory legislation, policies, and practices. We also consider targeted stigma-reduction interventions that acknowledge the wider challenges faced by marginalized populations. CONCLUSIONS: HIV stigma and intersectional stigma in CEE drive poor engagement with HIV testing services and care. Widespread adoption of evidence-based interventions to tackle stigma highlighted in this review will improve the quality of life of people living with HIV, improve HIV care engagement, and ultimately slow the surging HIV prevalence and concentrated epidemics occurring throughout CEE.

Home direct-to-consumer telehealth solutions for children with mental health disorders and the impact of Covid-19.

Delivery of mental health treatment in the home can close gaps in care. Telehealth also provides access to healthcare that has been disrupted due to the COVID-19 pandemic. In 2016, a home direct-to-consumer telehealth program was initiated. Mental health encounters made up a significant portion of all telehealth encounters and COVID-19 had a significant impact on accelerating the utilization of telehealth. Telemental health has been more successful at meeting targeted volumes than the overall health system. Of all the mental health diagnoses before and during COVID-19, attention deficit hyperactivity disorder, Autism Spectrum Disorder, and Anxiety Disorder were most common. The direct-to-consumer telehealth program saved patients a significant amount of travel miles and associated time, based on data from the period before COVID-19. Payment reimbursement for direct-to-consumer telehealth professional services was similar to reimbursement for in-person visits. This program demonstrates direct-to-consumer telehealth is a feasible and acceptable care modality for a variety of youth mental health disorders.

Effects of a Staff Training Intervention on Seclusion Rates on an Adult Inpatient Psychiatric Unit.

The current article presents the effects of a 90-minute staff training intervention aimed at reducing inpatient psychiatric seclusion rates through strengthened staff commitment to seclusion alternatives and improved de-escalation skills. The intervention occurred at an 18-bed adult inpatient psychiatric unit whose seclusion rates in 2015 were seven times the national average. Although the project's primary outcome compared patient seclusion rates before and after the intervention, anonymous staff surveys measured several secondary outcomes. Seclusion rates were reduced from a 6-month pre-intervention average of 2.95 seclusion hours per 1,000 patient hours to a 6-month post-intervention average of 0.29 seclusion hours per 1,000 patient hours, a 90.2% reduction. Completed staff surveys showed significant staff knowledge gains, non-significant changes in staff attitudes about seclusion, non-significant changes in staff de-escalation skill confidence, and use of the new resource sheet by only 17% of staff. The key study implication is that time-limited, focused staff training interventions can have a measurable impact on reducing inpatient seclusion rates. [Journal of Psychosocial Nursing and Mental Health Services, 56(6), 23-30.].

Neuropsychological Functioning in Preterm-Born Twins and Singletons at Preschool Age.

OBJECTIVES: A limited body of research is available on the relationships between multiplicity of birth and neuropsychological functioning in preterm children who were conceived in the age of assisted reproductive technology and served by the modern neonatal intensive care unit. Our chief objective was to evaluate whether, after adjustment for sociodemographic factors and perinatal complications, twin birth accounted for a unique portion of developmental outcome variance in children born at-risk in the surfactant era. METHODS: We compared the neuropsychological functioning of 77 twins and 144 singletons born preterm (<34 gestational weeks) and served by William Beaumont Hospital, Royal Oak, MI. Children were evaluated at preschool age, using standardized tests of memory, language, perceptual, and motor abilities. RESULTS: Multiple regression analyses, adjusting for sociodemographic and perinatal variables, revealed no differences on memory or motor indices between preterm twins and their singleton counterparts. In contrast, performance of language and visual processing tasks was significantly lower in twins despite reduced perinatal risk in comparison to singletons. Effect sizes ranged from .33 to .38 standard deviations for global language and visual processing ability indices, respectively. No significant group by sex interactions were observed, and comparison of first-, or second-born twins with singletons yielded medium effect sizes (Cohen's d=.56 and .40, respectively). CONCLUSIONS: The modest twin disadvantage on language and visual processing tasks at preschool-age could not be readily attributable to socioeconomic or perinatal variables. The possibility of biological or social twinning-related phenomena as mechanisms underlying the observed performance gaps are discussed. (JINS, 2016, 22, 865-877).

Physical growth in the neonatal intensive-care unit and neuropsychological performance at preschool age in very preterm-born singletons.

We studied the associations between early postnatal growth gains and neuropsychological outcome in very preterm-born children. Specifically, we wished to establish whether relationships exist between gains in head circumference (relative to gains in body-weight or length), from birth to hospital discharge, and intellectual, language, or motor, performance at preschool age. We used data from 127 preschoolers, born <33 weeks, all graduates of the William Beaumont Hospital Neonatal Intensive-Care Unit (NICU) in Royal Oak, MI. Cognitive, motor, and language outcomes were evaluated using the Wechsler Preschool and Primary Scales of Intelligence-Revised, Peabody Developmental Scales - 2(nd) Edition, and the Preschool Language Scale - 3(rd) Edition, respectively. Differences between Z-scores at birth and hospital discharge, calculated for three anthropometric measures (head circumference, weight, length), were variables of interest in separate simultaneous multiple regression procedures. We statistically adjusted for sex, socioeconomic status, birth weight, length of hospitalization, perinatal complications, and intrauterine growth. Examination of the relationships between anthropometric indices and outcome measures revealed a significant association between NICU head growth and global intelligence, with the Z-difference score for head circumference accounting for a unique portion of the variance in global intelligence (ηp(2) =.04). Early postnatal head growth is significantly associated with neuropsychological outcome in very preterm-born preschoolers. To conclude, despite its relative brevity, NICU stay, often overlapping with the end of 2(nd) and with the 3(rd) trimester of pregnancy, appears to be a sensitive developmental period for brain substrates underlying neuropsychological functions.

The Relation Between Testing Environment and Baseline Performance in Child and Adolescent Concussion Assessment.

BACKGROUND: Previous research has demonstrated differences in cognitive performance when baseline concussion assessment is performed in a group versus an individual setting. Accurate baseline assessment is imperative when such data are used to make clinical decisions regarding cognitive and symptom recovery after concussion. HYPOTHESIS: The use of similar standardized test administration procedures and test conditions across group and individual settings results in no differences in cognitive performance or symptom reporting. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 939 participants (aged 5-18 years), including 313 tested individually and 626 tested in a group setting, matched on age, sex, and attention-deficit/hyperactivity disorder status, were administered concussion baseline assessment using the desktop version of the Immediate Post-Concussion Assessment and Cognitive Testing and a new pediatric measure, the Multimodal Assessment of Cognition & Symptoms for Children. Cognitive performance, symptom reports, and rates of invalid performance were compared between settings. RESULTS: No significant differences were found between individual and group testing settings for the age-based Learning and Memory Accuracy composite and Response Speed composite standard scores on the Multimodal Assessment of Cognition & Symptoms for Children. Accounting for age and sex, adolescents' performance on the Immediate Post-Concussion Assessment and Cognitive Testing revealed no differences between settings on the 4 composite raw scores (Verbal Memory, Visual Memory, Visual Motor Speed, and Reaction Time). Furthermore, symptom reporting was similar between settings on both measures. Rates of invalid performance did not differ between the 2 administration groups for either age group. There was an interaction effect for invalid performance between attention-deficit/hyperactivity disorder and setting in younger children (aged 5-12 years), with higher rates of invalid performance for children in the group setting with attention-deficit/hyperactivity disorder compared with those without, although there were no differences in the individual setting. CONCLUSION: In this sample, children given a baseline assessment in a group setting performed no differently than children tested individually when standardized administration procedures were used by trained test administrators. Previous evidence suggesting differences between settings may be attributable to the variability in test administration and supervision rather than the environment itself. The importance of standardized procedures and proper supervision during baseline concussion assessment is supported by these findings.

Performance of direct estradiol immunoassays with human male serum samples.

BACKGROUND: Steroid immunoassays originally required solvent extraction, chromatography, and structurally authentic tracers to avoid interference from steroid cross-reactivity and matrix effects. The demand for steroid assays has driven assay simplification, bypassing this triplet of validity criteria to allow use of unextracted serum, which has introduced bias and nonspecificity at low steroid concentrations. We aimed to evaluate the performance of commercial direct estradiol (E2) immunoassays relative to the reference method of LC-MS and compared serum E2 measurements from each assay with biomarkers of estrogen action. METHODS: We measured serum E2 in duplicate using 5 commercial direct immunoassays and LC-MS in a nested cohort of 101 healthy, asymptomatic men >40 years old from the Healthy Man Study. For each immunoassay, we evaluated the detectability and distribution of serum E2 measurements, CV, and bias (relative to LC-MS) by Passing-Bablok regression and deviance plots. RESULTS: Three assays detected E2 in all samples, whereas E2 was detected in only 53% and 72% of samples by 2 other assays. All 5 assays had positive biases, ranging from 6% to 74%, throughout their ranges. CVs were lower with 4 immunoassays than with LC-MS. LC-MS, but none of the direct immunoassays, correlated with serum testosterone and sex steroid-binding globulin. CONCLUSIONS: The positive bias of direct E2 immunoassays throughout their working range reflects the nonspecific effects of steroid cross-reactivity and/or matrix interference arising from the violation of the triplet validity criteria for steroid immunoassay.

Postnatal growth and neuropsychological performance in preterm-birth preschoolers.

OBJECTIVE: Compromised postnatal growth is an important risk factor accounting for poorer neuropsychological performance of preterm children during the preschool years, yet its unique contribution to explaining outcome variance within this high risk group has yet to be determined. Therefore, we examined within a large preterm sample (1) the relationships between head growth, measured either at birth or preschool age, and outcome; (2) the relationships of binary versus dimensional head growth measures and performance; and (3) the unique contribution of preschool-age head growth, after adjustment for general physical development (indexed by stature), to variance in neuropsychological functioning. METHOD: We evaluated 264 preterm (<36 weeks) preschoolers, without severe handicaps, using cognitive, language, and motor skill measures. Multiple regression analyses, adjusting for sociodemographic factors and pre-, peri-, and postnatal confounds, were used to study associations between growth indices and performance. RESULTS: While suboptimal head growth classification at birth was significantly associated only with motor performance, suboptimal head growth at preschool age explained a significant portion of variance in intellectual and language measures (g = .46 to .60). Treating preschool head size as a continuous dimension yielded null results, however, with body-height explaining a significant portion of the variance across several domains. CONCLUSION: Among postnatal anthropometric indices, preschool stature, rather than head circumference, remains a consistent correlate of preschool outcome in preterm children, highlighting the contribution of general physical development to neuropsychological performance. Further investigation of the underlying mechanisms likely involves exploration of complex relationships between postnatal nutrition, growth hormone levels, body and brain development, and neuropsychological functioning.

Assessment of processing speed in children with mild TBI: a "first look" at the validity of pediatric ImPACT.

UNLABELLED: Deficit in the speed of cognitive processing is a commonly identified neuropsychological change in children recovering from a mild TBI. However, there are few validated child assessment instruments that allow for serial assessment over the course of recovery in this population. Pediatric ImPACT is a novel measure that purports to assess cognitive speed, learning, and efficiency in this population. The current study sought to validate the use of this new measure by comparing it to traditional paper and pencil measures of processing speed. METHOD: One hundred and sixty-four children (71% male) age 5-12 with mild TBI evaluated in an outpatient concussion clinic were administered Pediatric ImPACT and other neuropsychological test measures as part of a flexible test battery. RESULTS: Performance on the Response Speed Composite of Pediatric ImPACT was more strongly associated with other measures of cognitive processing speed, than with measures of immediate/working memory and learning/memory in this sample of injured children. CONCLUSIONS: There is preliminary support for convergent and discriminant validity of Pediatric ImPACT as a measure for use in post-concussion evaluations of processing speed in children.

Rotenone formulation fate in Lake Davis following the 2007 treatment.

In September 2007, Lake Davis (near Portola, California) was treated by the California Department of Fish and Game with CFT Legumine, a rotenone formulation, to eradicate the invasive northern pike (Esox lucius). The objective of this report is to describe the fate of the five major formulation constituents-rotenone, rotenolone, methyl pyrrolidone (MP), diethylene glycol monethyl ether (DEGEE), and Fennedefo 99-in water, sediment, and brown bullhead catfish (Ameiurus nebulosus; a rotenone-resistant species) by determination of their half-lives (t(1/2)) and pseudo first-order dissipation rate constants (k). The respective t(1/2) values in water for rotenone, rotenolone, MP, DEGEE, and Fennedefo 99 were 5.6, 11.1, 4.6, 7.7, and 13.5 d; in sediments they were 31.1, 31.8, 10.0, not able to calculate, and 48.5 d; and in tissues were 6.1, 12.7, 3.7, 3.2, and 10.4 d, respectively. Components possessing low water solubility values (rotenone and rotenolone) persisted longer in sediments (not detectable after 157 d) and tissues (<212 d) compared with water, whereas the water-miscible components (MP and DEGEE) dissipated more quickly from all matrices, except for Fennedefo 99, which was the most persistent in water (83 d). None of the constituents was found to bioaccumulate in tissues as a result of treatment. In essence, the physicochemical properties of the chemical constituents effectively dictated their fate in the lake following treatment.

Intrauterine growth and neuropsychological performance in very low birth weight preschoolers.

In this study we examined the association between intrauterine growth, indexed either as a categorical variable or continuous dimension, and neuropsychological outcome, in a very low birth weight (VLBW) sample of 143 preschoolers. When the commonly used split at the 10th percentile rank was applied to classify intrauterine growth restriction (IUGR), we found that the growth restricted group (n = 25) exhibited significantly poorer performance in the global motor domain, but not on any other neuropsychological measure. In contrast, when adequacy of intrauterine growth was indexed by standardized birth weight, a continuous dimension, this early risk factor explained a unique portion of the variance in global cognitive abilities and visuospatial skills, as well as in global, fine, and gross motor skills. These findings are consistent with recent magnetic resonance imaging data disclosing global neurodevelopmental changes in the brains of preterm infants with IUGR. When cases classified with IUGR (<10th percentile) were excluded, the relationship between adequacy of intrauterine growth and global cognitive abilities remained significant despite range restriction. Hence, an association between appropriateness of intrauterine growth and global intellectual outcome may be observed even within the population of VLBW preschoolers with adequate standardized birth weight.

Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.

The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.

Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel.

TrpA1 is an ion channel involved in nociceptive and inflammatory pain. It is implicated in the detection of chemical irritants through covalent binding to a cysteine-rich intracellular region of the protein. While performing an HTS of the Pfizer chemical collection, a class of pyrimidines emerged as a non-reactive, non-covalently binding family of agonists of the rat and human TrpA1 channel. Given the issues identified with the reference agonist Mustard Oil (MO) in screening, a new, non-covalently binding agonist was optimized and proved to be a superior agent to MO for screening purposes. Compound 16a (PF-4840154) is a potent, selective agonist of the rat and human TrpA1 channel and elicited TrpA1-mediated nocifensive behaviour in mouse.

Neonatal respiratory dysfunction and neuropsychological performance at the preschool age: a study of very preterm infants with bronchopulmonary dysplasia.

OBJECTIVE: The neuropsychological outcome of chronic lung disease (CLD) in the very preterm (VP) infant may be determined by a process involving chronic hypoxia, with superimposed acute hypoxic episodes, in the developing brain. We wished to study the differences in quality of outcome between VP preschoolers with and without history of the most common form of CLD in the preterm infant, bronchopulmonary dysplasia (BPD). We also examined the strength of association between BPD severity and neuropsychological outcome, with degree of severity defined according to the National Institute of Child Health and Human Development (NICHD) National Heart, Lung and Blood Institute (NHLBI) Workshop categorical ranking scheme (Jobe & Bancalari, 2001) or in accord with dimensional views of severity of respiratory illness. METHOD: We evaluated the intellectual, language, and motor outcomes of 156, predominantly middle-class preschoolers with history of VP birth, with (n = 80) or without (n = 76) BPD. We used supplemental oxygen requirement or need for mechanical ventilation as indirect indexes of respiratory dysfunction. RESULTS: Following adjustment for potentially confounding sociodemographic variables and perinatal medical risk factors, we found no group differences in neuropsychological outcome based on categorical ranking of BPD severity. However, continuous measures of BPD severity accounted for a unique portion of the variance in fine motor performance (η²p = .05), while patent ductus arteriosus, a risk marker or antecedent of BPD, explained a unique portion of the variance in both receptive language (η²p = .048), and gross motor (η²p = .061) function. CONCLUSION: A significant, yet circumscribed, association was demonstrated between neonatal hypoxic risk, in the VP infant, and neuropsychological outcome assessed in the preschool years.

Part 3: Design and synthesis of proline-derived α2δ ligands.

A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.

Part 2: Design, synthesis and evaluation of hydroxyproline-derived α2δ ligands.

Conformational constraint has been used to design a potent series of α(2)δ ligands derived from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development.

Extreme prematurity and neuropsychological outcome in the preschool years.

With the increasing survival of extremely preterm (EP) birth infants in the surfactant era, the longer-term outcome of infants born at the threshold of viability has become a vital topic of study. The goal of this investigation was twofold. First, while taking into account the influence of sociodemographic confounds, we wished to investigate neuropsychological outcome differences between two groups of EP preschoolers: 23-24 weeks (n = 20), and 25-26 weeks' (n = 21) gestation at delivery. Second, we wished to explore whether, within the population of EP preschoolers, gestational maturity accounts for a unique portion of the variance in neuropsychological outcome, over and above the variance explained by ante-, peri-, and neonatal complications, or treatment factors. The findings revealed group differences, ranging from .70 to .80 of a standard deviation in general intellectual abilities, nonverbal intelligence, and global motor performance, in favor of the more mature EP group. Additionally, gestational maturity was found to explain a unique portion of the variance in global intellectual and motor abilities. These findings are interpreted from the perspective that gestational age is an index of the vulnerability of the central nervous system to disruption of developmentally regulated processes.

Assessing hypogonadism in men--how helpful are current testosterone assays?

In recent years, hormone therapy (HT) with testosterone has gained increasing prominence and popularity in aging men. It has a demonstrated ability to decrease fat mass and increase lean body mass in men with initial 'low' testosterone levels. The Australian Pharmaceutical Benefits Scheme (PBS) only allows subsidisation of male HT if two morning testosterone values are <8.0 nmol/L (or 8-15 nmol/L with elevated luteinising hormone [LH]). The scientific basis of this 'cut off' for testosterone replacement is unclear but it is close to the lower limit of normal for some laboratories. There is well documented diurnal variation (and even seasonal variation) of testosterone. However, the PBS requirements avoid such diurnal variation by requiring two morning blood samples. The underlying assumption is that all laboratories obtain similar results.

Sorption and degradation of pesticides in nursery recycling ponds.

Knowledge of pesticide distribution and persistence in nursery recycling pond water and sediment is critical for preventing phytotoxicity of pesticides during water reuse and to assess their impacts to the environment. In this study, sorption and degradation of four commonly used pesticides (diazinon, chlorpyrifos, chlorothalonil, and pendimethalin) in sediments from two nursery recycling ponds was investigated. Results showed that diazinon and chlorothalonil were moderately sorbed [K(OC) (soil organic carbon distribution coefficient) from 732 to 2.45 x 10(3) mL g(-1)] to the sediments, and their sorption was mainly attributable to organic matter content, whereas chlorpyrifos and pendimethalin were strongly sorbed (K(OC) > or = 7.43 x 10(3) mL g(-1)) to the sediments, and their sorption was related to both organic matter content and sediment texture. The persistence of diazinon and chlorpyrifos was moderate under aerobic conditions (half-lives = 8 to 32 d), and increased under anaerobic conditions (half-lives = 12 to 53 d). In contrast, chlorothalonil and pendimethalin were quickly degraded under aerobic conditions with half-lives < 2.8 d, and their degradation was further enhanced under anaerobic conditions (half-lives < 1.9 d). The strong sorption of chlorpyrifos and pendimethalin by the sediments suggests that the practice of recycling nursery runoff would effectively retain these compounds in the recycling pond, minimizing their offsite movement. The prolonged persistence of diazinon and chlorpyrifos, however, implies that incidental spills, such as overflows caused by storm events, may contribute significant loads of such pesticides into downstream surface water bodies.