Interpreting treatment effect size from single case experimental design data: a preliminary analysis of differential effects of treatments designed to increase or decrease behaviour.

BACKGROUND: Estimates of treatment effect size from single case experimental design (SCED) data may be impacted by the direction for treatment effects (i.e. ascending or descending slope for the dependent variable). Estimating effect sizes for treatments designed to decrease behaviour are potentially more restricted because the intended direction for treatment is zero (i.e. an absolute basal). Conversely, effect sizes for interventions that increase behaviour are less restricted due to a relatively unconstrained ceiling from a pure measurement standpoint (i.e. no absolute ceiling). That is, treatments that increase behaviour have a broader range of possible effect size values as the ceiling is only limited by demand characteristics and the learners' skills and motivation to exhibit the behaviour. METHOD: The current study represents a preliminary analysis of the mean and range of SCED effect sizes for treatments designed to either increase or decrease target behaviour. A within-case Cohen's d measure that was developed for SCED data was used to estimate treatment effect sizes. RESULTS: Results indicated that the mean and range of effect size values for treatments that increased behaviour were significantly greater compared with treatments that decreased behaviour. CONCLUSIONS: Results are discussed in terms of developing standards, or best practices, specific to interpreting effect size values and meeting quality control requirements for inclusion of the data set in future SCED meta-analytic studies estimating treatment effect size. Specifically, preliminary results suggest that benchmarks for low, medium and high SCED effect size values need to be developed separately for treatments that increase or decrease levels of the dependent variable.

Clinical Features and Disease Management in Adult Patients With Atopic Dermatitis Receiving Care at Reference Hospitals in Brazil: the ADAPT Study.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disease with a prevalence of 0.02% to 8.1% in adults. Adult patients with moderate-to-severe atopic dermatitis are affected by frequent relapses and a significant disease burden. Objective: To determine the clinical, immunological, and therapeutic profile of Brazilian adults with atopic dermatitis. METHODS: A multicenter, observational, retrospective, descriptive registry-based study was conducted at reference hospitals between December 2016 and October 2017. The data collected were demographics, personal and family history of atopic diseases, clinical manifestations, laboratory tests, disease severity and management. RESULTS: Of the 187 patients included in the analysis, 56.1% were female and 71.7% were White, with a mean age of 24.7 years. Mean follow-up was 9 years. Asthma or other allergic diseases were reported by 80.2% of patients. The main comorbidity was hypertension (10.2%), and common disease manifestations included pruritus and erythema. Lesions generally affected flexural and nonflexural areas, with typical morphology. Around 83% of patients had moderate-to-severe disease, and 8.6% reported at least 1 hospitalization. Most patients received topical and/or systemic pharmacological therapies, including omalizumab (5.9%); 4.3% received phototherapy. Moreover, 66.8% of patients received adjuvant therapy, and 79.1% changed or discontinued treatment for atopic dermatitis due to remission (46.5%), poor effectiveness (33.7%), or lack of adherence (12.9%). Most patients presented characteristics of type 2 inflammation, with immunoglobulin E levels above 100 IU/mL (94.4%) and peripheral blood eosinophils above 5% (55.9%). CONCLUSION: Brazilian adult patients with severe atopic dermatitis need treatment to efficiently control the disease and improve quality of life.

ß Decay of

The interpretation of observations of cooling neutron star crusts in quasipersistent x-ray transients is affected by predictions of the strength of neutrino cooling via crust Urca processes. The strength of crust Urca neutrino cooling depends sensitively on the electron-capture and ß-decay ground-state-to-ground-state transition strengths of neutron-rich rare isotopes. Nuclei with a mass number of A=61 are predicted to be among the most abundant in accreted crusts, and the last remaining experimentally undetermined ground-state-to-ground-state transition strength was the ß decay of ^{61}V. This Letter reports the first experimental determination of this transition strength, a ground-state branching of 8.1_{-3.1}^{+4.0}%, corresponding to a log ft value of 5.5_{-0.2}^{+0.2}. This result was achieved through the measurement of the ß-delayed γ rays using the total absorption spectrometer SuN and the measurement of the ß-delayed neutron branch using the neutron long counter system NERO at the National Superconducting Cyclotron Laboratory at Michigan State University. This method helps to mitigate the impact of the pandemonium effect in extremely neutron-rich nuclei on experimental results. The result implies that A=61 nuclei do not provide the strongest cooling in accreted neutron star crusts as expected by some predictions, but that their cooling is still larger compared to most other mass numbers. Only nuclei with mass numbers 31, 33, and 55 are predicted to be cooling more strongly. However, the theoretical predictions for the transition strengths of these nuclei are not consistently accurate enough to draw conclusions on crust cooling. With the experimental approach developed in this work, all relevant transitions are within reach to be studied in the future.

Community HIV-1 drug resistance is associated with transmitted drug resistance.

OBJECTIVES: As community viral load (CVL) measurements are associated with the incidence of new HIV-1 infections in a population, we hypothesized that similarly measured community drug resistance (CDR) could predict the prevalence of transmitted drug resistance (TDR). METHODS: Between 2001 and 2011, the prevalences of HIV-1 drug resistance for patients with established infection receiving HIV care (i.e. CDR) and TDR in recently infected patients were determined in San Diego. At each position in HIV-1 reverse transcriptase (RT) and protease (pro), drug resistance was evaluated both as the overall prevalence of resistance-associated mutations and by weighting each resistance position to the concurrent viral load of the patient and its proportion to the total viral load of the clinic (CVL). The weighting was the proportion of the CVL associated with patients identified with resistance at each residue. Spearman ranked correlation coefficients were used to determine associations between CDR and TDR. RESULTS: We analysed 1088 resistance tests for 971 clinic patients and baseline resistance tests for 542 recently infected patients. CDR at positions 30, 46, and 88 in pro was associated with TDR between 2001 and 2011. When CDR was weighted by the viral load of patients, CDR was associated with TDR at position 103 in RT. Each of these associations was corroborated at least once using shorter measurement intervals. CONCLUSIONS: Despite evaluation of a limited percentage of chronically infected patients in San Diego, CDR correlated with TDR at key resistance positions and therefore may be a useful tool with which to predict the prevalence of TDR.

A case cluster demonstrating the relationship between HLA concordance and virologic and disease outcomes in human immunodeficiency virus infection.

We present a detailed analysis of sexual HIV transmission from one source partner to two recipients. The HLA haplotypes between the source partner and one recipient were very similar with 7 out of 8 HLA alleles from four loci (HLA A, B, C and DRB) shared, while the other recipient shared only one allele. The immunologic outcomes between the two recipients differed dramatically, despite the absence of apparent virologic differences in their inoculums. We suggest that non-viral factors, which might be related to differences in the HLA profile, played a role in determining different CD4+ T-cells dynamics for these two recipients.

Predictors of self-injurious behaviour exhibited by individuals with autism spectrum disorder.

BACKGROUND: Presence of an autism spectrum disorder is a risk factor for development of self-injurious behaviour (SIB) exhibited by individuals with developmental disorders. The most salient SIB risk factors historically studied within developmental disorders are level of intellectual disability, communication deficits and presence of specific genetic disorders. Recent SIB research has expanded the search for risk factors to include less commonly studied variables for people with developmental disorders: negative affect, hyperactivity and impulsivity. METHOD: A heterogeneous sample of 617 individuals with autism spectrum disorder diagnoses was derived from the National Database of Autism Research. Latent constructs were estimated from items of the community version of the Aberrant Behaviour Checklist. Structural equation modelling was used to assess whether impulsivity, hyperactivity, negative affect, severity of stereotypy, intellectual functioning or severity of autism symptoms predicted severity of SIB. RESULTS: Impulsivity (ß = 0.46), followed by intellectual functioning (ß = -0.39), and stereotypy (ß = 0.23) were the variables most highly predictive of increased SIB; impulsivity and stereotypy remained significant predictors of SIB after severity of autism symptoms and intelligence quotient (IQ) were controlled for. CONCLUSIONS: High levels of impulsivity and stereotypy were significant predictors of SIB in a large and diverse sample of people with confirmed autism diagnoses. Future research is needed on the effects of reducing impulsivity and stereotypy on the outcomes of treatment, early intervention and attempts to prevent the development of SIB.

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy.

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Resting cerebral blood flow: a potential biomarker of the effects of HIV in the brain.

OBJECTIVE: HIV enters the brain soon after infection causing neuronal damage and microglial/astrocyte dysfunction leading to neuropsychological impairment. We examined the impact of HIV on resting cerebral blood flow (rCBF) within the lenticular nuclei (LN) and visual cortex (VC). METHODS: This cross-sectional study used arterial spin labeling MRI (ASL-MRI) to measure rCBF within 33 HIV+ and 26 HIV- subjects. Nonparametric Wilcoxon rank sum test assessed rCBF differences due to HIV serostatus. Classification and regression tree (CART) analysis determined optimal rCBF cutoffs for differentiating HIV serostatus. The effects of neuropsychological impairment and infection duration on rCBF were evaluated. RESULTS: rCBF within the LN and VC were significantly reduced for HIV+ compared to HIV- subjects. A 2-tiered CART approach using either LN rCBF < or =50.09 mL/100 mL/min or LN rCBF >50.09 mL/100 mL/min but VC rCBF < or =37.05 mL/100 mL/min yielded an 88% (29/33) sensitivity and an 88% (23/26) specificity for differentiating by HIV serostatus. HIV+ subjects, including neuropsychologically unimpaired, had reduced rCBF within the LN (p = 0.02) and VC (p = 0.001) compared to HIV- controls. A temporal progression of brain involvement occurred with LN rCBF significantly reduced for both acute/early (<1 year of seroconversion) and chronic HIV-infected subjects, whereas rCBF in the VC was diminished for only chronic HIV-infected subjects. CONCLUSION: Resting cerebral blood flow (rCBF) using arterial spin labeling MRI has the potential to be a noninvasive neuroimaging biomarker for assessing HIV in the brain. rCBF reductions that occur soon after seroconversion possibly reflect neuronal or vascular injury among HIV+ individuals not yet expressing neuropsychological impairment.

Detection of HIV-1 in alternative specimen types using the APTIMA HIV-1 RNA Qualitative Assay.

Peripheral blood mononuclear cells (PBMCs), saliva, seminal plasma, and dried blood spots were evaluated as specimen types for the APTIMA HIV-1 RNA Qualitative Assay (APTIMA HIV-1 Assay), which employs a target capture step to recover HIV-1-specific sequences from complex specimen types. Analytical sensitivity studies were carried out using samples that were either diluted or eluted with a buffered detergent and spiked with different concentrations of HIV-1 ranging from 1 to 10,000 copies/mL. PBMC samples spiked with HIV-1 had comparable analytical sensitivity to HIV-1 spiked plasma with a 95% limit of detection of 13.1 and 17.2 copies/mL, respectively. Analytical sensitivity in seminal plasma specimens diluted 1:5 and saliva diluted 1:2 was comparable to HIV-1 spiked dilution buffer alone. Whole blood and dried blood spot specimens spiked with HIV-1 had equivalent reactivity at 250 copies/spot (5000 copies/mL). However, the 95% limit of detection values were significantly different (293.7 copies/mL for whole blood and 2384 copies/mL for dried blood spot specimens). No significant effect on analytical sensitivity was observed when one HIV-1 positive dried blood spot punch was pooled with up to 9 HIV-1 negative dried blood spot punches. Together, these studies demonstrate that the APTIMA HIV-1 RNA Qualitative Assay can be used to process a diverse array of specimen types with minimal impact on analytical sensitivity for most specimen types.

An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis.

BACKGROUND: This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with myasthenia gravis (MG). METHODS: Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America [MGFA] criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety. RESULTS: A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%). CONCLUSIONS: Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.

Estimating selection pressures on HIV-1 using phylogenetic likelihood models.

Human immunodeficiency virus (HIV-1) can rapidly evolve due to selection pressures exerted by HIV-specific immune responses, antiviral agents, and to allow the virus to establish infection in different compartments in the body. Statistical models applied to HIV-1 sequence data can help to elucidate the nature of these selection pressures through comparisons of non-synonymous (or amino acid changing) and synonymous (or amino acid preserving) substitution rates. These models also need to take into account the non-independence of sequences due to their shared evolutionary history. We review how we have developed these methods and have applied them to characterize the evolution of HIV-1 in vivo. To illustrate our methods, we present an analysis of compartment-specific evolution of HIV-1 env in blood and cerebrospinal fluid and of site-to-site variation in the gag gene of subtype C HIV-1.

Early intervention and prevention of self-injurious behaviour exhibited by young children with developmental disabilities.

The ontogeny of self-injurious behaviour exhibited by young children with developmental delays or disabilities is due to a complex interaction between neurobiological and environmental variables. In this manuscript, the literature on emerging self-injury in the developmental disability population is reviewed with a focus on an operant conceptual model of how topographies of self-injurious behaviour can change structurally and become sensitive to various environmental consequences. Results of previous studies are reviewed in terms of extending our research focus from a reactive model of assessment and treatment of well-established cases of self-injury to an early intervention and prevention model.

Maintenance of Nef-mediated modulation of major histocompatibility complex class I and CD4 after sexual transmission of human immunodeficiency virus type 1.

Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and recipients. These results weighed against the selection of specific Nef functions by transmission or during acute infection. Measurement of Nef function provided no evidence that the down-regulation of either CD4 or MHC-I was optimized by transmission or during acute infection, although rare nef clones from sources that were impaired in these activities were not detected in recipients. Nef-specific CTL activity was detected as early as 3 weeks after infection and appeared to be an evolutionary force driving the diversification of nef. Despite the change in selective pressure between the source and recipient immune systems and concomitant genetic diversity, the majority of Nef proteins maintained robust abilities to down-regulate MHC-I and CD4. These data suggest that both functions are important for the successful establishment of infection in a new host.

A measure of food seeking in individuals with Prader-Willi syndrome.

BACKGROUND: Individuals with Prader-Willi syndrome (PWS), a chromosome 15 genetic disorder, often have a significant preoccupation with food and problem behaviour related to food seeking is often prevalent. METHODS: In the present study, we compared how individuals with PWS responded on a survey regarding the acceptability of food in various locations that varied according to degree of appropriateness for human consumption (e.g. food on a plate, food in a garbage can). For a subgroup of participants, we observed how they actually responded when placed in a room with food items placed in the same locations depicted in the survey. In the first part of the study, three groups (25 typically developing individuals, 7 individuals with intellectual disability (ID), and 19 individuals with PWS) responded to a visual survey to determine the degree of acceptability of food items in various locations (e.g. on a table near a hairbrush, on the floor behind a toy box, in a trash can). In the second part of the study, these food items (popcorn, jelly beans) were placed in the 12 locations described above. Nine individuals diagnosed with PWS (deletion type) and three individuals with ID were given some break time in the room for 15 min. The amount of food consumed, the time spent food seeking, and time spent interacting with materials were measured. RESULTS: Results of the survey indicated that the PWS group differed significantly with regard to how they responded on the survey from the typically developing group, but did not differ significantly from the ID group. Results of the food seeking observations indicated that only three individuals with PWS ate a significant number of items. The three individuals did not differ from the rest of the group according to IQ or compulsivity score; however, they had significantly lower body mass index (BMI) scores and were younger than the other participants. CONCLUSIONS: The findings from the survey indicate that individuals with PWS are able to discriminate the appropriateness of eating items in more or less contaminated areas; however, the amount of time spent seeking food and the amount of food covertly consumed appeared to depend more directly on age and BMI.

Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy.

Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance (P = 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits (P = 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns (P = 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS.

Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence.

Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.

Spatiotemporal dynamics of HIV propagation.

Although viral propagation is a localized process, mathematical models of viral replication kinetics have been limited to systems of ordinary differential equations describing spatially averaged behavior. In this paper, we introduce a cellular automaton model of viral propagation based on the known biophysical properties of HIV. In particular, we include the competition between viral lability and Brownian motion. The model predicts three testable effects not present in previous descriptions. First, we find a profound dependence of viral infectivity on cell concentration; virion instability decreases infectivity more than 100-fold under typical experimental conditions, resulting in misleading estimates of the number of infectious particles. Second, we find that, in a large parameter regime, infection extinguishes itself due to insufficient target cell replenishment. Finally, we find that propagation is limited by viral stability at low cell density and by geometry at high cell density. The geometry-limited regime can be modulated by downregulation of CD4. These different properties are analysed quantitatively and compared with previous experimental results.

Evidence for increased T cell turnover and decreased thymic output in HIV infection.

The effects of HIV infection upon the thymus and peripheral T cell turnover have been implicated in the pathogenesis of AIDS. In this study, we investigated whether decreased thymic output, increased T cell proliferation, or both can occur in HIV infection. We measured peripheral blood levels of TCR rearrangement excision circles (TREC) and parameters of cell proliferation, including Ki67 expression and ex vivo bromodeoxyuridine incorporation in 22 individuals with early untreated HIV disease and in 15 HIV-infected individuals undergoing temporary interruption of therapy. We found an inverse association between increased T cell proliferation with rapid viral recrudescence and a decrease in TREC levels. However, during early HIV infection, we found that CD45RO-CD27high (naive) CD4+ T cell proliferation did not increase, despite a loss of TREC within naive CD4+ T cells. A possible explanation for this is that decreased thymic output occurs in HIV-infected humans. This suggests that the loss of TREC during HIV infection can arise from a combination of increased T cell proliferation and decreased thymic output, and that both mechanisms can contribute to the perturbations in T cell homeostasis that underlie the pathogenesis of AIDS.

Stimulus characteristics within directives: effects on accuracy of task completion.

Three experiments were conducted in an outpatient setting with young children who had been referred for treatment of noncompliant behavior and who had coexisting receptive language or receptive vocabulary difficulties. Experiment 1 studied differential responding of the participants to a brief hierarchical directive analysis (least-to-most complex stimulus prompts) to identify directives that functioned as discriminative stimuli for accurate responding. Experiment 1 identified distinct patterns of accurate responding relative to manipulation of directive stimulus characteristics. Experiment 2 demonstrated that directives identified as effective or ineffective in obtaining stimulus control of accurate responding during Experiment 1 continued to control accurate responding across play activities and academic tasks. Experiment 3 probed effects of the interaction between the type of directive (effective vs. ineffective) and the reinforcement contingency (differential reinforcement for attempts vs. differential reinforcement for accurate responses) on accurate task completion and disruptive behavior. Results suggested that behavioral escalation from inaccurate responding to disruptive behavior occurred only when ineffective directives were combined with differential reinforcement for accurate task completion. The overall results are discussed in terms of developing a methodology for identifying stimulus characteristics of directives that affect accurate responding.