Addressing Syndemics and Self-care in Individuals with Uncontrolled HIV: An Open Trial of a Transdiagnostic Treatment.

Interventions addressing syndemics and ART adherence are needed for individuals with uncontrolled HIV and psychosocial problems. Twenty-seven participants with detectable HIV plasma viral load (PVL) or recent STI participated in an open trial of transdiagnostic adherence counseling and cognitive behavioral therapy. Outcomes were collected at baseline, 4-, and 8-months. Log PVL improved from baseline to 4-month (γ = - 1.13, 95% CI - 1.72, - 0.55, p < 0.001) and 8-month (γ = - 0.93, 95% CI - 1.57, - 0.30, p = 0.006), with more participants suppressed at 4- (χ2(1) = 9.09, p = 0.001) and 8-month (χ2(1) = 5.14, p = 0.016). Self-reported adherence improved across major assessments (γ = 0.87, 95% CI 0.28, 1.46, p = .005); Wisepill adherence did not. Negative affect declined during treatment (γ = - 0.28, 95% CI - 0.40, - 0.16, p < 0.001), with improvement at 4- (γ = - 4.34, 95% CI - 6.99, - 1.69, p = 0.002) but not 8-month. Positive affect trended positively during treatment and from baseline to 4-month, with significant 8-month improvement (γ = 3.84, 95% CI 0.33, 7.44, p = 0.04). Depressive symptoms did not change. In a complicated sample of participants selected for uncontrolled HIV, the intervention yielded improved PVL and self-reported adherence. Efforts to end HIV should improve upon strategies such as these, addressing syndemics. Registration: clinicaltrial.gov: NCT02696681.

Transition-transversion encoding and genetic relationship metric in ReliefF feature selection improves pathway enrichment in GWAS.

BACKGROUND: ReliefF is a nearest-neighbor based feature selection algorithm that efficiently detects variants that are important due to statistical interactions or epistasis. For categorical predictors, like genotypes, the standard metric used in ReliefF has been a simple (binary) mismatch difference. In this study, we develop new metrics of varying complexity that incorporate allele sharing, adjustment for allele frequency heterogeneity via the genetic relationship matrix (GRM), and physicochemical differences of variants via a new transition/transversion encoding. METHODS: We introduce a new two-dimensional transition/transversion genotype encoding for ReliefF, and we implement three ReliefF attribute metrics: 1.) genotype mismatch (GM), which is the ReliefF standard, 2.) allele mismatch (AM), which accounts for heterozygous differences and has not been used previously in ReliefF, and 3.) the new transition/transversion metric. We incorporate these attribute metrics into the ReliefF nearest neighbor calculation with a Manhattan metric, and we introduce GRM as a new ReliefF nearest-neighbor metric to adjust for allele frequency heterogeneity. RESULTS: We apply ReliefF with each metric to a GWAS of major depressive disorder and compare the detection of genes in pathways implicated in depression, including Axon Guidance, Neuronal System, and G Protein-Coupled Receptor Signaling. We also compare with detection by Random Forest and Lasso as well as random/null selection to assess pathway size bias. CONCLUSIONS: Our results suggest that using more genetically motivated encodings, such as transition/transversion, and metrics that adjust for allele frequency heterogeneity, such as GRM, lead to ReliefF attribute scores with improved pathway enrichment.

Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors.

As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo.

Morphine for the relief of breathlessness in patients with chronic heart failure--a pilot study.

BACKGROUND: Chronic heart failure (CHF) patients can experience significant breathlessness despite maximum medication for their heart failure. Morphine has long been used to relieve symptoms in acute failure, but there is little evidence about this potentially useful palliative therapy in CHF. AIMS: To determine the efficacy of morphine for the relief of breathlessness in patients with CHF. METHOD: Ten out-patients with NYHA III/IV CHF entered a randomised, double-blind, placebo controlled, crossover pilot study. The active arm was 4 days of 5 mg oral morphine four times daily (2.5 mg morphine if creatinine > 200 micromol/l). There were 2 days wash-out between active and placebo arms. RESULTS: 6/10 patients indicated that morphine improved their breathlessness. On morphine, the median breathlessness score fell by 23 mm (P = 0.022) by day 2. The improvement was maintained. Sedation scores increased until day 3 (P = 0.013), reducing on day 4. Four patients developed constipation (P = 0.026). On placebo, there was no significant difference in breathlessness or sedation. One patient had constipation. There were no significant differences in either arm in nausea, quality of life scores, blood pressure, pulse, respiratory rate, or catecholamines. Brain natriuretic peptide fell in both arms; significantly in the morphine arm. CONCLUSION: Morphine relieves breathlessness due to CHF. A larger study is indicated.

Structures of personality and their relevance to psychopathology.

Trait concepts are used extensively in psychopathology research, but much of this research has failed to consider recent advances in the dimensional structure of personality. Many investigators have discounted the importance of this structural research, arguing that (a) little progress has been made in this area, (b) structural models have little direct relevance for psychopathology research, and (c) the principal methodological tool of structural research--factor analysis--is too subjective to yield psychologically meaningful results. We dispute each of these objections. Specifically, we offer an integrative hierarchical model--composed of four higher order traits--that is congruent with each of the major structural subtraditions within personality. We also discuss the implications of this integrative scheme for basic trait research, for the conceptualization and assessment of psychopathology, and for the etiology of disorder.

Differential convergence of self-report and informant data for multidimensional personality questionnaire traits: implications for the construct of negative emotionality.

Construct validation work on Tellegen's (1982) Multidimensional Personality Questionnaire (MPQ) resulted in further inferences about Negative Emotionality. Two hundred thirty-two students were rated by three knowledgeable informants, yielding a total of 928 participants. The median monotrait correlation of MPQ primary scores with summed observer ratings was .48, and all were significant, p < .01. These data show higher self-report to informant rating convergences in the Positive Emotionality (Extroversion) domain than in the Negative Emotionality (Neuroticism) domain. Furthermore, in the Negative Emotionality domain, peers, mothers, and fathers were not equivalent as classes of raters. Stress Reaction ratings showed uniformly lower levels of convergence with self-report (relative to Positive Emotionality traits) across all rater classes. For Alienation, peer and maternal ratings were comparable, but paternal ratings correlated significantly less with self-report scores than did maternal ratings. And finally, with Aggression, peer ratings correlated significantly higher with self-report than either maternal or paternal ratings. These findings, taken in the context of the literature, have implications for a hierarchical model of Negative Emotionality, support inferences about the display of cues of Negative Emotionality, and offer new cautions for rating-based assessment.

A trial of feprazone in ankylosing spondylitis.

Feprazone, a non-steroidal anti-inflammatory drug, was compared with indomethacin in a double-blind cross-over trial in 24 patients with ankylosing spondylitis, over eight weeks. Both regimes caused significant reduction in pain. There were fewer side-effects and more patient preferences with feprazone but these differences did not reach statistical significance.

Ecto 5'-nucleotidase deficiency in primary hypogammaglobulinaemia.

The activity of the lymphocyte ectoenzyme 5'-nucleotidase is very low in the majority of patients with primary 'common variable' hypogammaglobulinaemia. In order to test whether this can be explained by lymphocyte subpopulation deficiencies we measured 5'-nucleotidase activity, using both biochemical and histochemical techniques, in purified T and B cells from patients and healthy subjects. Purified B cells from normal subjects have about four times the activity of T cells. This explains why the levels of lymphocyte 5'-nucleotidase activity are at the lower limit of the normal range in patients with X-linked hypogammaglobulinaemia who lack B cells. The low levels in the 'common variable' group can be explained by low activity in their T lymphocytes associated with either low activity in their B cells or depletion of B cells. The finding that inhibition of the enzyme does not interfere with in vitro lymphocyte transformation or immunoglobulin production in normal subjects indicates that the enzyme deficiency is not directly responsible for the hypogammaglobulinaemia. These and other studies suggest that this enzyme appears on lymphocytes at a certain stage of development and that both T and B lymphocytes in some patients with 'common variable' hypogammaglobulinaemia are developmentally immature.

Screening for primary speech and language delay: a systematic review of the literature.

Screening young children for developmental conditions such as speech and language delay is considered to be a part of the Child Health Surveillance programme in the UK. It is currently practised in many different ways throughout the country and like screening for other conditions conventionally identified in infancy, has been the subject of some concern for those responsible for providing such services. This systematic review (Law et al. 1998) was hypothesis driven and aimed to: i) establish whether, given the available evidence, there was sufficient evidence to warrant the introduction of universal screening for speech and language delays in children up to seven years of age; ii) identify gaps in the available literature; iii) identify priority areas in need of further investigation and iv); provide evidence-based recommendations for the future provision of services.

Prevalence and natural history of primary speech and language delay: findings from a systematic review of the literature.

The prevalence and the natural history of primary speech and language delays were two of four domains covered in a systematic review of the literature related to screening for speech and language delay carried out for the NHS in the UK. The structure and process of the full literature review is introduced and criteria for inclusion in the two domains are specified. The resulting data set gave 16 prevalence estimates generated from 21 publications and 12 natural history studies generated from 18 publications. Results are summarized for six subdivisions of primary speech and language delays: (1) speech and/or language, (2) language only, (3) speech only, (4) expression with comprehension, (5) expression only and (6) comprehension only. Combination of the data suggests that both concurrent and predictive case definition can be problematic. Prediction improves if language is taken independently of speech and if expressive and receptive language are taken together. The results are discussed in terms of the need to develop a model of prevalence based on risk of subsequent difficulties.

Structural models of captivity trauma, resilience, and trauma response among former prisoners of war 20 to 40 years after release.

Long-term responses to captivity trauma were measured in a national sample of American former prisoners of war. Their responses included negative affect, positive affect, and somatic symptoms as assessed by the Cornell Medical Index in 1967 and the Center for Epidemiological Study Depression Scale in 1985. These responses were strongly associated with captivity trauma (as indexed by captivity weight loss, torture, and disease) and resilience (as indexed by age and education at capture). Symptoms reported in 1967 were related to symptoms reported in 1985, suggesting symptom stability. These results are consistent with a model of trauma response that incorporates both trauma exposure and individual resilience. The findings are interpreted within a theoretical view of trauma response as adaptive when viewed from an evolutionary perspective.

The natural history of change in intellectual performance: who changes? How much? Is it meaningful?

A prerequisite step for studying the magnitude and meaning of IQ change is to distinguish between true IQ change that is a researchable phenomenon and IQ "change" that can be accounted for by measurement error. We studied the reliability, magnitude and meaning of IQ change using scores on the WISC--R obtained from a representative sample of 794 children at ages 7, 9, 11 and 13. The findings suggest that, in the majority of children, IQ change is either negligible in amount, unreliably measured or both. In a nontrivial minority of children, naturalistic IQ change is marked and real, but this change is variable in its timing, idiosyncratic in its source and transient in its course. We discuss the implications of these findings for interventions that aspire to improve IQ scores.

The feasibility of universal screening for primary speech and language delay: findings from a systematic review of the literature.

This paper reports on a systematic review of the literature commissioned to examine the feasibility of universal screening for speech and language delay. The results, based on an examination of productivity figures, including positive predictive ability and likelihood ratio, indicate that a number of screening tests are adequate. Sensitivity was generally lower than specificity, and study quality was inversely related to both sensitivity and likelihood ratio, suggesting that it is easier to identify accurately children who do not have language and speech problems than those who do. The review concluded that there is insufficient evidence to warrant the introduction of universal screening at this stage. This paper discusses the type of data that would be needed to address this issue further and recommendations are made for alternative approaches to early identification.

Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazephine AMPA antagonists.

A novel series of 3-aryl-5H-2,3-benzodiazepines with N-3 aromatic substituents has been synthesized. Good in vivo anticonvulsant activity of the new compounds has been demonstrated employing the maximal electroshock seizure test in mice. Evaluation of a subset of the compounds in the cortical wedge assay confirmed the new structures to be AMPA antagonists.

Longterm methotrexate use in rheumatoid arthritis: 12 year followup of 460 patients treated in community practice.

OBJECTIVE: To extend our observations on the longterm tolerability of methotrexate (MTX) and reasons for discontinuation in a cohort of 460 patients with rheumatoid arthritis (RA). METHODS: We studied all patients with RA who started MTX before June 1986 and attended the community based private practices of 6 rheumatologists in Melbourne. Information to at least April 1, 1995, or within one year of death was updated from the patient's medical records to include MTX discontinuation and reasons for discontinuation. Addition of disease modifying antirheumatic drugs (DMARD) concomitant with MTX was noted. Survival analyses based upon life table methods were used with MTX discontinuation as the observable endpoint. Three different definitions of MTX discontinuation were used (1) according to whether the patient was taking the drug at last followup irrespective of any periods of temporary discontinuation; (2) MTX discontinuation for > 3 months considered to be a treatment endpoint; and (3) addition of concomitant DMARD considered to be only partial success of MTX (as a need for additional therapy to meet treatment goals). RESULTS: At 12 years, 53% of patients were continuing to take MTX (irrespective of any periods of temporary discontinuation). If discontinuation of the drug for 3 or more months was considered a treatment termination then 38% were still taking the drug at 12 years, and if addition of concomitant DMARD was regarded as a treatment endpoint only 17% of patients were continuing MTX at 12 years. Withdrawal for gastrointestinal toxicity declined over time but the risk of other adverse effects appeared to persist over time. CONCLUSION: MTX in RA is well tolerated over the longer term, with > 50% of patients starting MTX in a community based rheumatology private practice continuing to take it 12 years later. However, a substantial number of patients had 2nd line therapies added over this time. Monitoring for toxicity should continue throughout the course of therapy.

Methotrexate therapy in rheumatoid arthritis: a life table review of 587 patients treated in community practice.

To determine whether methotrexate (MTX) maintains its effectiveness in rheumatoid arthritis (RA) in the setting of community based private rheumatology practice we used life table analysis to review the combined experience of a group of these practices. Of 587 patients with RA who started to take MTX, total termination rate at 70 months was 24.4% with most terminations prompted by drug toxicity. Older age (greater than 65 years) was associated with higher rates of toxicity. Treatment termination rates varied substantially between rheumatologists. We conclude that MTX therapy for RA is well tolerated and maintains effectiveness for at least 70 months.