In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

Is decoupling GDP growth from environmental impact possible?

© 2016 Ward et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The argument that human society can decouple economic growth-defined as growth in Gross Domestic Product (GDP)-from growth in environmental impacts is appealing. If such decoupling is possible, it means that GDP growth is a sustainable societal goal. Here we show that the decoupling concept can be interpreted using an easily understood model of economic growth and environmental impact. The simple model is compared to historical data and modelled projections to demonstrate that growth in GDP ultimately cannot be decoupled from growth in material and energy use. It is therefore misleading to develop growth-oriented policy around the expectation that decoupling is possible. We also note that GDP is increasingly seen as a poor proxy for societal wellbeing. GDP growth is therefore a questionable societal goal. Society can sustainably improve wellbeing, including the wellbeing of its natural assets, but only by discarding GDP growth as the goal in favor of more comprehensive measures of societal wellbeing

Using a model of group psychotherapy to support social research on sensitive topics

This article describes the exploratory use of professional therapeutic support by social researchers working on a sensitive topic. Talking to recently bereaved parents about the financial implications of their child's death was expected to be demanding work, and the research design included access to an independent psychotherapeutic service. Using this kind of professional support is rare within the general social research community, and it is useful to reflect on the process. There are likely to be implications for collection and interpretation of data, research output and the role and experience of the therapist. Here, the primary focus is the potential impact on researcher well-being

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels

Detection of chromosome aberrations in metaphase and interphase tumor cells by in situ hybridization using chromosome-specific library probes

Chromosome aberrations in two glioma cell lines were analyzed using biotinylated DNA library probes that specifically decorate chromosomes 1, 4, 7, 18 and 22 from pter to qter. Numerical changes, deletions and rearrangements of these chromosomes were radily visualized in metaphase spreads, as well as in early prophase and interphase nuclei. Complete chromosomes, deleted chromosomes and segments of translocated chromosomes were rapidly delineated in very complex karyotypes. Simultaneous hybridizations with additional subregional probes were used to further define aberrant chromosomes. Digital image analysis was used to quantitate the total complement of specific chromosomal DNAs in individual metaphase and interphase cells of each cell line. In spite of the fact that both glioma lines have been passaged in vitro for many years, an under-representation of chromosome 22 and an over-representation of chromosome 7 (specifically 7p) were observed. These observations agree with previous studies on gliomas. In addition, sequences of chromosome 4 were also found to be under-represented, especially in TC 593. These analyses indicate the power of these methods for pinpointing chromosome segments that are altered in specific types of tumors

Deconstructing interventions: approaches to studying behavior change techniques across obesity interventions

Deconstructing interventions into the specific techniques that are used to change behavior represents a new frontier in behavioral intervention research. This paper considers opportunities and challenges in employing the Behavior Change Techniques Taxonomy (BCTTv1) developed by Michie and colleagues, to code the behavior change techniques (BCTs) across multiple interventions addressing obesity and capture dose received at the technique level. Numerous advantages were recognized for using a shared framework for intervention description. Coding interventions at levels of the social ecological framework beyond the individual level, separate coding for behavior change initiation vs. maintenance, fidelity of BCT delivery, accounting for BCTs mode of delivery, and tailoring BCTs, present both challenges and opportunities. Deconstructing interventions and identifying the dose required to positively impact health-related outcomes could enable important gains in intervention science

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis

BACKGROUND: This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. METHODS: Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. RESULTS: Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)_{0-24} (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid C_{MAX} (P < .05), isoniazid C_{MAX}/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC_{0-24}/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05). CONCLUSIONS: Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as C_{MAX}/MIC and AUC_{0-24}/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings

Atypical bodily self-awareness in vicarious pain responders

Vicarious perception refers to the ability to co-represent the experiences of others. Prior research has shown considerable inter-individual variability in vicarious perception of pain, with some experiencing conscious sensations of pain on their own body when viewing another person in pain (conscious vicarious perception / mirror-pain synaesthesia). Self-Other Theory proposes that this conscious vicarious perception may result from impairments in self-other distinction and maintaining a coherent sense of bodily self. In support of this, individuals who experience conscious vicarious perception are more susceptible to illusions of body ownership and agency. However, little work has assessed whether trait differences in bodily self-awareness are associated with conscious vicarious pain. Here we addressed this gap by examining individual difference factors related to awareness of the body, in conscious vicarious pain responders. Increased self-reported depersonalisation and interoceptive sensibility was found for conscious vicarious pain responders compared with non-responders, in addition to more internally-oriented thinking (associated with lower alexithymia). There were no significant differences in trait anxiety. Results indicate that maintaining a stable sense of the bodily self may be important for vicarious perception of pain, and that vicarious perception might also be enhanced by attention towards internal bodily states

Injury Risk Estimation Expertise Assessing the ACL Injury Risk Estimation Quiz

Background: Available methods for screening anterior cruciate ligament (ACL) injury risk are effective but limited in application as they generally rely on expensive and time-consuming biomechanical movement analysis. A potential efficient alternative to biomechanical screening is skilled movement analysis via visual inspection (ie, having experts estimate injury risk factors based on observations of athletes’ movements). Purpose: To develop a brief, valid psychometric assessment of ACL injury risk factor estimation skill: the ACL Injury Risk Estimation Quiz (ACL-IQ). Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A total of 660 individuals participated in various stages of the study, including athletes, physicians, physical therapists, athletic trainers, exercise science researchers/students, and members of the general public in the United States. The ACL-IQ was fully computerized and made available online (www.ACL-IQ.org). Item sampling/reduction, reliability analysis, cross-validation, and convergent/discriminant validity analysis were conducted to optimize the efficiency and validity of the assessment. Results: Psychometric optimization techniques identified a short (mean time, 2 min 24 s), robust, 5-item assessment with high reliability (test-retest: r = 0.90) and consistent discriminability (average difference of exercise science professionals vs general population: Cohen d = 1.98). Exercise science professionals and general population individuals scored 74% and 53% correct, respectively. Convergent and discriminant validity was demonstrated. Scores on the ACL-IQ were most associated with ACL knowledge and various cue utilities and were least associated with domain-general spatial/decision-making ability, personality, or other demographic variables. Overall, 23% of the total sample (40% exercise science professionals; 6% general population) performed better than or equal to the ACL nomogram. Conclusion: This study presents the results of a systematic approach to assess individual differences in ACL injury risk factor estimation skill; the assessment approach is efficient (ie, it can be completed in\3 min) and psychometrically robust. The results provide evidence that some individuals have the ability to visually estimate ACL injury risk factors more accurately than other instrument-based ACL risk estimation methods (ie, ACL nomogram). The ACL-IQ provides the foundation for assessing the efficacy of observational ACL injury risk factor assessment (ie, does simple skilled visual inspection reduce ACL injuries?). It also provides a representative task environment that can be used to increase our understanding of the perceptual-cognitive mechanisms underlying observational movement analysis and to improve injury risk assessment performance

Characterization of Residential Pesticide Use and Chemical Formulations through Self-Report and Household Inventory: The Northern California Childhood Leukemia Study

Background: Home and garden pesticide use has been linked to cancer and other health outcomes in numerous epidemiological studies. Exposure has generally been self-reported, so the assessment is potentially limited by recall bias and lack of information on specific chemicals. Objectives: As part of an integrated assessment of residential pesticide exposure, we identified active ingredients and described patterns of storage and use. Methods: During a home interview of 500 residentially stable households enrolled in the Northern California Childhood Leukemia Study during 2001–2006, trained interviewers inventoried residential pesticide products and queried participants about their storage and use. U.S. Environmental Protection Agency registration numbers, recorded from pesticide product labels, and pesticide chemical codes were matched to public databases to obtain information on active ingredients and chemical class. Poisson regression was used to identify independent predictors of pesticide storage. Analyses were restricted to 259 participating control households. Results: Ninety-five percent (246 of 259) of the control households stored at least one pesticide product (median, 4). Indicators of higher sociodemographic status predicted more products in storage. We identified the most common characteristics: storage areas (garage, 40%; kitchen, 20%), pests treated (ants, 33%; weeds, 20%), pesticide types (insecticides, 46%; herbicides, 24%), chemical classes (pyrethroids, 77%; botanicals, 50%), active ingredients (pyrethrins, 43%) and synergists (piperonyl butoxide, 42%). Products could contain multiple active ingredients. Conclusions: Our data on specific active ingredients and patterns of storage and use will inform future etiologic analyses of residential pesticide exposures from self-reported data, particularly among households with young children