IMPORTANCE: Depression commonly affects adults with HIV and complicates the management of HIV. Depression among individuals with HIV tends to be chronic and cyclical, but the association of this ...chronicity with HIV outcomes (and the related potential for screening and intervention to shorten depressive episodes) has received little attention. OBJECTIVE: To examine the association between increased chronicity of depression and multiple HIV care continuum indicators (HIV appointment attendance, treatment failure, and mortality). DESIGN, SETTING, AND PARTICIPANTS: The study comprised an observational clinical cohort of 5927 patients with 2 or more assessments of depressive severity who were receiving HIV primary care at 6 geographically dispersed US academic medical centers from September 22, 2005, to August 6, 2015. MAIN OUTCOMES AND MEASURES: Missing a scheduled HIV primary care visit, detectable HIV RNA viral load (≥75 copies/mL), and all-cause mortality. Consecutive depressive severity measures were converted into a time-updated measure: percentage of days with depression (PDD), following established methods for determining depression-free days. RESULTS: During 10 767 person-years of follow-up, the 5927 participants (5000 men, 926 women, and 1 intersex individual; median age, 44 years range, 35-50 years) had a median PDD of 14% (interquartile range, 0%-48%). During follow-up, 10 361 of 55 040 scheduled visits (18.8%) were missed, 6191 of 28 455 viral loads (21.8%) were detectable, and the mortality rate was 1.5 deaths per 100 person-years. Percentage of days with depression showed a dose-response relationship with each outcome. Each 25% increase in PDD led to an 8% increase in the risk of missing a scheduled appointment (risk ratio, 1.08; 95% CI, 1.05-1.11), a 5% increase in the risk of a detectable viral load (risk ratio, 1.05; 95% CI, 1.01-1.09), and a 19% increase in the mortality hazard (hazard ratio, 1.19; 95% CI, 1.05-1.36). These estimates imply that, compared with patients who spent no follow-up time with depression (PDD, 0%), those who spent the entire follow-up time with depression (PDD, 100%) faced a 37% increased risk of missing appointments (risk ratio, 1.37; 95% CI, 1.22-1.53), a 23% increased risk of a detectable viral load (risk ratio, 1.23; 95% CI, 1.06-1.43), and a doubled mortality rate (hazard ratio, 2.02; 95% CI, 1.20-3.42). CONCLUSIONS AND RELEVANCE: Greater chronicity of depression increased the likelihood of failure at multiple points along the HIV care continuum. Even modest increases in the proportion of time spent with depression led to clinically meaningful increases in negative outcomes. Clinic-level trials of protocols to promptly identify and appropriately treat depression among adults living with HIV should be conducted to understand the effect of such protocols on shortening the course and preventing the recurrence of depressive illness and improving clinical outcomes.
Precision medicine is an approach to developing drugs that focuses on employing biomarkers to stratify patients in clinical trials with the goal of improving efficacy and/or safety outcomes, ...ultimately increasing the odds of clinical success and drug approval. Precision medicine is an important tool for toxicologists to utilize, because its principles can be used to decide whether to pursue a drug target, to understand interindividual differences in response to drugs in both nonclinical and clinical settings, to aid in selecting doses that optimize efficacy or reduce adverse events, and to facilitate understanding of a drug’s mode-of-action. Nonclinical models such as the mouse and non-human primate can be used to understand genetic variation and its potential translation to humans, and are available for toxicologists to employ in advance of drugs moving into clinical development. Understanding interindividual differences in response to drugs and how these differences can influence the drug’s risk-benefit profile and lead to the identification of biomarkers that enhance patient efficacy and safety is of critical importance for toxicologists today, and in the future, as the fields of pharmacogenomics and genetics continue to advance.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Persons living with HIV (PLWH) and depression or anxiety in the rural South may have suboptimal HIV outcomes. We sought to examine the proportion of PLWH from rural Florida with symptoms of ...depression or anxiety, the proportion who received depression or anxiety treatment, and the relationship between untreated and treated symptoms of depression or anxiety and HIV outcomes. Cross-sectional survey data collected between 2014 and 2018 were analyzed. Among 187 PLWH residing in rural Florida (median age 49 years, 61.5%, male 45.5% Black), 127 (67.9%) met criteria for symptoms of depression and/or anxiety. Among these 127 participants, 60 (47.2%) were not on depression or anxiety treatment. Participants with untreated symptoms of depression and anxiety (OR 3.2, 95% CI 1.2–9.2, p = 0.03) and treated depression and anxiety with uncontrolled symptoms (OR 1.4, 95% CI 0.5–4.0, p = 0.52) were more likely to have viral non-suppression compared to those without depression or anxiety in an unadjusted bivariate analysis. Only the association between untreated symptoms of depression and anxiety and viral non-suppression was statistically significant, and when adjusting for social and structural confounders the association was attenuated and was no longer statistically significant. This suggests that social and structural barriers impact both mental health and HIV outcomes. Our findings support the need for increased mental health services and resources that address the social and structural barriers to care for PLWH in the rural South.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Strains of
Drosophila melanogaster with resistance to the insecticides spinosyn A, spinosad, and spinetoram were produced by chemical mutagenesis. These spinosyn-resistant strains were not ...cross-resistant to other insecticides. The two strains that were initially characterized were subsequently found to have mutations in the gene encoding the nicotinic acetylcholine receptor (nAChR) subunit Dα6. Subsequently, additional spinosyn-resistant alleles were generated by chemical mutagenesis and were also found to have mutations in the gene encoding Dα6, providing convincing evidence that Dα6 is a target site for the spinosyns in
D. melanogaster. Although a spinosyn-sensitive receptor could not be generated in
Xenopus laevis oocytes simply by expressing Dα6 alone, co-expression of Dα6 with an additional nAChR subunit, Dα5, and the chaperone protein ric-3 resulted in an acetylcholine- and spinosyn-sensitive receptor with the pharmacological properties anticipated for a native nAChR.
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GEOZS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBJE, UL, UM, UPCLJ, UPUK
We observed a dose-response relationship between the cumulative burden of depression and all-cause mortality among women living with human immunodeficiency virus (HIV). Shortening the duration of ...depressive episodes through enhanced treatment protocols in HIV primary care settings may interrupt accumulation of mortality risk.
Abstract
Background
Research linking depression to mortality among people living with human immunodeficiency virus (PLWH) has largely focused on binary "always vs never" characterizations of depression. However, depression is chronic and is likely to have cumulative effects on mortality over time. Quantifying depression as a cumulative exposure may provide a better indication of the clinical benefit of enhanced depression treatment protocols delivered in HIV care settings.
Methods
Women living with HIV (WLWH), naive to antiretroviral therapy, from the Women's Interagency HIV Study were followed from their first visit in or after 1998 for up to 10 semiannual visits (5 years). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. An area-under-the-curve approach was used to translate CES-D scores into a time-updated measure of cumulative days with depression (CDWD). We estimated the effect of CDWD on all-cause mortality using marginal structural Cox proportional hazards models.
Results
Overall, 818 women contributed 3292 woman-years over a median of 4.8 years of follow-up, during which the median (interquartile range) CDWD was 366 (97-853). Ninety-four women died during follow-up (2.9 deaths/100 woman-years). A dose-response relationship was observed between CDWD and mortality. Each additional 365 days spent with depression increased mortality risk by 72% (hazard ratio, 1.72; 95% confidence interval, 1.34-2.20).
Conclusions
In this sample of WLWH, increased CDWD elevated mortality rates in a dose-response fashion. More frequent monitoring and enhanced depression treatment protocols designed to reduce CDWD may interrupt the accumulation of mortality risk among WLWH.
Systemic toxicity assessments for oral or parenteral drugs often utilize the concentration of drug in plasma to enable safety margin calculations for human risk assessment. For topical drugs, there ...is no standard method for measuring drug concentrations in the stratum basale of the viable epidermis. This is particularly important since the superficial part of the epidermis, the stratum corneum (SC), is nonviable and where most of a topically applied drug remains, never penetrating deeper into the skin. We investigated the relative concentrations of a prototype kinase inhibitor using punch biopsy, laser capture microdissection, and imaging mass spectrometry methods in the SC, stratum basale, and dermis of minipig skin following topical application as a cream formulation. The results highlight the value of laser capture microdissection and mass spectrometry imaging in quantifying the large difference in drug concentration across the skin and even within the epidermis, and supports use of these methods for threshold-based toxicity risk assessments in specific anatomic locations of the skin, like of the stratum basale.
•Measurement of topical drug concentrations in viable epidermis.•Drug concentration measurement in skin for risk assessment.•Skin concentrations by laser capture microdissection.•Skin concentrations and distribution by mass spectrometry.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although rarely occurring in humans, hemangiosarcomas (HS) have become important in evaluating the potential human risk of several chemicals, including industrial, agricultural, and pharmaceutical ...agents. Spontaneous HS arise frequently in mice, less commonly in rats, and frequently in numerous breeds of dogs. This review explores knowledge gaps and uncertainties related to the mode of action (MOA) for the induction of HS in rodents, and evaluates the potential relevance for human risk. For genotoxic chemicals (vinyl chloride and thorotrast), significant information is available concerning the MOA. In contrast, numerous chemicals produce HS in rodents by nongenotoxic, proliferative mechanisms. An overall framework is presented, including direct and indirect actions on endothelial cells, paracrine effects in local tissues, activation of bone marrow endothelial precursor cells, and tissue hypoxia. Numerous obstacles are identified in investigations into the MOA for mouse HS and the relevance of the mouse tumors to humans, including lack of identifiable precursor lesions, usually late occurrence of the tumors, and complexities of endothelial biology. This review proposes a working MOA for HS induced by nongenotoxic compounds that can guide future research in this area. Importantly, a common MOA appears to exist for the nongenotoxic induction of HS, where there appears to be a convergence of multiple initiating events (e.g., hemolysis, decreased respiration, adipocyte growth) leading to either dysregulated angiogenesis and/or erythropoiesis that results from hypoxia and macrophage activation. These later events lead to the release of angiogenic growth factors and cytokines that stimulate endothelial cell proliferation, which, if sustained, provide the milieu that can lead to HS formation.
OBJECTIVE:Depression is highly prevalent among people living with HIV/AIDS (PLWHA) and has deleterious effects on HIV clinical outcomes. We examined changes in depression symptoms, viral suppression ...and CD4 T-cells/mm among PLWHA diagnosed with depression who initiated antidepressant treatment during routine care, and compared the effectiveness of dual-action and single-action antidepressants for improving those outcomes.
DESIGN:Comparative effectiveness study of new user dual-action or single-action antidepressant treatment episodes occurring from 2004–2014 obtained from the Center for AIDS Research Network of Integrated Clinical Systems.
METHODS:We identified new user treatment episodes with no antidepressant use in the preceding 90 days. We completed intent-to-treat and per-protocol evaluations for the main analysis. Primary outcomes, were viral suppression (HIV viral load < 200 copies/mL) and CD4 T-cells/mm. In a secondary analysis, we used the Patient Health Questionnaire-9 (PHQ-9) to evaluate changes in depression symptoms and remission (PHQ < 5). Generalized estimating equations with inverse probability of treatment weights were fitted to estimate treatment effects.
RESULTS:In weighted intent-to-treat analyses, the probability of viral suppression increased 16% after initiating antidepressants 95% Confidence Interval (CI) = (1.12,1.20). We observed an increase of 39 CD4 T-cells/mm after initiating antidepressants (30,48). Both the frequency of remission from depression and PHQ-9 scores improved after antidepressant initiation. Comparative effectiveness estimates were null in all models.
CONCLUSIONS:Initiating antidepressant treatment was associated with improvements in depression, viral suppression and CD4 T-cells/mm, highlighting the health benefits of treating depression in PLWHA. Dual- and single-action antidepressants had comparable effectiveness.
Several chemicals and pharmaceuticals increase the incidence of hemangiosarcomas (HSAs) in mice, but the relevance to humans is uncertain. Recently, canine HSAs were identified as a powerful tool for ...investigating the pathogenesis of human HSAs. To characterize the cellular phenotype of canine HSAs, we evaluated immunoreactivity and/or messenger RNA (mRNA) expression of markers for hematopoietic stem cells (HSCs), endothelial cells (ECs), a tumor suppressor protein, and a myeloid marker in canine HSAs. Neoplastic canine cells expressed EC markers and a myeloid marker, but expressed HSC markers less consistently. The canine tumor expression results were then compared to previously published immunoreactivity results for these markers in human and mouse HSAs. There are 2 noteworthy differences across species: (1) most human HSAs had HSC marker expression, indicating that they were comprised of tumor cells that were less differentiated than those in canine and mouse tumors; and (2) human and canine HSAs expressed a late-stage EC maturation marker, whereas mouse HSAs were negative, suggesting that human and canine tumors may retain greater differentiation potential than mouse tumors. These results indicate that HSA development is variable across species and that caution is necessary when discussing translation of carcinogenic risk from animal models to humans.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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