Stigma and negative self-perceptions of young people living with human immunodeficiency virus in Bandung, Indonesia: a case series.

Background: Young people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) (PLWA) are at risk for HIV stigma. Methods: The HIV/AIDS Stigma Instrument for PLWA was administered to 36 young PLWA across six clinics in Bandung, Indonesia, to assess the fear of contagion (FC), verbal abuse (VA), social isolation (SI), workplace stigma (WS), health care neglect (HCN) and negative self-perception (NSP). Results: The median scores for FC, VA, SI, WS and HCN were all 0 while the median score for NSP was 4. In the last 3 months approximately 45% of surveyed PLWA felt they did not deserve to live and 64% felt completely worthless. Conclusions: While these results are preliminary, access to mental health services should be a priority in the clinics that provide antiretroviral therapies.

Salmonella typhimurium-induced IL-1 release from primary human monocytes requires NLRP3 and can occur in the absence of pyroptosis.

Large molecular complexes known as inflammasomes regulate the release of IL-1ß from immune cells in response to infection and injury. Salmonella typhimurium infection is reported to activate NLRP3 and NLRC4 inflammasomes which are subsequently involved in pyroptosis of the cell and pathogen clearance. However, the response to S. typhimurium in primary human monocytes has not been studied in detail. The aim of this study was to investigate the effect of S. typhimurium on inflammasomes in primary human monocytes. Much of the previous research in the field has been conducted in murine models and human THP-1 cells, which may not reflect the responses of primary human monocytes. Here, we report that inhibiting NLRP3 with the selective inhibitor MCC950, blocked release of IL-1ß and the related cytokine IL-1α from primary human monocytes in response to S. typhimurium. Additionally, under these conditions S. typhimurium-induced IL-1 release occurred independently of pyroptosis. We propose that IL-1ß release without pyroptosis may occur in early-recruited monocytes to regulate a maximal innate immune response to Salmonella infection, allowing a sustained inflammatory signal. This insight into the mechanisms involved in IL-1 release from primary human monocytes highlights major differences between immune cell types, and the defences they employ during bacterial infection.

Another Generation of Stigma? Assessing Healthcare Student Perceptions of HIV-Positive Patients in Mwanza, Tanzania.

HIV-related stigma remains a persistent global health concern among people living with HIV/AIDS (PLWA) in developing nations. The literature is lacking in studies about healthcare students' perceptions of PLWA. This study is the first effort to understand stigmatizing attitudes toward HIV-positive patients by healthcare students in Mwanza, Tanzania, not just those who will be directly treating patients but also those who will be indirectly involved through nonclinical roles, such as handling patient specimens and private health information. A total of 208 students were drawn from Clinical Medicine, Laboratory Sciences, Health Records and Information Management, and Community Health classes at the Tandabui Institute of Health Sciences and Technology for a voluntary survey that assessed stigmatizing beliefs toward PLWA. Students generally obtained high scores on the overall survey instrument, pointing to low stigmatizing beliefs toward PLWA and an overall willingness to treat PLWA with the same standard of care as other patients. However, there are gaps in knowledge that exist among students, such as a comprehensive understanding of all routes of HIV infection. The study also suggests that students who interact with patients as part of their training are less likely to exhibit stigmatizing beliefs toward PLWA. A comprehensive course in HIV infection, one that includes classroom sessions focused on the epidemiology and routes of transmission as well as clinical opportunities to directly interact with PLWA-perhaps through teaching sessions led by PLWA-may allow for significant reductions in stigma toward such patients and improve clinical outcomes for PLWA around the world.

Community Schools: a Public Health Opportunity to Reverse Urban Cycles of Disadvantage.

Community schools link students, families, and communities to educate children and strengthen neighborhoods. They have become a popular model for education in many US cities in part because they build on community assets and address multiple determinants of educational disadvantage. Since community schools seek to have an impact on populations, not just the children enrolled, they provide an opportunity to improve community health. Community schools influence the health and education of neighborhood residents though three pathways: building trust, establishing norms, and linking people to networks and services. Through such services as school-based health centers, nutrition education, family mental health counseling, violence prevention, and sexuality education, these schools build on the multiple reciprocal relationships between health and education. By developing closer ties between community schools and neighborhood health programs, public health professionals can help to mobilize a powerful new resource for reducing the health and educational inequalities that now characterize US cities. We suggest an agenda for research, practice, and policy that can build the evidence needed to guide such a strategy.

Investigating IL-1ß Secretion Using Real-Time Single-Cell Imaging.

The pro-inflammatory cytokine interleukin (IL)-1ß is an important mediator of the inflammatory response. In order to perform its role in the inflammatory cascade, IL-1ß must be secreted from the cell, yet it lacks a signal peptide that is required for conventional secretion, and the exact mechanism of release remains undefined. Conventional biochemical methods have limited the investigation into the processes involved in IL-1ß secretion to population dynamics, yet heterogeneity between cells has been observed at a single-cell level. Here, greater sensitivity is achieved with the use of a newly developed vector that codes for a fluorescently labelled version of IL-1ß. Combining this with real-time single-cell confocal microscopy using the methods described here, we have developed an effective protocol for investigating the mechanisms of IL-1ß secretion and the testing of the hypothesis that IL-1ß secretion requires membrane permeabilisation.

Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes.

Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1ß. The biologically inactive IL-1ß precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1. Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone. Although this lineage-restricted mechanism is likely to contribute to the pathology of endotoxin shock, signalling pathways regulating this mechanism are currently unknown. Here we report that caspase-4 and caspase-5 mediate IL-1α and IL-1ß release from human monocytes after LPS stimulation. Although caspase-4 remains uncleaved, caspase-5 undergoes rapid processing upon LPS treatment. We also identify an additional caspase-5 cleavage product in LPS-stimulated monocytes, which correlates with IL-1 secretion. This one-step pathway requires Syk activity and Ca(2+) flux instigated by CD14/TLR4-mediated LPS internalization. Identification of caspase-4/5 as the key determinants of one-step inflammasome activation in human monocytes provides potential targets for therapeutic intervention in endotoxin shock.

Keeping the "public" in schools of public health.

In this article, we compared the characteristics of public and private accredited public health training programs. We analyzed the distinct opportunities and challenges that publicly funded schools of public health face in preparing the nation's public health workforce. Using our experience in creating a new, collaborative public school of public health in the nation's largest urban public university system, we described efforts to use our public status and mission to develop new approaches to educating a workforce that meets the health needs of our region and contributes to the goal of reducing health inequalities. Finally, we considered policies that could protect and strengthen the distinct contributions that public schools of public health make to improving population health and reducing health inequalities.

Novel perspectives on non-canonical inflammasome activation.

Inflammasomes are cytosolic multi-protein complexes that regulate the secretion of the proinflammatory cytokines, IL-1ß and IL-18, and induce pyroptosis, an inflammatory form of cell death. The NLRP3 inflammasome is the most well-characterized member of this family and functions by sensing intracellular pathogen- and damage-associated molecular patterns and activating caspase-1, which processes the biologically inactive IL-1ß and IL-18 precursors into active cytokines. Recent studies have identified an alternative mechanism of inflammasome activation, termed the non-canonical inflammasome, which is triggered by cytosolic sensing of lipopolysaccharide (LPS) derived from bacteria that have escaped phagolysosomes. This pathway is independent of Toll-like receptor 4 (TLR4), the well-known extracellular receptor for LPS, but instead depends on the inflammatory protease, caspase-11. Although our understanding of caspase-11 activation is still in its infancy, it appears to be an essential mediator of septic shock and attenuates intestinal inflammation. In this review, we bring together the latest data on the roles of caspase-11 and the mechanisms underlying caspase-11-mediated activation of the non-canonical inflammasome, and consider the implications of this pathway on TLR4-independent immune responses to LPS.

The development of building wellness™, a youth health literacy program.

Health literacy research has concentrated on adults; there has been inadequate research on youth health literacy and the effect it may have on health outcomes. Low-income, minority populations have low levels of health literacy and are at higher risk of illness and disease. Building Wellness™ is a youth health literacy curriculum targeting low-income youth from 3rd grade to 8th grade in order to prepare the youth to be active, educated participants in their healthcare. Lessons focus on asthma, obesity and overweight, accidental injury, and drug and alcohol use. Curriculum development was based on qualitative and quantitative assessment of the target population. The preliminary findings from the pilot project show an increase in knowledge, improved healthy behaviors, and enthusiasm from participants and facilitators. The development of the pilot project is described, with a suggestion for future development of youth health literacy assessment tools.

Quality of life, characteristics and survival of patients with HIV and lymphoma.

PURPOSE: We sought to compare the quality of life (QOL), characteristics, and survival of patients with non-Hodgkin lymphoma (NHL) with and without human immunodeficiency virus (HIV) infection. METHODS: Using the population-based cancer registry for Orange and San Diego Counties, We recruited 50 patients with HIV and systemic NHL (cases) and 50 age, sex and race-matched NHL patients without HIV (controls) diagnosed with NHL during 2002-2006. Patients completed a medical history survey and QOL instrument, the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) for cases and Functional Assessment of Cancer Therapy-General (FACT G) for controls. RESULTS: HIV-infected patients had worse overall QOL and survival than uninfected patients. QOL differences were more marked in the areas of functional, physical and social well-being than in the area of emotional well-being. HIV-infected patients had lower income and were less likely to have private insurance and more likely to have diffuse large B cell histology than uninfected patients. CONCLUSION: HIV-infected NHL patients had worse QOL and survival than uninfected patients, due to a combination of co-morbidity, aggressive histology and lack of social support. However, their emotional well-being was comparable to that of uninfected NHL patients and better than historical norms for the HIV-infected.

Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients.

OBJECTIVES: To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF). DESIGN AND METHODS: This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined. RESULTS: Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (-0.15 log10 per day vs. -0.16 log10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/10 cells) 3293 vs. 4638; P = 0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/10 cells) 3238 vs. 4534; P = 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (rho = -0.529; P = 0.045). CONCLUSION: In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.

The implementation and assessment of a comprehensive communication skills training curriculum for oncologists.

OBJECTIVE: The objective of this paper is to report the implementation and assessment of the Comskil Training Curriculum at Memorial Sloan-Kettering Cancer Center. METHOD: Twenty-eight attending physicians and surgeons participated in communication skills training modules as part of a train-the-trainer program. Doctors were video recorded in clinical consultations with patients two times before training and two times after training, resulting in 112 video recordings for analysis. Recordings were coded using the Comskil Coding System. RESULTS: Communication skills related to two of the six major skill sets, Establishing the Consultation Framework and Checking, increased following training. Limited changes emerged in three skill sets, while one skill set, Shared Decision Making, did not change. Doctors who attended more training modules had higher levels of change. Female participants demonstrated three skills more frequently than males post-training. CONCLUSIONS: The intervention produced significant communication skills uptake in a group of experienced attending clinicians, mediated by the amount of training. Future research should focus on the dose of training necessary to achieve skills uptake and the effect of skills training on patient outcomes.

Assessing facilitator competence in a comprehensive communication skills training programme.

OBJECTIVES: Evidence suggests that the most important component of communication skills training (CST) is experiential learning through role-play sessions that rely on facilitators to guide learners. However, there is little published evidence about processes of assessing facilitator competence in CST. This paper reports on the development and application of procedures to assess facilitator competence in a large-scale CST programme. METHODS: Thirty-two novice facilitators in a large CST programme were audio-recorded while facilitating small-group CST training sessions in order to explore whether the training they had received had prepared them to competently facilitate. Audio-recordings were assessed using the Comskil facilitator assessment coding system. Facilitators were rated as having achieved basic competence, advanced competence or expert competence. RESULTS: Facilitation tasks that were most frequently coded as being used always included inviting the learner to give feedback first and inviting all group members to give feedback. The facilitation task coded least frequently as being used always was involving group members in solving problems. Of the 32 facilitators, 18 reached at least a basic level of competence. Psychosocially trained facilitators and MD facilitators differed in their use of five facilitation tasks. CONCLUSIONS: Modest training and minimal practice does not result in complete facilitator competence. Some facilitation skills appear to be more easily acquired than others. These findings highlight which skills should be prioritised in the further training of novice facilitators. A long-term project currently underway will study whether facilitator competence improves with practice and regular feedback.

Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy.

BACKGROUND: Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. METHODS: We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. RESULTS: Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. CONCLUSIONS: Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.

A randomized controlled trial of therapeutic drug monitoring in treatment-naive and -experienced HIV-1-infected patients.

OBJECTIVE: To improve the utility of therapeutic drug monitoring (TDM) by defining the proportion of patients with and predictors of above or below target protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) concentrations. METHODS: This 48-week, multicenter, open-label clinical trial randomized patients to TDM versus standard of care (SOC). Serial pharmacokinetics, including a week-2 3-sample sparse collection, and expert committee TDM recommendations were given to TDM-arm patients' providers. RESULTS: Seventy-four (39%) of 190 patients had week-2 concentrations outside of targets and 122 (64%) of 190 had nontarget exposure at least once over 48 weeks. Providers accepted 75% of TDM recommendations. Among patients with below-target concentrations, more TDM-arm than SOC-arm patients achieved targets (65% vs. 45%; P = 0.09). Increased body weight and efavirenz or lopinavir/ritonavir use were significant predictors of nontarget concentrations. Patients at target and patients who achieved targets after TDM-directed dose modifications trended toward greater viral load reductions at week 48 than patients with below-target exposures (HIV RNA reductions: 2.4, 2.3, and 1.9 log10 copies/mL, respectively; P = 0.09). CONCLUSIONS: Most patients had nontarget PI and/or NNRTI concentrations over 48 weeks. TDM recommendations were well accepted and improved exposure. Patients below TDM targets trended toward worse virologic response.

A computer-based system to aid in the interpretation of plasma concentrations of antiretrovirals for therapeutic drug monitoring.

OBJECTIVES: To develop a computer-based system for modelling and interpreting plasma antiretroviral concentrations for therapeutic drug monitoring (TDM). METHODS: Data were extracted from a prospective TDM study of 199 HIV-infected patients (CCTG 578). Lopinavir (LPV) and efavirenz (EFV) pharmacokinetic (PK) parameters were modelled using a Bayesian method and interpreted by an expert committee of HIV specialists and pharmacologists who made TDM recommendations. These PK models and recommendations formed the knowledge base to develop an artificial intelligence (AI) system that could estimate drug exposure, interpret PK data and generate TDM recommendations. The modelled PK exposures and expert committee TDM recommendations were considered optimum and used to validate results obtained by the AI system. RESULTS: A group of patients, 67 on LPV, 46 on EFV and three on both drugs, were included in this analysis. Correlations were high for LPV and EFV estimated trough and 4 h post-dose concentrations between the Al estimates and modelled values (r > 0.79 for all comparisons; P < 0.0001). Although trough concentrations were similar, significant differences were seen for mean predicted 4 h concentrations for EFV (4.16 microg/ml versus 3.89 microg/ml; P = 0.02) and LPV (7.99 microg/ml versus 8.79 microg/ml; P < 0.001). The AI and expert committee TDM recommendations agreed in 53 out of 69 LPV cases [kappa (kappa) = 0.53; P < 0.001] and 47 out of 49 EFV cases (kappa = 0.91; P < 0.001). CONCLUSION: The AI system successfully estimated LPV and EFV trough concentrations and achieved good agreement with expert committee TDM recommendations for EFV- and LPV-treated patients.