Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification

Detoxification and clearance of extracellular hemoglobin (Hb) have been attributed to its removal by the CD163 scavenger receptor pathway. However, even low-level hydrogen peroxide (H(2)O(2)) exposure irreversibly modifies Hb and severely impairs Hb endocytosis by CD163. We show here that when Hb is bound to the high-affinity Hb scavenger protein haptoglobin (Hp), the complex protects Hb from structural modification by preventing alpha-globin cross-links and oxidations of amino acids in critical regions of the beta-globin chain (eg, Trp15, Cys93, and Cys112). As a result of this structural stabilization, H(2)O(2)-exposed Hb-Hp binds to CD163 with the same affinity as nonoxidized complex. Endocytosis and lysosomal translocation of oxidized Hb-Hp by CD163-expressing cells were found to be as efficient as with nonoxidized complex. Hp complex formation did not alter Hb's ability to consume added H(2)O(2) by redox cycling, suggesting that within the complex the oxidative radical burden is shifted to Hp. We provide structural and functional evidence that Hp protects Hb when oxidatively challenged with H(2)O(2) preserving CD163-mediated Hb clearance under oxidative stress conditions. In addition, our data provide in vivo evidence that unbound Hb is oxidatively modified within extravascular compartments consistent with our in vitro findings

Let\u27s talk about antibiotics: A randomised trial of two interventions to reduce antibiotic misuse

BACKGROUND: Children with acute respiratory tract infections (ARTIs) receive ≈11.4 million unnecessary antibiotic prescriptions annually. A noted contributor is inadequate parent-clinician communication, however, efforts to reduce overprescribing have only indirectly targeted communication or been impractical. OBJECTIVES: Compare two feasible (higher vs lower intensity) interventions for enhancing parent-clinician communication on the rate of inappropriate antibiotic prescribing. DESIGN: Multisite, parallel group, cluster randomised comparative effectiveness trial. Data collected between March 2017 and March 2019. SETTING: Academic and private practice outpatient clinics. PARTICIPANTS: Clinicians (n=41, 85% of eligible approached) and 1599 parent-child dyads (ages 1-5 years with ARTI symptoms, 71% of eligible approached). INTERVENTIONS: All clinicians received 20 min ARTI diagnosis and treatment education. Higher intensity clinicians received an additional 50 min communication skills training. All parents viewed a 90 second antibiotic education video. MAIN OUTCOMES AND MEASURES: Inappropriate antibiotic treatment was assessed via blinded medical record review by study clinicians and a priori defined as prescriptions for the wrong diagnosis or use of the wrong agent. Secondary outcomes were revisits, adverse drug reactions (both assessed 2 weeks after the visit) and parent ratings of provider communication, shared decision-making and visit satisfaction (assessed at end of the visit on Likert-type scales). RESULTS: Most clinicians completed the study (n=38, 93%), were doctors (n=25, 66%), female (n=30, 78%) and averaged 8 years in practice. All parent-child dyad provided data for the main outcome (n=855 (54%) male, n=1043 (53%) CONCLUSIONS AND RELEVANCE: Rate of inappropriate prescribing was low in both arms. Clinician education coupled with parent education may be sufficient to yield low inappropriate antibiotic prescribing rates. The absence of a significant difference between groups indicates that communication principles previously thought to drive inappropriate prescribing may need to be re-examined or may not have as much of an impact in practices where prescribing has improved in recent years. TRIAL REGISTRATION NUMBER: NCT03037112

Time Preferences Predict Mortality among HIV-Infected Adults Receiving Antiretroviral Therapy in Kenya

Background: Identifying characteristics of HIV-infected adults likely to have poor treatment outcomes can be useful for targeting interventions efficiently. Research in economics and psychology suggests that individuals’ intertemporal time preferences, which indicate the extent to which they trade-off immediate vs. future cost and benefits, can influence various health behaviors. While there is empirical support for the association between time preferences and various non-HIV health behaviors and outcomes, the extent to which time preferences predict outcomes of those receiving antiretroviral therapy (ART) has not been examined previously. Methods: HIV-infected adults initiating ART were enrolled at a health facility in Kenya. Participants’ time preferences were measured at enrollment and used to classify them as having either a low or high discount rate for future benefits. At 48 weeks, we assessed mortality and ART adherence, as measured by Medication Event Monitoring System (MEMS). Logistic regression models adjusting for socio-economic characteristics and risk factors were used to determine the association between time preferences and mortality as well as MEMS adherence ≥90%. Results: Overall, 44% (96/220) of participants were classified as having high discount rates. Participants with high discount rates had significantly higher 48-week mortality than participants with low discount rates (9.3% vs. 3.1%; adjusted odds ratio 3.84; 95% CI 1.03, 14.50). MEMS adherence ≥90% was similar for participants with high vs. low discount rates (42.3% vs. 49.6%, AOR 0.70; 95% CI 0.40, 1.25). Conclusion: High discount rates were associated with significantly higher risk of mortality among HIV-infected patients initiating ART. Greater use of time preference measures may improve identification of patients at risk of poor clinical outcomes. More research is needed to further identify mechanisms of action and also to build upon and test the generalizability of this finding

Economic Returns to Investment in AIDS Treatment in Low and Middle Income Countries

Since the early 2000s, aid organizations and developing country governments have invested heavily in AIDS treatment. By 2010, more than five million people began receiving antiretroviral therapy (ART) – yet each year, 2.7 million people are becoming newly infected and another two million are dying without ever having received treatment. As the need for treatment grows without commensurate increase in the amount of available resources, it is critical to assess the health and economic gains being realized from increasingly large investments in ART. This study estimates total program costs and compares them with selected economic benefits of ART, for the current cohort of patients whose treatment is cofinanced by the Global Fund to Fight AIDS, Tuberculosis and Malaria. At end 2011, 3.5 million patients in low and middle income countries will be receiving ART through treatment programs cofinanced by the Global Fund. Using 2009 ART prices and program costs, we estimate that the discounted resource needs required for maintaining this cohort are $14.2 billion for the period 2011–2020. This investment is expected to save 18.5 million life-years and return$12 to $34 billion through increased labor productivity, averted orphan care, and deferred medical treatment for opportunistic infections and end-of-life care. Under alternative assumptions regarding the labor productivity effects of HIV infection, AIDS disease, and ART, the monetary benefits range from 81 percent to 287 percent of program costs over the same period. These results suggest that, in addition to the large health gains generated, the economic benefits of treatment will substantially offset, and likely exceed, program costs within 10 years of investment

Short Message Service (SMS)-Based Intervention to Improve Treatment Adherence among HIV-Positive Youth in Uganda: Focus Group Findings

This paper presents one of the first qualitative studies to discuss programmatic barriers to SMS-based interventions for HIV-positive youth and discusses pathways through which youth perceive them to work. We conducted six focus groups with 20 male and 19 female HIV-positive youths in two clinics in Kampala, Uganda. We find that youth commonly use SMS as over 90% of this study’s youths knew how to read, write and send messages and almost three-fourths of them had phones. Youth strongly felt that the success of this intervention hinged on ensuring confidentiality about their HIV-positive status. Key programmatic challenges discussed where restrictions on phone use and phone sharing that could exclude some youth. Participants felt that the intervention would improve their adherence by providing them with needed reminders and social support. Youths’ suggestions about intervention logistics related to content, frequency, timing and two-way messages will be helpful to practitioners in the field

Participant characteristics and outcomes.

<p>Participant characteristics and outcomes.</p

Protocol for a randomised trial of higher versus lower intensity patient-provider communication interventions to reduce antibiotic misuse in two paediatric ambulatory clinics in the USA

Introduction Children with acute respiratory tract infections (ARTIs) are prescribed up to 11.4 million unnecessary antibiotic prescriptions annually. Inadequate parent–provider communication is a chief contributor, yet efforts to reduce overprescribing have only indirectly targeted communication or been impractical. This paper describes our multisite, parallel group, cluster randomised trial comparing two feasible interventions for enhancing parent–provider communication on the rate of inappropriate antibiotic prescribing (primary outcome) and revisits, adverse drug reactions and parent-rated quality of shared decision-making, parent–provider communication and visit satisfaction (secondary outcomes). Methods/analysis We will attempt to recruit all eligible paediatricians and nurse practitioners (currently 47) at an academic children’s hospital and a private practice. Using a 1:1 randomisation, providers will be assigned to a higher intensity education and communication skills or lower intensity education-only intervention and trained accordingly. We will recruit 1600 eligible parent–child dyads. Parents of children ages 1–5 years who present with ARTI symptoms will be managed by providers trained in either the higher or lower intensity intervention. Before their consultation, all parents will complete a baseline survey and view a 90 s gain-framed antibiotic educational video. Parent–child dyads consulting with providers trained in the higher intensity intervention will, in addition, receive a gain-framed antibiotic educational brochure promoting cautious use of antibiotics and rate their interest in receiving an antibiotic which will be shared with their provider before the visit. All parents will complete a postconsultation survey and a 2-week follow-up phone survey. Due to the two-stage nested design (parents nested within providers and clinics), we will employ generalised linear mixed-effect regression models.</p