Publications

Human regulatory T cells (Tregs) suppress other T cells by converting the latent, inactive form of TGF-β1 into active TGF-β1. In Tregs, TGF-β1 activation requires GARP, a transmembrane protein that binds and presents latent TGF-β1 on the surface of Tregs stimulated through their T cell receptor. However, GARP is not sufficient because transduction of GARP in non-Treg T cells does not induce active TGF-β1 production. RGD-binding integrins were shown to activate TGF-β1 in several non-T cell types. Here we show that αVβ8 dimers are present on stimulated human Tregs but not in other T cells, and that antibodies against αV or β8 subunits block TGF-β1 activation in vitro. We also show that αV and β8 interact with GARP/latent TGF-β1 complexes in human Tregs. Finally, a blocking antibody against β8 inhibited immunosuppression by human Tregs in a model of xenogeneic graft-vs.-host disease induced by the transfer of human T cells in immunodeficient mice. These results show that TGF-β1 activation on the surface of human Tregs implies an interaction between the integrin αVβ8 and GARP/latent TGF-β1 complexes. Immunosuppression by human Tregs can be inhibited by antibodies against GARP or against the integrin β8 subunit. Such antibodies may prove beneficial against cancer or chronic infections.

SETTING

Seven public tuberculosis (TB) units in Kampala, Uganda, where Uganda's national TB program recently introduced household contact investigation, as recommended by 2012 guidelines from WHO.

OBJECTIVE

To apply a cascade analysis to implementation of household contact investigation in a programmatic setting.

DESIGN

Prospective, multi-center observational study.

METHODS

We constructed a cascade for household contact investigation to describe the proportions of: 1) index patient households recruited; 2) index patient households visited; 3) contacts screened for TB; and 4) contacts completing evaluation for, and diagnosed with, active TB.

RESULTS

338 (33%) of 1022 consecutive index TB patients were eligible for contact investigation. Lay health workers scheduled home visits for 207 (61%) index patients and completed 104 (50%). Among 287 eligible contacts, they screened 256 (89%) for symptoms or risk factors for TB. 131 (51%) had an indication for further TB evaluation. These included 59 (45%) with symptoms alone, 58 (44%) children <5, and 14 (11%) with HIV. Among 131 contacts found to be symptomatic or at risk, 26 (20%) contacts completed evaluation, including five (19%) diagnosed with and treated for active TB, for an overall yield of 1.7%. The cumulative conditional probability of completing the entire cascade was 5%.

CONCLUSION

Major opportunities exist for improving the effectiveness and yield of TB contact investigation by increasing the proportion of index households completing screening visits by lay health workers and the proportion of at-risk contacts completing TB evaluation.

BACKGROUND

To improve management of severely ill hospitalized patients in low-income settings, the World Health Organization (WHO) established a triage tool called "Quick Check" to provide clinicians with a rapid, standardized approach to identify patients with severe illness based on recognition of abnormal vital signs. Despite the availability of these guidelines, recognition of severe illness remains challenged in low-income settings, largely as a result of infrequent vital sign monitoring.

METHODS

We conducted a staggered, pre-post quasi-experimental study at four inpatient health facilities in western Uganda to assess the impact of a multi-modal intervention for improving quality of care following formal training on WHO "Quick Check" guidelines for diagnosis of severe illness in low-income settings. Intervention components were developed using the COM-B ("capability," "opportunity," and "motivation" determine "behavior") model and included clinical mentoring by an expert in severe illness care, collaborative improvement meetings with external support supervision, and continuous audits of clinical performance with structured feedback.

RESULTS

There were 5759 patients hospitalized from August 2014 to May 2015: 1633 were admitted before and 4126 during the intervention period. Designed to occur twice monthly, collaborative improvement meetings occurred every 2-4 weeks at each site. Clinical mentoring sessions, designed to occur monthly, occurred every 4-6 months at each site. Audit and feedback reports were implemented weekly as designed. During the intervention period, there were significant increases in the site-adjusted likelihood of initial assessment of temperature, heart rate, blood pressure, respiratory rate, mental status, and pulse oximetry. Patients admitted during the intervention period were significantly more likely to be diagnosed with sepsis (4.3 vs. 0.4%, risk ratio 10.1, 95% CI 3.0-31.0, p < 0.001) and severe respiratory distress (3.9 vs. 0.9%, risk ratio 4.5, 95% CI 1.8-10.9, p = 0.001).

CONCLUSIONS

Theory-informed quality improvement programs can improve vital sign collection and diagnosis of severe illness in low-income settings. Further implementation, evaluation, and scale-up of such interventions are needed to enhance hospital-based triage and severe illness management in these settings.

TRIAL REGISTRATION

Severe illness management system (SIMS) intervention development, ISRCTN46976783.

BACKGROUND

Many medical schools use admissions Multiple Mini-Interviews (MMIs) rather than traditional interviews (TIs), partly because MMIs are thought to be more reliable. Yet prior studies examined single-school samples of candidates completing either an MMI or TI (not both). Using data from five California public medical schools, the authors examined the within- and between-school reliabilities of TIs and MMIs.

METHODS

The analyses included applicants interviewing at ≥1 of the five schools during 2011-2013. Three schools employed TIs (TI1, TI2, TI3) and two employed MMIs (MMI1, MMI2). Mixed linear models accounting for nesting of observations within applicants examined standardized TI and MMI scores (mean = 0, SD = 1), adjusting for applicant socio-demographics, academic metrics, year, number of interviews, and interview date.

RESULTS

A total of 4993 individuals (completing 7516 interviews [TI = 4137, MMI = 3379]) interviewed at ≥1 school; 428 (14.5%) interviewed at both MMI schools and 687 (20.2%) at more than one TI school. Within schools, inter-interviewer consistency was generally qualitatively lower for TI1, TI2, and TI3 (Pearson's r 0.07, 0.13, and 0.29, and Cronbach's α, 0.40, 0.44, and 0.61, respectively) than for MMI1 and MMI 2 (Cronbach's α 0.68 and 0.60, respectively). Between schools, the adjusted intraclass correlation coefficient was 0.27 (95% CI 0.20-0.35) for TIs and 0.47 (95% CI 0.41-0.54) for MMIs.

CONCLUSIONS

Within and between-school reliability was qualitatively higher for MMIs than for TIs. Nonetheless, TI reliabilities were higher than anticipated from prior literature, suggesting TIs may not need to be abandoned on reliability grounds if other factors favor their use.

OBJECTIVE

Osteoporotic fractures are associated with high morbidity and mortality. Persons with rheumatoid arthritis (RA) have twice the risk of osteoporosis-related fracture than age-matched controls, the causes for which remain unknown. We investigated contributions of RA characteristics, medication use, and body composition to low bone mineral density (BMD) in patients with RA.

METHODS

Data were from the Arthritis, Body Composition, and Disability Study (n = 138; 82 women, 56 men). Demographic, clinical, laboratory, and functional variables were collected at study visits. Body composition (fat, lean muscle, and BMD) was measured by dual x-ray absorptiometry. Linear regression analyses evaluated the association between predictors and femoral neck BMD.

RESULTS

Average disease duration was 19 years, 70% of patients were rheumatoid factor positive, and 55% were high-positive anti-cyclic citrullinated peptide (anti-CCP). Age and high anti-CCP positivity were negatively associated with BMD after controlling for other variables (β = -0.003 and -0.055, respectively, P < 0.05). Appendicular lean mass index (ALMI) was positively associated with BMD (β = 0.053, P < 0.0001). In high anti-CCP positivity participants, increasing anti-CCP levels were associated with a negative linear trend in BMD (β = -0.011, P = 0.026).

CONCLUSION

High anti-CCP positivity and ALMI were strongly associated with BMD in patients with RA. The linear relationship of anti-CCP levels with lower BMD supports the hypothesis that processes specific to RA negatively impact BMD. In contrast, ALMI was positively associated with BMD, emphasizing the importance of this potentially modifiable risk factor. Our findings highlight the complicated interplay of RA disease-specific and functional factors and their impact on bone mass.