A patient-driven clinicogenomic partnership for metastatic prostate cancer.

Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but have predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere in the US and Canada in molecular research. Here, we present results from our partnership with the first 706 MPCproject participants. While 41% of patient partners live in rural, physician-shortage, or medically underserved areas, the MPCproject has not yet achieved racial diversity, a disparity that demands new initiatives detailed herein. Among molecular data from 333 patient partners (572 samples), exome sequencing of 63 tumor and 19 cell-free DNA (cfDNA) samples recapitulated known findings in MPC, while inexpensive ultra-low-coverage sequencing of 318 cfDNA samples revealed clinically relevant AR amplifications. This study illustrates the power of a growing, longitudinal partnership with patients to generate a more representative understanding of MPC.

If we build it, will they come? Results of a quasi-experimental study assessing the impact of maternity waiting homes on facility-based childbirth and maternity care in Zambia.

INTRODUCTION: Maternity waiting homes (MWHs) aim to increase access to maternity and emergency obstetric care by allowing women to stay near a health centre before delivery. An improved MWH model was developed with community input and included infrastructure, policies and linkages to health centres. We hypothesised this MWH model would increase health facility delivery among remote-living women in Zambia. METHODS: We conducted a quasi-experimental study at 40 rural health centres (RHC) that offer basic emergency obstetric care and had no recent stockouts of oxytocin or magnesium sulfate, located within 2 hours of a referral hospital. Intervention clusters (n=20) received an improved MWH model. Control clusters (n=20) implemented standard of care. Clusters were assigned to study arm using a matched-pair randomisation procedure (n=20) or non-randomly with matching criteria (n=20). We interviewed repeated cross-sectional random samples of women in villages 10+ kilometres from their RHC. The primary outcome was facility delivery; secondary outcomes included postnatal care utilisation, counselling, services received and expenditures. Intention-to-treat analysis was conducted. Generalised estimating equations were used to estimate ORs. RESULTS: We interviewed 2381 women at baseline (March 2016) and 2330 at endline (October 2018). The improved MWH model was associated with increased odds of facility delivery (OR 1.60 (95% CI: 1.13 to 2.27); p<0.001) and MWH utilisation (OR 2.44 (1.62 to 3.67); p<0.001). The intervention was also associated with increased odds of postnatal attendance (OR 1.55 (1.10 to 2.19); p<0.001); counselling for family planning (OR 1.48 (1.15 to 1.91); p=0.002), breast feeding (OR 1.51 (1.20 to 1.90); p<0.001), and kangaroo care (OR 1.44 (1.15, 1.79); p=0.001); and caesarean section (OR 1.71 (1.16 to 2.54); p=0.007). No differences were observed in household expenditures for delivery. CONCLUSION: MWHs near well-equipped RHCs increased access to facility delivery, encouraged use of facilities with emergency care capacity, and improved exposure to counselling. MWHs can be useful in the effort to increase delivery at advanced facilities in areas where substantial numbers of women live remotely. TRIAL REGISTRATION NUMBER: NCT02620436.

Building financial management capacity for community ownership of development initiatives in rural Zambia.

BACKGROUND: Building financial management capacity is increasingly important in low- and middle-income countries to help communities take ownership of development activities. Yet, many community members lack financial knowledge and skills. METHODS: We designed and conducted financial management trainings for 83 members from 10 community groups in rural Zambia. We conducted pre-training and post-training tests and elicited participant feedback. We conducted 28 in-depth interviews over 18 months and reviewed financial records to assess practical application of skills. RESULTS: The training significantly improved knowledge of financial concepts, especially among participants with secondary education. Participants appreciated exercises to contextualize financial concepts within daily life and liked opportunities to learn from peers in small groups. Language barriers were a particular challenge. After trainings, sites successfully adhered to the principles of financial management, discussing the benefits they experienced from practicing accountability, transparency, and accurate recordkeeping. CONCLUSION: Financial management trainings need to be tailored to the background and education level of participants. Trainings should relate financial concepts to more tangible applications and provide time for active learning. On-site mentorship should be considered for a considerable time. This training approach could be used in similar settings to improve community oversight of resources intended to strengthen developmental initiatives.

Beta-2 adrenergic receptors increase TREG cell suppression in an OVA-induced allergic asthma mouse model when mice are moderate aerobically exercised.

BACKGROUND: The potency of T regulatory (TREG) cells to inhibit T helper (Th)-driven immune cell responses has been linked to increased intracellular cyclic-AMP (cAMP) levels of TREG cells. In an ovalbumin (OVA)-driven allergic asthma mouse model, moderate aerobic exercise increases TREG cell function in a contact-dependent manner that leads to a significant reduction in chronic inflammation and restoration of lung function. However, the mechanism, whereby exercise increases TREG function, remains unknown and was the focus of these investigations. Exercise can communicate with TREG cells by their expression of ß2-adrenergic receptors (ß2-AR). Activation of these receptors results in an increase in intracellular levels of cyclic-AMP, potentially creating a potent inhibitor of Th cell responses. RESULTS: For the allergic asthma model, female wildtype BALB/c mice were challenged with OVA, and exercised (13.5 m/min for 45 min) 3×/week for 4 weeks. TREG cells were isolated from all mouse asthma/exercise groups, including ß2-AR-/- mice, to test suppressive function and intracellular cAMP levels. In these studies, cAMP levels were increased in TREG cells isolated from exercised mice. When ß2-AR expression was absent on TREG cells, cAMP levels were significantly decreased. Correlatively, their suppressive function was compromised. Next, TREG cells from all mouse groups were tested for suppressive function after treatment with either a pharmaceutical ß2-adrenergic agonist or an effector-specific cAMP analogue. These experiments showed TREG cell function was increased when treated with either a ß2-adrenergic agonist or effector-specific cAMP analogue. Finally, female wildtype BALB/c mice were antibody-depleted of CD25+CD4+ TREG cells (anti-CD25). Twenty-four hours after TREG depletion, either ß2-AR-/- or wildtype TREG cells were adoptively transferred. Recipient mice underwent the asthma/exercise protocols. ß2-AR-/- TREG cells isolated from these mice showed no increase in TREG function in response to moderate aerobic exercise. CONCLUSION: These studies offer a novel role for ß2-AR in regulating cAMP intracellular levels that can modify suppressive function in TREG cells.

Epidemiology of Emergency Medical Services (EMS) Utilization in Four Indian Emergency Departments.

Introduction Without a universal Emergency Medical Services (EMS) system in India, data on the epidemiology of patients who utilize EMS are limited. This retrospective chart review aimed to quantify and describe the burden of disease and patient demographics of patients who arrived by EMS to four Indian emergency departments (EDs) in order to inform a national EMS curriculum. METHODS: A retrospective chart review was performed on patients transported by EMS over a three-month period in 2014 to four private EDs in India. A total of 17,541 patient records were sampled from the four sites over the study period. Of these records, 1,723 arrived by EMS and so were included for further review. RESULTS: A range of 1.4%-19.4% of ED patients utilized EMS to get to the ED. The majority of EMS patients were male (59%-64%) and adult or geriatric (93%-99%). The most common chief complaints and ED diagnoses were neurological, pulmonary, cardiovascular, gastrointestinal, trauma, and infectious disease. CONCLUSIONS: Neurological, pulmonary, cardiovascular, gastrointestinal, trauma, and infectious disease are the most common problems found in patients transported by EMS in India. Adult and geriatric male patients are the most common EMS utilizers. Emergency Medical Services curricula should emphasize these knowledge areas and skills. Wijesekera O , Reed A , Chastain PS , Biggs S , Clark EG , Kole T , Chakrapani AT , Ashish N , Rajhans P , Breaud AH , Jacquet GA . Epidemiology of Emergency Medical Services (EMS) utilization in four Indian emergency departments. Prehosp Disaster Med. 2016;31(6):675-679.

Moderate aerobic exercise alters migration patterns of antigen specific T helper cells within an asthmatic lung.

Studies have indicated increased incidence and severity of allergic asthma due to western lifestyle and increased sedentary activity. Investigations also indicate that exercise reduces the severity of asthma; however, a mechanism of action has not been elucidated. Additional work implicates re-distribution of T helper (Th) cells in mediating alterations of the immune system as a result of moderate aerobic exercise in vivo. We have previously reported that exercise decreases T helper 2 (Th2) responses within the lungs of an ovalbumin (OVA)-sensitized murine allergic asthma model. Therefore, we hypothesized that exercise alters the migration of OVA-specific Th cells in an OVA-challenged lung. To test this hypothesis, wildtype mice received OVA-specific Th cells expressing a luciferase-reporter construct and were OVA-sensitized and exercised. OVA-specific Th cell migration was decreased in OVA-challenged lungs of exercised mice when compared to their sedentary controls. Surface expression levels of lung-homing chemokine receptors, CCR4 and CCR8, on Th cells and their cognate lung-homing chemokine gradients revealed no difference between exercised and sedentary OVA-sensitized mice. However, transwell migration experiments demonstrated that lung-derived Th cells from exercised OVA-sensitized mice exhibited decreased migratory function versus controls. These data suggest that Th cells from exercised mice are less responsive to lung-homing chemokine. Together, these studies demonstrate that moderate aerobic exercise training can reduce the accumulation of antigen-specific Th cell migration into an asthmatic lung by decreasing chemokine receptor function.