Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse.

T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.

Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

Managing Ischemic Heart Disease in Women: Role of a Women's Heart Center.

PURPOSE OF REVIEW: Heart centers for women (HCW) were developed due to the rising cardiovascular morbidity and mortality in women in the United States in the early 1990s. Our review encompasses the epidemiology, risk factors, diagnostic strategies, treatments, and the role of HCW in managing women with ischemic heart disease (IHD). RECENT FINDINGS: HCW use a multidisciplinary team to manage women with IHD. Due to the paucity of randomized controlled trials investigating various manifestations of IHD, some treatments are not evidence-based such as those for coronary microvascular dysfunction and spontaneous coronary artery dissection. Sex-specific risk factors have been identified and multimodality cardiac imaging is improving in diagnosing IHD in women. Treatments are being studied to help improve symptoms and outcomes in women with IHD. There has been progress in the care of women with IHD. HCW can be instrumental in treating women with IHD, doing research, and being a source of research study participants.

Venous Thromboembolism Associated With Pregnancy: JACC Focus Seminar.

Venous thromboembolism (VTE), composed of pulmonary embolism and deep venous thrombosis, is a significant cause of maternal mortality in the developed world. Normal physiological changes of pregnancy increase coagulability, which is compounded by patient-inherited and acquired risk factors. Depending on these risks and peripartum stage, the benefits of thromboprophylaxis can outweigh potential side effects. Diagnosis requires cautious clinical acumen because many symptoms of normal pregnancy mimic those of VTE and algorithmic tools used in the nonpregnant population are not equally applicable. Choice of imaging technique must account for potential risk to the fetus and altered test accuracy (sensitivity and specificity) in the setting of pregnancy. When VTE is diagnosed, anticoagulation is the backbone of treatment, with more advanced therapies being options for those with right ventricular dysfunction or unstable hemodynamics. Overall, pregnancy-associated VTE is complex, and management decisions should be individualized and informed by patient preferences.

The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD.

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.

An intestinal organoid-based platform that recreates susceptibility to T-cell-mediated tissue injury.

A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.

Analysis of Patient Visits and Collections After Opening a Satellite Pediatric Emergency Department.

OBJECTIVE: Satellite pediatric emergency departments (PEDs) have emerged as a strategy to increase patient capacity. We sought to determine the impact on patient visits, physician fee collections, and value of emergency department (ED) time at the primary PED after opening a nearby satellite PED. We also illustrate the spatial distribution of patient demographics and overlapping catchment areas for the primary and satellite PEDs using geographical information system. METHODS: A structured, financial retrospective review was conducted. Aggregate patient demographic data and billing data were collected regarding physician fee charges, collections, and patient visits for both PEDs. All ED visits from January 2009 to December 2013 were analyzed. Geographical information system mapping using ArcGIS mapped ED patient visits. RESULTS: Patient visits at the primary PED were 53,050 in 2009 before the satellite PED opened. The primary PED visits increased after opening the satellite PED to 55,932 in 2013. The satellite PED visits increased to 21,590 in 2013. Collections per visit at the primary PED decreased from $105.13 per visit in 2011 to $86.91 per visit in 2013. Total collections at the satellite PED decreased per visit from $155.41 per visit in 2011 to $128.53 per visit in 2013. CONCLUSIONS: After opening a nearby satellite PED, patient visits at the primary PED did not substantially decrease, suggesting that there was a previously unrecognized demand for PED services. The collections per ED visit were greater at the satellite ED, likely due to a higher collection rate.

When dementia is in the house: needs assessment survey for young caregivers.

OBJECTIVE: To learn more about the needs and experiences of young carers for patients of frontotemporal dementia (FTD) in order to create a relevant support website for young caregivers to dementia patients. METHODS: Two focus groups were held with a total of fourteen young carers aged 11-18. The data corpus was collected through a semi-structured interview facilitated by a medical journalist who had prior experience as a caregiver to a patient with FTD. The transcripts were narrowed to a dataset for descriptive analysis using a coding scheme to reveal the main themes of their responses. RESULTS: Seven overlapping theme areas were: emotional impact of living with a parent with FTD, caregiving, coping, symptoms, diagnosis, relationships, and support. Based on the participants' responses, a website was launched providing supportive information and counsel for young carers. CONCLUSION: Young carers saw the experience of caring for a parent with early-onset dementia as positive overall, but identified opportunities for professionals to assist them in overcoming stigma and the challenge of balancing childhood and adolescent development within this context.

The effect of social determinants on immunization programs.

Vaccine preventable diseases have been responsible for a significant portion of childhood mortality in low-income countries, and have been re-emerging in medium- and high-income countries. The effectiveness of routine childhood immunization programs relies on multiple factors. Social determinants have the potential to affect immunization programs around the world, with globalization and ease of communication facilitating their effect. Exploring the types of social determinants affecting immunization efforts in various countries is of great importance to the ability of nations to address them, prevent the spread of disease and lower mortality rates. The social determinants affecting vaccination programs can vary among countries of different income levels, with some social determinants overlapping among these country groups. In this article we explore the various social determinants affecting routine immunization programs in low-, middle- and high-income countries and possible interventions to address them.

Factors affecting the introduction of new vaccines to poor nations: a comparative study of the Haemophilus influenzae type B and hepatitis B vaccines.

BACKGROUND: A major effort to introduce new vaccines into poor nations of the world was initiated in recent years with the help of the GAVI alliance. The first vaccines introduced have been the Haemophilus influenzae type B (Hib) and the hepatitis B (Hep B) vaccines. The introduction of these vaccines during the first phase of GAVI's operations demonstrated considerable variability. We set out to study the factors affecting the introduction of these vaccines. The African Region (AFRO), where new vaccines were introduced to a substantial number of countries during the first phase of GAVI's funding, was selected for this study. METHODOLOGY/PRINCIPAL FINDINGS: GAVI-eligible AFRO countries with a population of 0.5 million or more were included in the study. Countries were analyzed and compared for new vaccine introduction, healthcare indicators, financial indicators related to healthcare and country-level Governance Indicators, using One Way ANOVA, correlation analysis and Qualitative Comparative Analysis (QCA). Introduction of new vaccines into AFRO nations was associated primarily with high country-level Governance Indicator scores. The use of individual Governance Indicator scores, as well as a combined Governance Indicator score we developed, demonstrated similar results. CONCLUSIONS/SIGNIFICANCE: Our study results indicate that good country-level governance is an imperative pre-requisite for the successful early introduction of new vaccines into poor African nations. Enhanced support measures may be required to effectively introduce new vaccines to countries with low governance scores. The combined governance score we developed may thus constitute a useful tool for helping philanthropic organizations make decisions regarding the type of support needed by different countries to achieve success.

A University of Chicago consortium phase II trial of SB-715992 in advanced renal cell cancer.

BACKGROUND: Advanced renal cell cancer (RCC) continues to have a poor overall prognosis despite new FDA-approved therapies. Although taxane-based therapies are generally ineffective in RCC, research into the role of the von Hippel-Lindau protein has shown an association with microtubule dynamics. Mitotic kinesins are a class of molecular motors that also interact with microtubules and are required for proper mitotic function. SB-715992 is a new agent that inhibits the function of a mitotic kinesin known as kinesin spindle protein and leads to cell death. PATIENTS AND METHODS: Twenty patients with previously treated advanced RCC were enrolled on this phase II trial of SB-715992, with response rate as a primary endpoint. RESULTS: No patients responded with complete or partial remission. Six patients had stable disease, and 1 patient continues on therapy after 12 cycles. Common toxicities included anemia (80%), elevated creatinine (70%), lymphopenia (45%), fatigue (50%), hyperglycemia (50%), and dyspnea (45%). Reported grade 3/4 toxicities included dyspnea, fatigue, neutropenia with skin infection, dizziness, hyperuricemia, and hypertension. CONCLUSION: This dose and schedule of SB-715992 does not appear to have a significant cytotoxic effect for patients with previously treated advanced RCC.