Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT.

B-cell immune dysfunction contributes to the risk of severe infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Delayed B-cell regeneration is found in patients with systemic graft-versus-host disease (GVHD) and is often accompanied by bone marrow (BM) suppression. Little is known about human BM GVHD. We analyzed the reconstitution kinetics of B-cell subsets in adult leukemic patients within 6 months after allo-HSCT. B-cell deficiency already existed before transplant and was aggravated after transplant. Onset of B-cell reconstitution characterized by transitional B-cell recovery occurred either early (months 2-3) or late (from month 6 on) and correlated highly positively with reverse transcription-polymerase chain reaction quantified numbers of κ-deleting recombination excision circles (KRECs). Delayed recovery was associated with systemic acute GVHD and full-intensity conditioning therapy. Histological analysis of BM trephines revealed increased T-cell infiltration in late recovering patients, which was associated with reduced numbers of osteoblasts. Functionally, late recovering patients displayed less pneumococcal polysaccharide-specific immunoglobin M-producing B cells on ex vivo B-cell activation than early recovering patients. Our results provide evidence for acute BM GVHD in allo-HSCT patients with infiltrating donor T cells and osteoblast destruction. This is associated with delayed B-cell reconstitution and impaired antibody response. Herein, KREC appears suitable to monitor BM B-cell output after transplant.

Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients. METHODS: We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3+CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively. RESULTS: By comparing two recently proposed naïve T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naïve B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively. CONCLUSION: We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia.

Rabbit antithymocyte globulin (thymoglobulin) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients.

Rabbit antithymocyte globulin-Genzyme™ is used to prevent graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Common disadvantages of treatment are infectious complications. The effects of rabbit antithymocyte globulin-Genzyme™ on thymic function have not been well-studied. Multicolor flow cytometry was used to analyze the kinetics of conventional and regulatory T cells in adult patients treated (n=12) or not treated (n=8) with rabbit antithymocyte globulin-Genzyme™ during the first 6 months after allogeneic hematopoietic stem cell transplantation. Patients treated with rabbit antithymocyte globulin-Genzyme™ had almost undetectable levels of recent thymic emigrants (CD45RA(+)CD31(+)) of both conventional and regulatory CD4T cells throughout the 6 months after allogeneic hematopoietic stem cell transplantation whereas CD4(+)CD45RA-memory T cells were less affected, but their levels were also significantly lower than in patients not treated with rabbit antithymocyte globulin-Genzyme™. In vitro, rabbit antithymocyte globulin-Genzyme™ induced apoptosis and cytolysis of human thymocytes, and its cytotoxic effects were greater than those of rabbit antithymocyte globulin-Fresenius™. Rabbit antithymocyte globulin-Genzyme™ in combination with a conditioning regimen strongly impairs thymic recovery of both conventional and regulatory CD4(+) T cells. The sustained depletion of conventional and regulatory CD4(+)T cells carries a high risk of both infections and graft-versus-host disease. Our data indicate that patients treated with rabbit antithymocyte globulin-Genzyme™ could benefit from thymus-protective therapies and that trials comparing this product with other rabbit antithymocyte globulin preparations or lymphocyte-depleting compounds would be informative.

Hospital payment systems based on diagnosis-related groups: experiences in low- and middle-income countries.

OBJECTIVE: This paper provides a comprehensive overview of hospital payment systems based on diagnosis-related groups (DRGs) in low- and middle-income countries. It also explores design and implementation issues and the related challenges countries face. METHODS: A literature research for papers on DRG-based payment systems in low- and middle-income countries was conducted in English, French and Spanish through Pubmed, the Pan American Health Organization's Regional Library of Medicine and Google. FINDINGS: Twelve low- and middle-income countries have DRG-based payment systems and another 17 are in the piloting or exploratory stage. Countries have chosen from a wide range of imported and self-developed DRG models and most have adapted such models to their specific contexts. All countries have set expenditure ceilings. In general, systems were piloted before being implemented. The need to meet certain requirements in terms of coding standardization, data availability and information technology made implementation difficult. Private sector providers have not been fully integrated, but most countries have managed to delink hospital financing from public finance budgeting. CONCLUSION: Although more evidence on the impact of DRG-based payment systems is needed, our findings suggest that (i) the greater portion of health-care financing should be public rather than private; (ii) it is advisable to pilot systems first and to establish expenditure ceilings; (iii) countries that import an existing variant of a DRG-based system should be mindful of the need for adaptation; and (iv) countries should promote the cooperation of providers for appropriate data generation and claims management.

Comparison of hospital costs and length of stay associated with open-mesh, totally extraperitoneal inguinal hernia repair, and transabdominal preperitoneal inguinal hernia repair: an analysis of observational data using propensity score matching.

BACKGROUND: Laparoscopic inguinal hernia surgery is increasingly seen as the superior technique in hernia repair. Compared to open-mesh hernia repair, laparoscopic approaches are often reported to be more cost-effective but incur higher costs for the provider. The objective of this study was to analyze the effect of transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) repair of nonincarcerated inguinal hernias in men on hospital costs and length of stay (LoS). METHODS: We used routine administrative, highly standardized, patient-level cost data from 15 German hospitals participating in the national cost data study. We compared TEP, TAPP, and open-mesh repair. We conducted propensity score matching to account for baseline differences between treatment groups and subsequently estimated the treatment effect on costs and LoS. RESULTS: Total costs for both TEP and TAPP surgery were significantly lower than those for open-mesh repair (p < 0.0001 and p < 0.05, respectively). TEP repair also had a slight but nonsignificant advantage in total costs compared to TAPP repair, while TAPP surgery was associated with a significantly shorter LoS than TEP (p < 0.001). CONCLUSION: Results suggest that laparoscopic approaches in hernia repair are not necessarily associated with higher hospital resource consumption than open-mesh repair.

Single-cell clonal tracking of persistent T-cells in allogeneic hematopoietic stem cell transplantation.

The critical balance between intended and adverse effects in allogeneic hematopoietic stem cell transplantation (alloHSCT) depends on the fate of individual donor T-cells. To this end, we tracked αßT-cell clonotypes during stem cell mobilization treatment with granulocyte-colony stimulating factor (G-CSF) in healthy donors and for six months during immune reconstitution after transfer to transplant recipients. More than 250 αßT-cell clonotypes were tracked from donor to recipient. These clonotypes consisted almost exclusively of CD8+ effector memory T cells (CD8TEM), which exhibited a different transcriptional signature with enhanced effector and cytotoxic functions compared to other CD8TEM. Importantly, these distinct and persisting clonotypes could already be delineated in the donor. We confirmed these phenotypes on the protein level and their potential for selection from the graft. Thus, we identified a transcriptional signature associated with persistence and expansion of donor T-cell clonotypes after alloHSCT that may be exploited for personalized graft manipulation strategies in future studies.

Paired Donor and Recipient Immunophenotyping in Allogeneic Hematopoietic Stem Cell Transplantation: A Cellular Network Approach.

Success and complications of allogeneic hematopoietic stem cell transplantation (alloHSCT) are closely connected to the transferred graft and immune reconstitution post alloHSCT. Due to the variety of immune cells and their distinct roles, a broad evaluation of the immune cellular network is warranted in mobilization and reconstitution studies in alloHSCT. Here, we propose a comprehensive phenotypic analysis of 26 immune cell subsets with multicolor flow cytometry from only 100µl whole blood per time point. Using this approach, we provide an extensive longitudinal analysis of almost 200 time points from 21 donor-recipient pairs. We observe a broad mobilization of innate and adaptive immune cell subsets after granulocyte-colony stimulating factor (G-CSF) treatment of healthy donors. Our data suggest that the relative quantitative immune cell subset composition in recipients approaches that of healthy donors from day +180 post alloHSCT onwards. Correlation of donor and recipient cell counts reveals distinct association patterns for different immune cell subsets and hierarchical clustering of recipient cell counts identifies distinct reconstitution groups in the first month after transplantation. We suggest our comprehensive immune subset analysis as a feasible and time efficient approach for a broad immune assessment for future clinical studies in the context of alloHSCT. This comprehensive cell composition assessment can be a critical step towards personalized graft composition strategies and individualized therapy management in areas such as GvHD prophylaxis in the highly complex immunological setting of alloHSCT.

CD4+ T Cell Dependent B Cell Recovery and Function After Autologous Hematopoietic Stem Cell Transplantation.

Introduction: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers. Methods: Peripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed ex vivo using flow cytometry. Additionally, B cell function was assessed with T cell dependent (TD) and T cell independent (TI) stimulation assays, analyzing proliferation and differentiation of B cells by flow cytometry and numbers of immunoglobulin secreting cells in ELISpots. Results: Quantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells. Conclusion: Quantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies.

Paying hospital specialists: Experiences and lessons from eight high-income countries.

Payment systems for specialists in hospitals can have far reaching consequences for the efficiency and quality of care. This article presents a comparative analysis of payment systems for specialists in hospitals of eight high-income countries (Canada, England, France, Germany, Sweden, Switzerland, the Netherlands, and the USA/Medicare system). A theoretical framework highlighting the incentives of different payment systems is used to identify potentially interesting reform approaches. In five countries,most specialists work as employees - but in Canada, the Netherlands and the USA, a majority of specialists are self-employed. The main findings of our review include: (1) many countries are increasingly shifting towards blended payment systems; (2) bundled payments introduced in the Netherlands and Switzerland as well as systematic bonus schemes for salaried employees (most countries) contribute to broadening the scope of payment; (3) payment adequacy is being improved through regular revisions of fee levels on the basis of more objective data sources (e.g. in the USA) and through individual payment negotiations (e.g. in Sweden and the USA); and (4) specialist payment has so far been adjusted for quality of care only in hospital specific bonus programs. Policy-makers across countries struggle with similar challenges, when aiming to reform payment systems for specialists in hospitals. Examples from our reviewed countries may provide lessons and inspiration for the improvement of payment systems internationally.

Czech Republic: health system review.

This analysis of the Czech health system reviews recent developments in organization and governance, health financing, health-care provision, health reforms and health system performance. The Czech health-care system is based on compulsory statutory health insurance providing virtually universal coverage and a broad range of benefits, and doing so at 7.7 % of GDP in 2012 - well below the EU average - of which a comparatively high 85 % was publicly funded. Some important health indicators are better than the EU averages (such as mortality due to respiratory disease) or even among the best in the world (in terms of infant mortality, for example). On the other hand, mortality rates for diseases of the circulatory system and malignant neoplasms are well above the EU average, as are a range of health-care utilization rates, such as outpatient contacts and average length of stay in acute care hospitals. In short, there is substantial potential in the Czech Republic for efficiency gains and to improve health outcomes. Furthermore, the need for reform in order to financially sustain the system became evident again after the global financial crisis, but there is as yet no consensus about how to achieve this.

Switzerland: Health System Review.

This analysis of the Swiss health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. The Swiss health system is highly complex, combining aspects of managed competition and corporatism (the integration of interest groups in the policy process) in a decentralized regulatory framework shaped by the influences of direct democracy. The health system performs very well with regard to a broad range of indicators. Life expectancy in Switzerland (82.8 years) is the highest in Europe after Iceland, and healthy life expectancy is several years above the European Union (EU) average. Coverage is ensured through mandatory health insurance (MHI), with subsidies for people on low incomes. The system offers a high degree of choice and direct access to all levels of care with virtually no waiting times, though managed care type insurance plans that include gatekeeping restrictions are becoming increasingly important. Public satisfaction with the system is high and quality is generally viewed to be good or very good. Reforms since the year 2000 have improved the MHI system, changed the financing of hospitals, strengthened regulations in the area of pharmaceuticals and the control of epidemics, and harmonized regulation of human resources across the country. In addition, there has been a slow (and not always linear) process towards more centralization of national health policy-making. Nevertheless, a number of challenges remain. The costs of the health care system are well above the EU average, in particular in absolute terms but also as a percentage of gross domestic product (GDP) (11.5%). MHI premiums have increased more quickly than incomes since 2003. By European standards, the share of out-of-pocket payments is exceptionally high at 26% of total health expenditure (compared to the EU average of 16%). Low and middle-income households contribute a greater share of their income to the financing of the health system than higher-income households. Flawed financial incentives exist at different levels of the health system, potentially distorting the allocation of resources to different providers. Furthermore, the system remains highly fragmented as regards both organization and planning as well as health care provision.

Rabbit antithymocyte globulin induces rapid expansion of effector memory CD8 T cells without accelerating acute graft versus host disease.

Rabbit antithymocyte globulin (Thymoglobulin(®)) is commonly used as graft-versus-host disease (GvHD) prophylaxis. Since we found similar total CD8 T cell numbers in patients with and without Thymoglobulin(®) therapy within the first six months after allogeneic hematopoietic stem cell transplantation, we have analyzed the reconstitution of the CD8 T cell compartment in detail. After T cell-depletion, higher and more sustained proliferative capacity of memory CD8 T cells resulted in their rapid expansion, whereas the fraction of naive CD8 T cells decreased. Importantly, this shift towards effector memory CD8 T cells did not accelerate the incidence of GvHD.

Czech Republic: health system review

This analysis of the Czech health system reviews recent developments inorganization and governance, health financing, health-care provision,health reforms and health system performance. The Czech health-caresystem is based on compulsory statutory health insurance providing virtuallyuniversal coverage and a broad range of benefits, and doing so at 7.7% ofGDP in 2012 – well below the EU average – of which a comparatively high85% was publicly funded. Some important health indicators are better than theEU averages (such as mortality due to respiratory disease) or even among thebest in the world (in terms of infant mortality, for example). On the other hand,mortality rates for diseases of the circulatory system and malignant neoplasmsare well above the EU average, as are a range of health-care utilization rates,such as outpatient contacts and average length of stay in acute care hospitals. Inshort, there is substantial potential in the Czech Republic for efficiency gainsand to improve health outcomes. Furthermore, the need for reform in order tofinancially sustain the system became evident again after the global financialcrisis, but there is as yet no consensus about how to achieve this.

Switzerland: health system review

This analysis of the Swiss health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. The Swiss health system is highly complex, combining aspects of managed competition and “corporatism” (the integration of interest groups in the policy process) in a decentralized regulatory framework shaped by the influences of direct democracy. The health system performs very well with regard to a broad range of indicators. Coverage is ensured through mandatory health insurance (MHI), with subsidies for people on low incomes. The system offers a high degree of choice and direct access to all levels of care with virtually no waiting times, though managed care type insurance plans that include gatekeeping restrictions are becoming increasingly important. Public satisfaction is high and quality is viewed to be good or very good. Reforms since 2000 have improved the MHI system, changed the financing of hospitals, strengthened regulations in the area of pharmaceuticals and the control of epidemics, and harmonized regulation of human resources across the country. In addition, there has been a slow process towards more centralization of national health policy-making. Nevertheless, a number of challenges remain: the costs of the health care system are well above the EU average; MHI premiums have increased more quickly than incomes since 2003; by European standards, the share of out-of-pocket payments is exceptionally high; low- and middle-income households contribute a greater share of their income to the financing of the health system than higher-income households; and the system remains highly fragmented as regards both organization and planning as well as health care provision.