Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation.

Survival of pig cardiac xenografts in a non-human primate (NHP) model has improved significantly over the last 4 years with the introduction of costimulation blockade based immunosuppression (IS) and genetically engineered (GE) pig donors. The longest survival of a cardiac xenograft in the heterotopic (HHTx) position was almost 3 years and only rejected when IS was stopped. Recent reports of cardiac xenograft survival in a life-sustaining orthotopic (OHTx) position for 6 months is a significant step forward. Despite these achievements, there are still several barriers to the clinical success of xenotransplantation (XTx). This includes the possible transmission of porcine pathogens with pig donors and continued xenograft growth after XTx. Both these concerns, and issues with additional incompatibilities, have been addressed recently with the genetic modification of pigs. This review discusses the spectrum of issues related to cardiac xenotransplantation, recent progress in preclinical models, and its feasibility for clinical translation.

Expert Consensus: Telehealth Skills for Health Care Professionals.

Background: The COVID-19 pandemic has driven most clinicians, from those practicing in small independent practices to those in large system, to adopt virtual care. However, individuals and organizations may lack the experience and skills that would be considered fundamental prerequisites to adopting telehealth in less urgent times. What are those skills? Before the pandemic, the Association of American Medical Colleges (AAMC) convened national experts to identify and articulate a consensus set of critical telehealth skills for clinicians. Methods: Through a structured review of the literature, followed by several rounds of review and refinement by committee and community members via a modified Delphi process, the committee came to consensus on a set of skills required by clinicians to provide quality care via telehealth. Conclusion: The consensus set of telehealth skills presented in this paper, developed by the AAMC and national experts, can serve providers and health systems seeking to ensure that clinicians are prepared to meet the demand for care delivered via telehealth now and in the future.

Cardiac xenografts show reduced survival in the absence of transgenic human thrombomodulin expression in donor pigs.

A combination of genetic manipulations of donor organs and target-specific immunosuppression is instrumental in achieving long-term cardiac xenograft survival. Recently, results from our preclinical pig-to-baboon heterotopic cardiac xenotransplantation model suggest that a three-pronged approach is successful in extending xenograft survival: (a) α-1,3-galactosyl transferase (Gal) gene knockout in donor pigs (GTKO) to prevent Gal-specific antibody-mediated rejection; (b) transgenic expression of human complement regulatory proteins (hCRP; hCD46) and human thromboregulatory protein thrombomodulin (hTBM) to avoid complement activation and coagulation dysregulation; and (c) effective induction and maintenance of immunomodulation, particularly through co-stimulation blockade of CD40-CD40L pathways with anti-CD40 (2C10R4) monoclonal antibody (mAb). Using this combination of manipulations, we reported significant improvement in cardiac xenograft survival. In this study, we are reporting the survival of cardiac xenotransplantation recipients (n = 3) receiving xenografts from pigs without the expression of hTBM (GTKO.CD46). We observed that all grafts underwent rejection at an early time point (median 70 days) despite utilization of our previously reported successful immunosuppression regimen and effective control of non-Gal antibody response. These results support our hypothesis that transgenic expression of human thrombomodulin in donor pigs confers an independent protective effect for xenograft survival in the setting of a co-stimulation blockade-based immunomodulatory regimen.

Surgical ablation of atrial fibrillation during mitral-valve surgery.

BACKGROUND: Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited. METHODS: We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring). RESULTS: More patients in the ablation group than in the control group were free from atrial fibrillation at both 6 and 12 months (63.2% vs. 29.4%, P<0.001). There was no significant difference in the rate of freedom from atrial fibrillation between patients who underwent pulmonary-vein isolation and those who underwent the biatrial maze procedure (61.0% and 66.0%, respectively; P=0.60). One-year mortality was 6.8% in the ablation group and 8.7% in the control group (hazard ratio with ablation, 0.76; 95% confidence interval, 0.32 to 1.84; P=0.55). Ablation was associated with more implantations of a permanent pacemaker than was no ablation (21.5 vs. 8.1 per 100 patient-years, P=0.01). There were no significant between-group differences in major cardiac or cerebrovascular adverse events, overall serious adverse events, or hospital readmissions. CONCLUSIONS: The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00903370.).

CD4+CD25Hi FoxP3+ regulatory T cells in long-term cardiac xenotransplantation.

BACKGROUND: CD4+CD25Hi FoxP3+ T (Treg) cells are a small subset of CD4+ T cells that have been shown to exhibit immunoregulatory function. Although the absolute number of Treg cells in peripheral blood lymphocytes (PBL) is very small, they play an important role in suppressing immune reactivity. Several studies have demonstrated that the number of Treg cells, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of transplanted grafts. In this study, we analyzed Treg cells in PBL of long-term baboon recipients who have received genetically modified cardiac xenografts from pig donors. METHODS: Heterotopic cardiac xenotransplantation was performed on baboons using hearts obtained from GTKO.hCD46 (n = 8) and GTKO.hCD46.TBM (n = 5) genetically modified pigs. Modified immunosuppression regimen included antithymocyte globulin (ATG), anti-CD20, mycophenolate mofetil (MMF), cobra venom factor (CVF), and costimulation blockade (anti-CD154/anti-CD40 monoclonal antibody). FACS analysis was performed on PBLs labeled with anti-human CD4, CD25, and FoxP3 monoclonal antibodies (mAb) to analyze the percentage of Treg cells in six baboons that survived longer than 2 months (range: 42-945 days) after receiving a pig cardiac xenograft. RESULTS: Total WBC count was low due to immunosuppression in baboons who received cardiac xenograft from GTKO.hCD46 and GTKO.hCD46.hTBM donor pigs. However, absolute numbers of CD4+CD25Hi FoxP3 Treg cells in PBLs of long-term xenograft cardiac xenograft surviving baboon recipients were found to be increased (15.13 ± 1.50 vs 7.38 ± 2.92; P < .018) as compared to naïve or pre-transplant baboons. Xenograft rejection in these animals was correlated with decreased numbers of regulatory T cells. CONCLUSION: Our results suggest that regulatory T (Treg) cells may contribute to preventing or delaying xenograft rejection by controlling the activation and expansion of donor-reactive T cells, thereby masking the antidonor immune response, leading to long-term survival of cardiac xenografts.

Consideration of appropriate clinical applications for cardiac xenotransplantation.

The field of cardiac xenotransplantation has entered an exciting era due to recent advances in the field. Although several hurdles remain, the use of rapidly evolving transgenic technology has the potential to address current allogeneic donor pool constraints and mechanical circulatory system device limitations. The success of xenotransplantation will undoubtedly be dependent on specific patient selection criteria. Defining these particular indications for xenotransplantation is important as we approach the possibility of clinical applications.

Postoperative acute kidney injury following intraoperative blood product transfusions during cardiac surgery.

INTRODUCTION: This study explored the nature of the association between intraoperative usage of red blood cell, fresh frozen plasma, cryoprecipitate or platelet transfusions and acute kidney injury. METHODS: A total of 1175 patients who underwent cardiac surgery between 2008 and 2013 were retrospectively analyzed. We assessed the association between: (1) preoperative patient characteristics and acute kidney injury, (2) intraoperative blood product usage and acute kidney injury, (3) acute kidney injury and 30-day mortality or re-hospitalization. RESULTS: In our cohort of 1175 patients, 288 patients (24.5%) developed acute kidney injury. This included 162 (13.8%), 69 (5.9%) and 57 (4.9%) developing stage 1, stage 2 or stage 3 acute kidney injury, respectively. Increased red blood cell, fresh frozen plasma or platelet transfusions increased the odds of developing acute kidney injury. Specifically, every unit of red blood cells, fresh frozen plasma or platelets transfused was associated with an increase in the covariate-adjusted odds ratio of developing ⩾ stage 2 kidney injury of 1.18, 1.19 and 1.04, respectively. CONCLUSIONS: Intraoperative blood product transfusions were independently associated with an increased odds of developing acute kidney injury following cardiac surgery. Further randomized studies are needed to better define intraoperative transfusion criteria.

Mitral-valve repair versus replacement for severe ischemic mitral regurgitation.

BACKGROUND: Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited. METHODS: We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank. RESULTS: At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, -6.6 and -6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P=0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months. CONCLUSIONS: We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes. (Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.).

Encouraging experience using multi-transgenic xenografts in a pig-to-baboon cardiac xenotransplantation model.

BACKGROUND: Innovations in transgenic technology have facilitated improved xenograft survival. Additional gene expression appears to be necessary to overcome the remaining immune and biologic incompatibilities. We report for the first time the novel use of six-gene modifications within a pig-to-baboon cardiac xenotransplantation model. METHODS: Baboons (8-15 kg) underwent heterotopic cardiac transplantation using xenografts obtained from genetically engineered pigs. Along with previously described modifications (GTKO, hCD46), additional expression of human transgenes for thromboregulation (endothelial protein C receptor, tissue factor pathway inhibitor, thrombomodulin), complement inhibition (decay accelerating factor), and cellular immune suppression (hCD39, hCD47) was used. Immunosuppression consisted of targeted T-cell and B-cell depletion and conventional anti-rejection agents. RESULTS: Heterotopic cardiac transplantations were performed without complication. Flow cytometry and immunohistochemistry on donor biopsies confirmed transgenic phenotype. In contrast to the prior three-gene generation, significant coagulopathy or consumptive thrombocytopenia has not been observed in the six-gene cohort. As a result, these recipients have experienced decreased bleeding-related complications. Pro-inflammatory responses also appear to be mitigated based on cytokine analysis. Baboons survived the critical 30-day post-operative period when mortality has historically been highest, with no evidence of graft rejection. CONCLUSIONS: The inclusion of additional human genes in genetically engineered pigs appears to confer superior xenograft outcomes. Introduction of these genes has not been associated with adverse outcomes. This multifactorial approach to genetic engineering furthers the prospect of long-term cardiac xenograft survival and subsequent clinical application.

Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein.

We describe the incidence of early graft failure (EGF, defined as loss of function from any cause within 3 days after transplant) in a large cohort of GalTKO pig organs transplanted into baboons in three centers, and the effect of additional expression of a human complement pathway-regulatory protein, CD46 or CD55 (GalTKO.hCPRP). Baboon recipients of life-supporting GalTKO kidney (n = 7) or heterotopic heart (n = 14) grafts received either no immunosuppression (n = 4), or one of several partial or full immunosuppressive regimens (n = 17). Fourteen additional baboons received a GalTKO.hCPRP kidney (n = 5) or heart (n = 9) and similar treatment regimens. Immunologic, pathologic, and coagulation parameters were measured at frequent intervals. EGF of GalTKO organs occurred in 9/21 baboons (43%). hCPRP expression reduced the GalTKO EGF incidence to 7% (1/14; P < 0.01 vs. GalTKO alone). At 30 mins, complement deposits were more intense in organs in which EGF developed (P < 0.005). The intensity of peri-transplant platelet activation (as ß-thromboglobulin release) correlated with EGF, as did the cumulative coagulation score (P < 0.01). We conclude that (i) the transgenic expression of a hCPRP on the vascular endothelium of a GalTKO pig reduces the incidence of EGF and reduces complement deposition, (ii) complement deposition and platelet activation correlate with early GalTKO organ failure, and (iii) the expression of a hCPRP reduces EGF but does not prevent systemic coagulation activation. Additional strategies will be required to control coagulation activation.

Overexpression of FABP3 inhibits human bone marrow derived mesenchymal stem cell proliferation but enhances their survival in hypoxia.

Studying the proliferative ability of human bone marrow derived mesenchymal stem cells in hypoxic conditions can help us achieve the effective regeneration of ischemic injured myocardium. Cardiac-type fatty acid binding protein (FABP3) is a specific biomarker of muscle and heart tissue injury. This protein is purported to be involved in early myocardial development, adult myocardial tissue repair and responsible for the modulation of cell growth and proliferation. We have investigated the role of FABP3 in human bone marrow derived mesenchymal stem cells under ischemic conditions. MSCs from 12 donors were cultured either in standard normoxic or modified hypoxic conditions, and the differential expression of FABP3 was tested by quantitative (RT)PCR and western blot. We also established stable FABP3 expression in MSCs and searched for variation in cellular proliferation and differentiation bioprocesses affected by hypoxic conditions. We identified: (1) the FABP3 differential expression pattern in the MSCs under hypoxic conditions; (2) over-expression of FABP3 inhibited the growth and proliferation of the MSCs; however, improved their survival in low oxygen environments; (3) the cell growth factors and positive cell cycle regulation genes, such as PCNA, APC, CCNB1, CCNB2 and CDC6 were all down-regulated; while the key negative cell cycle regulation genes TP53, BRCA1, CASP3 and CDKN1A were significantly up-regulated in the cells with FABP3 overexpression. Our data suggested that FABP3 was up-regulated under hypoxia; also negatively regulated the cell metabolic process and the mitotic cell cycle. Overexpression of FABP3 inhibited cell growth and proliferation via negative regulation of the cell cycle and down-regulation of cell growth factors, but enhances cell survival in hypoxic or ischemic conditions.

Pathology of balloon-expandable and self-expanding stents following MRI-guided transapical aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: Balloon-expandable (BE) and self-expanding (SE) prostheses are both used for transcatheter aortic valve replacement (TAVR), but differences in long-term outcome using these types of device are unknown. The study aim was to monitor the histopathology, echocardiographic findings and structural integrity of BE and SE stents in a preclinical model for up to six months after TAVR. METHODS: Real-time magnetic resonance imaging (rtMRI)-guided TAVR was performed in 22 Yucatan pigs using either a BE (n = 10) or a SE (n = 12) prosthesis. Follow up echocardiography and MRI studies were performed at one-, three-, and six-month intervals. Additionally, high-contrast radiography was used to assess for strut fractures. The pigs were sacrificed after six months and tissues taken for histopathologic analysis. RESULTS: Stent malapposition was found in seven BE prostheses (70%), and in three SE prostheses (25%) (p = 0.046). Three of the SE group (25%) had a partial left coronary artery obstruction. The incidence and severity of aortic regurgitation were similar between the BE and SE groups. Three BE prostheses (30%) and one SE prosthesis (8.3%) had a gap between the stent frame and aorta. The mean (±SD) number of strut fractures was 6.1 ± 3.45 and 1.17 ± 2.32 in the BE and SE groups, respectively (p = 0.002). In addition, two implanted BE prostheses (20%) had a consequential compressed stent frame appearance. CONCLUSION: Long-term pathologic examination of necropsy specimens from a preclinical model of rtMRI-guided TAVR showed SE stent prostheses to be superior to their BE counterparts in terms of correct valve apposition and durability. These results may be attributed to the differing deployment methods and associated expansion forces employed by the BE and SE stents.

Role of anti-CD40 antibody-mediated costimulation blockade on non-Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon model.

BACKGROUND: Recently, we have shown that an immunosuppression regimen including costimulation blockade via anti-CD154 antibody significantly prolongs the cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon heterotopic xenotransplantation model. Unfortunately, many coagulation disorders were observed with the use of anti-CD154 antibody, and recipient survival was markedly reduced by these complications. MATERIAL AND METHODS: In this experiment, we replaced anti-CD154 antibody with a more clinically acceptable anti-CD40 antibody while keeping the rest of the immunosuppressive regimen and the donor pig genetics the same. This was carried out to evaluate the antibody's role in xenograft survival and prevention of coagulopathies. Two available clones of anti-CD40 antibody were tested. One mouse anti-human CD40 antibody, (clone 3A8), activated B lymphocytes in vitro and only modestly suppressed antibody production in vivo. Whereas a recombinant mouse non-human primate chimeric raised against macaque CD40, (clone 2C10R4), blocked B-cell activation in vitro and completely blocked antibody production in vivo. RESULTS: The thrombotic complications seen with anti-CD154 antibody were effectively avoided but the graft survival, although extended, was not as prolonged as observed with anti-CD154 antibody treatment. The longest survival for the 3A8 antibody group was 27 days, and the longest graft survival in the 2C10R4 antibody group was 146 days. All of the grafts except two rejected and were explanted. Only two recipient baboons had to be euthanized due to unrelated complications, and the rest of the baboons remained healthy throughout the graft survival period or after graft explantation. In contrast to our anti-CD 154 antibody-treated baboons, the non-Gal antibody levels started to rise after B cells made their appearance around 8 weeks post-transplantation. CONCLUSIONS: Anti-CD40 antibody at the current dose does not induce any coagulopathies but while effective, had reduced efficacy to induce similar long-term graft survival as with anti-CD154 antibody perhaps due to ineffective control of B-cell function and antibody production at the present dose. More experiments are required to determine antibody affinity and effective dose for inducing long-term cardiac xenograft survival.

Who participates in value-based care models? Physician characteristics and implications for value-based care.

Value-based care (VBC) payment models are becoming increasingly prevalent as alternatives to the traditional fee-for-service paradigm. This research quantifies the relationship between physician characteristics and participation in VBC payment models using the Association of American Medical Colleges' 2022 National Sample Survey of Physicians. We specified logistic regressions using physician-level variables to assess associations with current and new participation in Accountable Care Organizations, Primary Care First model, capitation, and bundled payments. Our results indicate that most respondents engaged in at least 1 VBC. Participation varied based on several characteristics, and physician specialty was highly predictive of overall participation. Compared with primary care physicians (PCPs), hospital-based physicians (odds ratio [OR] = 0.6, P < .001), medical specialists (OR = 0.5, P < .001), psychiatrists (OR = 0.4, P < .001), and surgeons (OR = 0.5, P < .001) were less likely to participate in VBC models. Medical specialists and surgeons were less likely to participate in commercial capitation than PCPs, while medical specialists and obstetricians/gynecologists were more likely to participate in certain bundles than PCPs. We suggest several policies to close the cross-specialty participation gap by including specialists and appealing to providers and patients.

What value do teaching hospitals provide commercial beneficiaries when in an ACO?

OBJECTIVES: The number of commercial beneficiaries cared for by accountable care organizations (ACOs) is growing, but the literature examining their trends is nascent. STUDY DESIGN: We examined commercial claims data from 2019 to 2021 to compare beneficiaries attributed to participants in Medicare Shared Savings Program ACOs with and without a major teaching hospital. METHODS: We calculated mortality and spending by setting for each ACO type by year. RESULTS: Compared with per-beneficiary rates at nonteaching ACOs, major teaching ACOs have lower mortality rates by up to 2.2 percentage points depending on the patient age group, $283 lower inpatient spending, and lower emergency department utilization in inpatient (-0.008) and outpatient (-0.013) settings, as well as $146 higher overall outpatient spending. Upward trends in mortality and beneficiary risk scores across both ACO types show disruption to health outcomes during COVID-19. CONCLUSIONS: These results provide evidence that ACOs with major teaching hospitals may be more likely to achieve the value-based goals of ACOs. Means to accomplish those goals may include avoiding higher-intensity care and supporting access to lower-cost alternatives where clinically appropriate, such as reducing inpatient and emergency department stays by delivering timely, high-quality outpatient care.

Trends in sepsis and pneumonia during COVID-19: lessons from BPCIA.

OBJECTIVES: The COVID-19 pandemic affected care delivery nationwide for all patients, influencing cost and utilization for patients both with and without COVID-19. Our first analysis assessed changes in utilization for patients with sepsis without COVID-19 prior to vs during the pandemic. Our second analysis assessed cost and utilization changes during the pandemic for patients with sepsis or pneumonia both with and without COVID-19. STUDY DESIGN: A retrospective case-control study was utilized to determine differences in cost and utilization for patients with sepsis or pneumonia, relative to a COVID-19 diagnosis. METHODS: Claims data from 8 teaching hospitals participating in sepsis and pneumonia episodes in the Bundled Payments for Care Improvement Advanced (BPCIA) model were utilized. BPCIA is a Medicare value-based care bundled payment program that aims to decrease costs and increase quality of care through a 90-day total cost of care model. RESULTS: The first analysis (N = 1092) found that non-COVID-19 patients with sepsis had 26% higher hospice utilization (P < .05) and 38% higher mortality (P < .0001) during the pandemic vs the prepandemic period. The second analysis (N = 640) found that during the pandemic, patients with sepsis or pneumonia with COVID-19 had 70% more skilled nursing facility (SNF) use (P < .0001), 132% higher SNF costs (P < .0001), and 21% higher total episode costs (P < .0001) compared with patients without COVID-19. CONCLUSIONS: COVID-19 has affected care patterns for all patients. Patients without COVID-19 postponed care and used lower-acuity care settings, whereas patients with COVID-19 were more costly and utilized postacute care at a higher rate. These analyses inform future care coordination initiatives, given the ongoing pandemic.

Succeeding in Medicare's newest bundled payment program: Results from teaching hospitals.

BACKGROUND: In 2018, Medicare implemented a successor to its Bundled Payments for Care Improvement (BPCI) program, BPCI Advanced, with stricter participation rules and new financial incentives to reduce spending. METHODS: Using claims-based episode data from thirteen participants, we compared spending and utilization in the first fifteen months of the new program (October 2018 to December 2019) to hospital- and episode-specific target prices, with a deep dive into clinical correlates for the most commonly-selected clinical episodes, sepsis and congestive heart failure. RESULTS: Twelve out of thirteen participants in a collaborative of teaching hospitals achieved shared savings for both Medicare and their own institution. Aggregate hospital shared savings were 5.8% of benchmark prices across 6,131 patients in 16 clinical episodes (p<0.001), appreciably higher than the reference savings rates reported after the first period of Medicare's predecessor BPCI program. Differences in shared savings across hospitals for sepsis and congestive heart failure correlated with reductions in patients' use of post-acute care, including reductions in skilled nursing facility, readmission, and home health rates. Evidence is presented showing reductions in patient utilization for cost-intensive post-acute settings accompanied increases in the proportion of patients exclusively utilizing non-institutional care after discharge from an anchor stay or procedure. CONCLUSIONS: These findings provide an example of the fulfillment of a core promise of bundled payments to uncover new opportunities for reduced spending. LEVEL OF EVIDENCE: Non-random cohort of hospitals.

Ex-vivo expanded baboon CD4+ CD25 Hi Treg cells suppress baboon anti-pig T and B cell immune response.

BACKGROUND: CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells play an important role in regulating immune responses. A very small number of Treg cells are present in peripheral blood and lymphoid organs, but due to their ability to suppress the immune response, they have a high potential for immunotherapy in clinics. Successful ex-vivo expansion of naturally occurring CD4(+) CD25(+) T cells has been achieved after TCR stimulation in the presence of T cell growth factors. In this study, we evaluated the role of these Treg cells in suppressing proliferative response of baboon T and B cells to pig xenoantigens. METHODS: Naturally occurring baboon CD4(+) CD25(+) regulatory T cells (nTreg) were sorted from peripheral blood and expanded in the presence of either anti-CD3/CD28 beads or irradiated pig peripheral blood mononuclear cells with IL-2. Treg cells were also enriched directly from CD4(+) T cells cultured in the presence of rapamycin (0.1-10 nm). Mixed lymphocyte culture and polyclonal B cell stimulation with ex-vivo Treg cells were performed to assess the function of ex-vivo expanded Treg cells. RESULTS: The nTreg cells were expanded to more than 200-fold in 4 weeks and retained all the nTreg cell phenotypic characteristics, including high levels of FoxP3 expression. 2-fold increase in enrichment of CD4(+) CD25(+) FoxP3(+) Treg cells from CD4(+) cells was observed with rapamycin compared to cultures without rapamycin. The ex-vivo expanded Treg cells obtained from both methods were able to suppress the baboon anti-porcine xenogeneic T and B cell immune response in-vitro efficiently (more than 90% suppression at 1:1 ratio of T regulatory cells: T effector cells), and their suppression potential was retained even at 1:256 ratio. However, freshly isolated nTreg cells had only 70% suppression at 1:1 ratio, and their suppressive ability was reduced to ≤ 50% at 1:16 ratio. Furthermore, we have found that ex-vivo expanded Treg can also suppress the proliferation of B cells after polyclonal stimulation. Forty to 50 percent reduction in B cell proliferation was observed when ex-vivo expanded Treg cells were added to the culture at a 1:1 ratio. The addition of CD4(+) CD25(Neg) cells however induced vigorous proliferation. CONCLUSION: Ex-vivo expanded CD4(+) CD25(+) FoxP3(+) Treg cells can be used to efficiently suppress xenogeneic immune responses by inhibiting T and B cell proliferation. These ex-vivo expanded Treg cells may also be used with other immunosuppressive agents to overcome xenograft rejection in preclinical xenotransplantation models.

Evaluating the Addition of Clinical and Staging Data to Improve the Pricing Methodology of the Oncology Care Model.

PURPOSE: The Oncology Care Model (OCM) is the largest value-based care model focusing on oncology, but the current pricing methodology excludes relevant data on the cancer stage and current clinical status, limiting the precision of the risk adjustment. METHODS: This analysis evaluated 15,580 episodes of breast cancer, lung cancer, and multiple myeloma, starting between July 1, 2016, and January 1, 2020, with data from a cohort of OCM practices affiliated with academic medical centers. The authors merged clinical data with claims for OCM episodes defined by the Center for Medicare and Medicaid Innovation to identify potential quality improvement opportunities. The regression model evaluated the association of the cancer stage at initial diagnosis and current clinical status with variance to the OCM target price. RESULTS: Cancer stage at the time of initial diagnosis was significant for breast and lung cancers, with stage IV episodes having the highest losses of -$6,700 (USD) for breast cancer (P < .001) and -$18,470 (USD) for lung cancer (P < .001). Current clinical status had a significant impact for all three cancers in the analysis, with losses correlated with clinical complexity. Breast cancer and multiple myeloma episodes categorized as recurrent or progressive disease had significantly higher losses than stable episodes, at -$6,755 (USD) for breast (P < .001) and -$19,448 (USD) for multiple myeloma (P < .001). Lung cancer episodes categorized as initial diagnosis had significantly fewer losses than stable episodes, at -$3,751 (USD) (P = .001). CONCLUSION: As the Center for Medicare and Medicaid Innovation designs and launches new oncology-related models, the agency should adopt methodologies that more accurately set target prices, by incorporating relevant clinical data within cancer types to minimize penalizing practices that provide guideline-concordant cancer care.

The Endangered State of Medicare Reimbursement for Cardiothoracic Surgery: A Call to Action.

Reimbursement for cardiothoracic surgery continues to be threatened with enormous financial cuts ranging from 5% to 10% in recent years. In this policy perspective, we describe the history of reimbursement for cardiothoracic surgery, highlight areas in need of urgent reform, propose possible solutions that Congress and the Executive Branch may enact, and call cardiothoracic surgeons to action on this critical issue. Meaningful engagement of members of The Society of Thoracic Surgeons with their elected representatives is the only way to prevent these cuts.