"Let's Not Have the Perfect Be the Enemy of the Good": Social Impact Bonds, Randomized Controlled Trials, and the Valuation of Social Programs.

This article uses the case of "social impact bonds" (SIBs) to explore the role of social science methods in new markets in "social investment." Pioneered in the UK in 2010, SIBs use private capital to fund social programs with governments paying returns for successful outcomes. Central to the SIB model is the question of evaluation and the method to be used in determining program outcomes and investor returns. In the United States, the randomized controlled trial (RCT) has been the dominant method. However, this has not been without controversy. Some SIB practitioners and investors have argued that, while this may be the perfect tool, the need to grow the SIB market demands a more pragmatic approach. Drawing from a three-year study of SIBs, and informed by Science and Technology Studies (STS)-inspired work on valuation and the social life of methods, the article explores RCTs as both a valuation technology central to SIB design and the object of a micropolitics of valuation which has impeded market growth. It is the relationship between, and the politics of, evaluation and valuation that is a key lesson of the SIB experiment and an important insight for future research on "social investment" and other settings where methods are constitutive of financial value.

Measured Resection Techniques Do Not Align to the Cylindrical Axis in Kinematic Total Knee Arthroplasty.

BACKGROUND: There has been increasing interest with improved functional results in kinematically aligned total knee arthroplasty. Kinematic alignment seeks to replicate the rotational axes of the individual knee. The femoral component can either be aligned to the estimated prearthritic distal and posterior joint lines via a measured-resection technique or by aligning to the cylindrical axis (CA). The CA is calculated using three-dimensional imaging and defined as a line equidistant from the medial and lateral condylar surfaces from 15° to 115° flexion. This study investigates whether these 2 techniques lead to similar alignment angles in the coronal plane. MATERIALS AND METHODS: One hundred three knees undergoing total knee arthroplasty were assessed using a computed tomography-based protocol. The image-based cylindrical axis coronal angle (CAA) was calculated, and the distal condylar coronal angle (DCA) was calculated to simulate a caliper measured resection technique. A computed tomographic planning software program was used to measure the offset from the distal-most extent of the calculated cylinder to the distal-most aspect of the condyles. RESULTS: The DCA measured 3.3° valgus (standard deviation 2.4°) and the CAA 1.8° valgus (standard deviation 2.1°). The mean difference in offset from CAA radius to DCA from the medial condyle and the lateral condyle was 2.85 mm and 1.51 mm, respectively, increasing valgus predilection. CONCLUSIONS: Caliper measured resection kinematically aligned techniques will position the femoral component in a significantly more valgus position than when aligning to the CA of the knee. This is due to an increased offset of the distal femoral articulation from the most distal aspect of the cylinder on the medial side of the knee.

Econometrics as evidence? Examining the 'causal' connections between financial speculation and commodities prices.

One of the lasting legacies of the financial crisis of 2008, and the legislative energies that followed from it, is the growing reliance on econometrics as part of the rulemaking process. Financial regulators are increasingly expected to rationalize proposed rules using available econometric techniques, and the courts have vacated several key rules emanating from Dodd-Frank on the grounds of alleged deficiencies in this evidentiary effort. The turn toward such econometric tools is seen as a significant constraint on and challenge to regulators as they endeavor to engage with such essential policy questions as the impact of financial speculation on food security. Yet, outside of the specialized practitioner community, very little is known about these techniques. This article examines one such econometric test, Granger causality, and its role in a pivotal Dodd-Frank rulemaking. Through an examination of the test for Granger causality and its attempts to distill the causal connections between financial speculation and commodities prices, the article argues that econometrics is a blunt but useful tool, limited in its ability to provide decisive insights into commodities markets and yet yielding useful returns for those who are able to wield it.

A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells.

Lupus nephritis (LN) is a challenging problem that affects 50% of patients with systemic lupus erythematosus (SLE) without effective therapy. Here, we report that A77 1726, the active metabolite of leflunomide, effectively inhibits development of LN and attenuates the generalized autoimmune features. A77 1726 suppresses the expansion of double negative (DN) T cells, and inhibits T and B cell activation. Intriguingly, A77 1726 treatment significantly increases CD4(+)Foxp3(+) regulatory T cells but suppresses potential "pathogenic" IL-17-producing DN T cells in lymph nodes. In vitro experiment shows that A77 1726 potentiates the conversion of naive CD4(+)CD25(-) T cells into CD4(+)CD25(+)Foxp3(+) inducible regulatory T cells (iTregs) by inhibiting Akt. Taken together, our data indicate that the therapeutic effects of A77 1726 in murine LN are mediated, at least in part, by augmenting iTregs which suppress pathogenic IL-17-producing DN T cells through an Akt-dependent mechanism.

Inhibition of p70 S6 kinase (S6K1) activity by A77 1726 and its effect on cell proliferation and cell cycle progress.

Leflunomide is a novel immunomodulatory drug prescribed for treating rheumatoid arthritis. It inhibits the activity of protein tyrosine kinases and dihydroorotate dehydrogenase, a rate-limiting enzyme in the pyrimidine nucleotide synthesis pathway. Here, we report that A77 1726, the active metabolite of leflunomide, inhibited the phosphorylation of ribosomal protein S6 and two other substrates of S6K1, insulin receptor substrate-1 and carbamoyl phosphate synthetase 2, in an A375 melanoma cell line. A77 1726 increased the phosphorylation of AKT, p70 S6 (S6K1), ERK1/2, and MEK through the feedback activation of the IGF-1 receptor-mediated signaling pathway. In vitro kinase assay revealed that leflunomide and A77 1726 inhibited S6K1 activity with IC50 values of approximately 55 and 80 µM, respectively. Exogenous uridine partially blocked A77 1726-induced inhibition of A375 cell proliferation. S6K1 knockdown led to the inhibition of A375 cell proliferation but did not potentiate the antiproliferative effect of A77 1726. A77 1726 stimulated bromodeoxyuridine incorporation in A375 cells but arrested the cell cycle in the S phase, which was reversed by addition of exogenous uridine or by MAP kinase pathway inhibitors but not by rapamycin and LY294002 (a phosphoinositide 3-kinase inhibitor). These observations suggest that A77 1726 accelerates cell cycle entry into the S phase through MAP kinase activation and that pyrimidine nucleotide depletion halts the completion of the cell cycle. Our study identified a novel molecular target of A77 1726 and showed that the inhibition of S6K1 activity was in part responsible for its antiproliferative activity. Our study also provides a novel mechanistic insight into A77 1726-induced cell cycle arrest in the S phase.

Plasma cell densities and glomerular filtration rates predict renal allograft outcomes following acute rejection.

The contribution of T cells and graft-reactive antibodies to acute allograft rejection is widely accepted, but the role of graft-infiltrating B and plasma cells is controversial. We examined 56 consecutive human renal transplant biopsies classified by Banff schema into T-cell-mediated (N = 21), antibody-mediated (N = 18), and mixed (N = 17) acute rejection, using standard immunohistochemistry for CD3, CD20, CD138, and CD45. In a predominantly African-American population (75%), neither Banff classification nor C4d deposition predicted the return to dialysis. Immunohistochemical analysis revealed CD3(+) T cells as the dominant cell type, followed by CD20(+) B cells and CD138(+) plasma cells in all acute rejection types. Using univariate Cox Proportional Hazard analysis, plasma cell density significantly predicted graft failure while B-cell density trended toward significance. Surprisingly T-cell density did not predict graft failure. The estimated glomerular filtration rate (eGFR) at diagnosis of acute rejection also predicted graft failure, while baseline eGFR ≥6 months prior to biopsy did not. Using multivariate analysis, a model including eGFR at biopsy and plasma cell density was most predictive of graft loss. These observations suggest that plasma cells may be a critical mediator and/or an independently sensitive marker of steroid-resistant acute rejection.

Natural history of post-liver transplantation hepatitis C: A review of factors that may influence its course.

Our aim was to assess long-term survival in patients transplanted for HCV-related end-stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV-related ESLD since the program's inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per-protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV-related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1-, 5-, and 7-year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI >or=6 and/or fibrosis >or=2) was present in 49%, "early recurrence" (within 1 year of LT) in 30.5% and biopsy-proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage >or=2 at 12-month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of "rapid fibrosers" may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV-positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV-positive recipients.

Clinical factors associated with graft fibrosis in kidney-transplant recipients on steroid-avoidance immunosuppression.

BACKGROUND: Recent studies have documented good patient and graft outcomes and a low risk of acute rejection with steroid-avoidance immunosuppression in kidney-transplant recipients, but the risk of progressive graft fibrosis is not well studied. METHODS: All adult primary kidney transplant or combined kidney and pancreas transplant recipients on steroid avoidance immunosuppression were eligible for study. All recipients received induction with antithymocyte globulin or basiliximab. Corticosteroids were stopped after day 4 post-transplantation. Patients were maintained with tacrolimus and mycophenolate mofetil. Protocol biopsies were done at reperfusion and at one, four, and 12 months after transplantation. RESULTS: Eighty one-yr protocol biopsies with adequate specimens were obtained from 132 kidney or kidney-pancreas transplant recipients. Fifteen (19%) of the biopsies showed moderate to severe graft interstitial fibrosis (GIF) (Banff ci score > or = 2). Recipients with GIF were older, had lower body mass index, greater human lymphocyte antigen (HLA) mismatch, older donors, serum creatinine > or = 1.6 mg/dL at one month, a Banff ci score > 0 on one-month biopsy, BK nephropathy, and interstitial cellular infiltrates on the one-yr biopsy. In the unadjusted logistic regression analysis, BK nephropathy, serum creatinine > or =1.6 mg/dL at one month, recipient age, Banff ci score > 0 on one-month biopsy, and donor age were the only variables associated with a higher risk of GIF on the one-year biopsy. In the multivariate logistic regression model adjusted for these variables, BK nephropathy, serum creatinine > or = 1.6 mg/dL at one month after transplantation, and recipient age were independently associated with the risk of GIF on the one-year biopsy. CONCLUSION: In this small study of primary kidney or combined kidney-pancreas transplant recipients on steroid-avoidance immunosuppression, we found that 19% had GIF on a one-year protocol biopsy. BK nephropathy, serum creatinine > or = 1.6 mg/dL one month after transplantation, and recipient age correlated with an increased risk for GIF on the one-yr biopsy.

Vitamin A toxicity: when one a day doesn't keep the doctor away.

Vitamin A toxicity has been reported to cause severe liver disease and, occasionally, liver failure. Herein we present the case of a 60-year-old male with symptoms of muscle soreness, alopecia, nail dystrophy, and ascites. He continued to deteriorate with the development of refractory ascites, renal insufficiency, encephalopathy, and failure to thrive. A liver biopsy demonstrated presence of Ito cells and vacuolated Kupffer cells without the presence of cirrhosis. His clinical history revealed ingestion of large doses of vitamin A. His worsening clinical situation ruled out the possibility of a transjugular intrahepatic portosystemic shunt. The patient underwent orthotopic liver transplantation with resolution of symptoms. Vitamin A toxicity should be considered in the differential diagnosis of noncirrhotic portal hypertension. In conclusion, liver transplantation is a valid option if no improvement occurs in spite of cessation of the medication.

Interobserver agreement in hepatitis C grading and staging and in the Banff grading schema for acute cellular rejection: the "hepatitis C 3" multi-institutional trial experience.

CONTEXT: Establishing adequate interobserver agreement is crucial not only for standardization of patient care but also to ensure validity of findings in multi-institutional trials. OBJECTIVE: To evaluate interobserver agreement in assessing chronic hepatitis C (HCV) and acute cellular rejection (ACR) among 17 hepatopathologists involved in the "Hepatitis C 3" trial. DESIGN: The trial is a randomized multicenter (17 institutions) study involving 312 patients undergoing transplantation for HCV. Patients are randomized to 3 treatment arms. For final data analysis, all biopsy specimens are reviewed by a central pathologist (G.J.N.). Recurrence of HCV is evaluated according to the Batts and Ludwig schema. The 1997 Banff schema is used to evaluate ACR. To assess interobserver agreement, hematoxylin-eosin-stained sections from 11 liver biopsy specimens (6 HCV and 5 ACR) were sent by the central pathologist to 16 local pathologists from 13 institutions. Statistical analysis was performed on raw ACR/HCV data as well as data grouped according to clinically significant primary endpoint cutoffs. RESULTS: Statistically significant agreement was found among all participating pathologists (P < .001). On kappa analysis, the degree of agreement was rated "moderate" for HCV grade and stage and ACR global grading (kappa = 0.30, 0.33, and 0.37, respectively). Interobserver agreement was weaker for rejection activity index scoring of ACR (kappa = 0.15). A stronger degree of agreement was found when scores were grouped based on endpoint cutoffs (kappa = 0.76 "almost perfect" for HCV and 0.62 "substantial" for ACR). CONCLUSIONS: An overall statistically significant interobserver agreement was found among 17 pathologists using the 1997 Banff schema and the Batts and Ludwig schema.

Telepathy: maximizing resident exposure to surgical pathology decision making.

BACKGROUND: General surgery residents are often not present for the critical intraoperative discussion between surgeon and pathologist regarding surgical pathology findings. METHODS: A prospective pilot study analyzed general surgery resident exposure to surgical pathology. Thereafter, an operating room was equipped to view frozen section images in real time and verbally communicate with the pathologist (TelePATHy). Total operative cases, cases using frozen sections, and use of TelePATHy were recorded. RESULTS: Most residents (78%) reported they were exposed to frozen-section surgical pathology < or =10% of the time. Overall, 202 operations were performed over the 123-day period. Forty-four cases had frozen-section specimens. General surgery residents were present for 40 cases. TelePATHy was successfully used in 32 cases (80%). CONCLUSIONS: General surgery resident exposure to intraoperative pathology findings increased from a reported < or =10% to an observed 80%. TelePATHy is a novel intraoperative tool capable of maximizing the intraoperative experience of the surgical resident.

Living donor liver transplantation for hepatitis C-related cirrhosis: no difference in histological recurrence when compared to deceased donor liver transplantation recipients.

The question of possible earlier and more aggressive recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation (LDLT) compared to deceased donor liver transplantation (DDLT) remains unanswered. To address this issue we retrospectively reviewed virological, histological, and clinical data in 67 patients (52 DDLT and 15 LDLT) who underwent liver transplant for their HCV-related cirrhosis since April 2001. Our data indicate that there is no statistical difference between LDLT and DDLT groups in mean age, Child-Turcotte-Pugh score, model for end-stage liver disease score, and gender distribution. The mean follow-up was 749 +/- 371 days in LDLT and 692 +/- 347 days in DDLT. The predominant genotype in the LDLT and DDLT are genotype 1 (LDLT, 91%; DDLT, 70%). All patients with histologically confirmed recurrent HCV had detectable HCV-RNA in serum. The histological recurrence rate of hepatitis C was 58% at 4 months, 90% at 1 year, and 100% at 2 years in LDLT patients vs. 71% at 4 months, 94% at 1 year, and 95% at 2 years in DDLT patients (not significant) Comparison of the activity of inflammation and fibrosis score at all time points failed to show a statistical difference. Kaplan-Meier survival analysis showed similar patient and graft survival rates between the 2 groups. Our data indicate that histological recurrence of HCV is an early event and virtually universal 2 years' posttransplantation, regardless of modality of donor procurement.

Auto-Rejection of Renal Donor-Origin Metastatic Melanoma.

We report a case of metastatic malignant melanoma discovered in a living related donor shortly after renal transplant and subsequently diagnosed in the recipient. The recipient hepatic metastases were followed with serial computed tomography (CT) during regression/rejection of tumor after cessation of immunosuppression and allograft removal. Correlation made with serial liver mass biopsies.

Polyoma virus infection of renal allografts: relationships of the distribution of viral infection, tubulointerstitial inflammation, and fibrosis suggesting viral interstitial nephritis in untreated disease.

Whether polyoma virus (PV) infection of renal allografts induces an antiviral or antigraft immune reaction is unclear. By examination of the relationships of tubular PV to graft inflammation and scarring, this study sought histological evidence of viral interstitial nephritis in allograft biopsies with untreated PV infection and compared the inflammatory indices to controls with acute rejection (AR). Morphological features including viral cytopathic changes (VCCs) and modified Banff 97 histological indices were evaluated in sections of 28 diagnostic biopsies from a group of patients receiving prednisone, tacrolimus, and mycophenolate mofetil at constant dosage before biopsy. Two-micrometer paraffin sections were stained for PV large T antigen (TAg) and for C4d, by immunohistochemistry. Tubular profiles with 1 or more nuclei expressing TAg per x200 field were scored using an interval scale (0-10; none to 91-100%) by 2 observers. Controls with AR (n = 38, TAg negative) were matched for time after transplantation and severity of Banff 97 interstitial inflammation (i) and tubulitis (t) scores. Median t scores for tubules with VCC or TAg or both exceeded scores for tubules without VCC or TAg (3 versus 0, P = .001). Tubular TAg score correlated with i score (r = 0.58, P < .01) and sum ct + ci score (r = 0.61, P < .001). Atrophic tubules in scars had persistent VCC and/or TAg. Interstitial plasma cells (75% versus 21%) and neutrophils (32% versus 0%) were more frequent, and interstitial fibrosis was more severe (ci >1 in 54% versus 21%) in polyoma virus nephropathy (PVN) than in the group with AR (P < .01). Intimal arteritis (0% versus 35.7%), peritubular capillary C4d (0% versus 47.4%), and interstitial hemorrhage (4% versus 37%) were almost exclusively found in AR (P < .01). Tubular inflammation in untreated PVN involves infected tubular profiles with greater severity than those without evidence of infection. The extent of tubular PV infection is proportional to interstitial inflammation and scarring. Tubulointerstitial inflammation in PV infection has significant qualitative differences from AR. Observations in these examples of untreated PVN suggest that the allograft inflammatory reaction may exhibit features of viral tubulointerstitial nephritis distinct from AR.

Mechanistic study of malononitrileamide FK778 in cardiac transplantation and CMV infection in rats.

BACKGROUND: FK778 is a malononitrilamide, a class of immune suppressive compounds with antiviral features and experimental activity in chronic rejection, a potentially interesting combination for organ transplantation. The goal of this project was to study the tolerability, immune suppressive efficacy, and anti-cytomegalovirus (CMV) activity of FK778 and to assess the in vivo relevance of its previously described inhibition of de novo pyrimidine synthesis. METHODS: Heart transplants were performed in rats (Brown Norway [BN] to Lewis) and treated with varying doses of FK778 or leflunomide for 28 days. At 28 days, at the time of rejection or at the death of the animal, the allograft and other vital organs were obtained for study by light microscopy and immunohistochemistry. In separate experiments, Lewis rats were given sublethal irradiation, inoculated with rat CMV (Maastricht strain), and treated with varying doses of FK778 and leflunomide. In both the transplant and CMV studies, IP uridine was given at 250 mg/kg to cohorts or animals receiving FK778 and leflunomide. RESULTS: FK778 controls acute rejection and inhibits CMV replication at 20 mg/kg but is toxic at 25 mg/kg. Toxicity is manifested as anemia, changes in hepatic and intestinal histology, and mortality. The toxicity but not the immune suppressive or antiviral efficacy, is reduced significantly by exogenous uridine administration. CONCLUSION: FK778 has both immune suppressive and antiviral activities, neither of which is entirely dependent on inhibition of pyrimidine synthesis. These, and other published observations, suggest that the antiviral activity and a considerable part of the efficacy of the malononitrilamide family of drugs is attributable to activities other than drug induced pyrimidine deficiency.

Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin: an open-label series.

BACKGROUND: Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence. METHODS: Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 microg/kg per week and titrated toward a maximum dose of 1.5 microg/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks. RESULTS: Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P=0.05) in nonresponders versus 6.8 to 2.6 (P<0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P<0.05 for both). CONCLUSIONS: Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.