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Untreated Cushing's disease and the resultant chronically elevated glucocorticoid levels lead to severe metabolic disturbances, including diabetes mellitus, obesity, hypertension, muscle wasting, and osteoporosis. Although transsphenoidal resection has become the standard of care for Cushing's disease with high initial success rates, little information is available on the long-term morbidity and mortality of patients in remission compared with patients with recurrent or persistent Cushing's disease after such treatment. We therefore conducted a retrospective study of 289 patients with Cushing's disease who underwent transsphenoidal microsurgery for an ACTH-secreting adenoma at a tertiary care center exclusively by one surgeon (C.B.W.). Postoperative remission was achieved in 82% (n = 236) of patients, with best initial remission rates observed in patients with grade I (86%) and II (83%) or stage 0 (88%), A (94%), and B (100%) tumors. Male gender, larger tumor size, and higher stage predicted poorer initial outcome. Long-term follow-up was obtained on 178 patients, with a median follow-up time of 11.1 yr (range, 0.6-24.1 yr). Thirteen of 150 (9%) of patients in initial remission developed recurrent disease, and 12 patients underwent additional treatment. At last follow-up, only two of these patients had active disease. However, of the 28 patients with initial persistent disease who had follow-up greater than 6 months, 10 patients continued to have active disease at last follow-up. Although overall survival rates in patients with initial remission did not differ significantly from expected compared with the general population based on age and sex distribution, patients with initial persistent disease had a significant increase in mortality compared with the expected mortality. Thus, successful treatment of Cushing's disease is associated with normal long-term survival. These results suggest that patients with persistent Cushing's disease require early and aggressive intervention to attempt to prevent this excess mortality.

SummaryIn the last decade, transplantation across previously incompatible barriers has increasingly become popular because of organ donor shortage, availability of better methods of detecting and characterizing anti-HLA antibodies, ease of diagnosis, better understanding of antibody-mediated rejection, and the availability of effective regimens. This review summarizes all manuscripts published since the first publication in 2000 on desensitized patients and discusses clinical outcomes including acute and chronic antibody-mediated rejection rate, the new agents available, kidney paired exchange programs, and the future directions in sensitized patients. There were 21 studies published between 2000 and 2010, involving 725 patients with donor-specific anti-HLA antibodies (DSAs) who underwent kidney transplantation with different desensitization protocols. All studies were single center and retrospective. The patient and graft survival were 95% and 86%, respectively, at a 2-year median follow-up. Despite acceptable short-term patient and graft survivals, acute rejection rate was 36% and acute antibody-mediated rejection rate was 28%, which is significantly higher than in nonsensitized patients. Recent studies with longer follow-up of those patients raised concerns about long-term success of desensitization protocols. The studies utilizing protocol biopsies in desensitized patients also reported higher subclinical and chronic antibody-mediated rejection. An association between the strength of DSAs determined by median fluorescence intensity values of Luminex single-antigen beads and risk of rejection was observed. Two new agents, bortezomib, a proteasome inhibitor, and eculizumab, an anti-complement C5 antibody, were recently introduced to desensitization protocols. An alternative intervention is kidney paired exchange, which should be considered first for sensitized patients.

IMPORTANCE Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts.OBJECTIVE To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs). DESIGN, SETTING, AND PARTICIPANTSThis multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list. INTERVENTIONS Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital. MAIN OUTCOMES AND MEASURESThe primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant. RESULTSOf 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant.CONCLUSIONS AND RELEVANCE This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use.

Background: Intestinal allograft rejection resembles Crohn's disease clinically and pathologically. An understanding of its mechanism could impact this life-saving procedure, as well as provide insight into the pathophysiology of inflammatory bowel disease. The NOD2 protein has been implicated as a key player in intestinal immune health, as a consequence of the discovery of three polymorphisms linked with Crohn's disease. An investigation was carried out to determine whether epithelial immune function and graft survival were influenced by NOD2 mutations in an intestinal transplant population. Methods: The NOD2 genotypes of 34 transplants performed consecutively over the past 3 years were determined. The NOD2 genotypes were related to clinical outcomes and the expression of certain intestinal antimicrobial peptides (AMPs) believed to protect the epithelium. Results: An unexpectedly high percentage of recipients, 35%, possessed NOD2 polymorphisms, while 8.6% of donors had comparable mutations. The likelihood of allograft failure was about 100-fold higher in recipients with mutant NOD2 alleles compared with recipients with wild-type NOD2 loci. Rejection in NOD2 mutant recipients was characterised by decreased expression of certain Paneth cell and enterocyte AMPs, prior to the onset of epithelial injury and inflammation.

A pproximately 4 million Americans are infected with hepatitis C virus (HCV). During their lifetime, an estimated 20% of HCV-infected individuals will develop cirrhosis and subsequently develop complications of cirrhosis, including ascites, encephalopathy, and/or variceal bleeding. A significant number of these individuals will eventually die of disease-related complications. For some, if not most, of these individuals, liver transplantation offers the only truly effective alternative. Unfortunately, the demand for liver transplants far exceeds the organ supply. Given the prevalence of HCV infection in the population, approximately 2% to 5% of potential organ donors are also infected with HCV. 1,2 Because of concerns about viral transmission and allograft dysfunction, these organs were not generally considered for use in transplantation, potentially wasting viable organs.One alternative is to transplant HCV-positive (HCV ϩ ) donor livers into HCV ϩ patients with endstage liver disease. Some groups have found this to be a safe and effective practice. Vargas et al 3 found no significant difference in 1-and 5-year survival of patients who received an HCV ϩ donor liver compared with those who received an HCV-negative (HCV Ϫ ) donor liver. Furthermore, there was no difference in graft failure rates between the 2 groups. Moreover, when they examined the risk for infection with donor viral strain, they found that patients in whom the predominant HCV genotype after transplantation was that of the donor were significantly less likely to develop recurrent hepatitis than those patients who retained their own strain. 3 Similarly, Testa et al 4 found no difference in patient and graft survival when they compared their institution's experience with recipients of an HCV ϩ donor liver versus recipients of an HCV Ϫ donor liver.Previous reports examining the use of HCV ϩ allografts have been hindered by small study populations.

We report the results of a large series of chain transplantations that were facilitated by a multicenter US database in which 57 centers pooled incompatible donor/recipient pairs. Chains, initiated by nondirected donors, were identified using a computer algorithm incorporating virtual cross-matches and potential to extend chains. The first 54 chains facilitated 272 kidney transplants (mean chain length = 5.0). Seven chains ended because potential donors became unavailable to donate after their recipient received a kidney; however, every recipient whose intended donor donated was transplanted. The remaining 47 chains were eventually closed by having the last donor donate to the waiting list. Of the 272 chain recipients 46% were ethnic minorities and 63% of grafts were shipped from other centers. The number of blood type O-patients receiving a transplant (n = 90) was greater than the number of blood type O-non-directed donors (n = 32) initiating chains. We have 1-year follow up on the first 100 transplants. The mean 1-year creatinine of the first 100 transplants from this series was 1.3 mg/dL. Chain transplantation enables many recipients with immunologically incompatible donors to be transplanted with high quality grafts.

BACKGROUND: Lack of healthcare access to due to physician shortages is a significant driver of telemedicine expansion in rural areas. Telemedicine is effective for management of chronic conditions such as diabetes but its effectiveness in primary care settings is unknown. OBJECTIVE: To evaluate differences in diabetes care before and after implementation of a longitudinal virtual primary care program. DESIGN: Propensity score-matched cohort study utilizing difference-in-differences analysis. PARTICIPANTS: Patients with diabetes who received care at VA primary care clinics between January 2018 and December 2019 where the Virtual Integrated Multisite Patient Aligned Care Teams (V-IMPACT) program was implemented. EXPOSURE: Patient participation in at least one V-IMPACT visit while usual care patients did not participate in V-IMPACT. MAIN MEASURES: The primary outcome was change in hemoglobin A1C (HbA1C) and secondary outcomes included change in the proportion of patients meeting diabetes quality indicators: blood pressure control, statin use, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACEi/ARB) use, and annual microalbuminuria testing. KEY RESULTS: Our propensity-matched cohort included 9010 patients split evenly between those who participated in V-IMPACT and those who remained in usual in-person care. Among individuals with diabetes who participated in V-IMPACT, the change in mean HbA1C was − 0.055% (95% CI − 0.088 to − 0.022%) while those in usual care had a − 0.047% (95% CI − 0.080 to − 0.014%) change before and after program implementation. We observed a 5.1% (95% CI 2.4 to 7.7%) absolute increase in the proportion prescribed statins in the V-IMPACT group, a 5.3% (95% CI 2.5 to 8.2%) increase prescribed ACE/ARBs, and a 4.6% (95% 1.7 to 7.5%) increase in completed yearly microalbuminuria testing. V-IMPACT was not associated with a significant difference in the proportion with controlled blood pressure at < 140/90 or < 130/90 mmHg thresholds. CONCLUSIONS: Quality of diabetes care delivered by a longitudinal virtual primary care model was similar if not better than traditional in-person care.