Search

The application of advanced biopreservation to organs donated for transplantation may make possible their indefinite storage and thereby improve the utility and equity they provide to patients. The technology is still at a preclinical stage, with many difficult, scientific issues that remain to be answered. At the moment, however, the actual capabilities of the technology are too indefinite to begin formulating the statutes, regulations, and ethical guidance that will be needed to obtain the benefits expected from its use. [ABSTRACT FROM AUTHOR]

Advanced biopreservation technologies using subzero approaches such as supercooling, partial freezing, and vitrification with reanimating techniques including nanoparticle infusion and laser rewarming are rapidly emerging as technologies with potential to radically disrupt biomedicine, research, aquaculture, and conservation. These technologies could pause biological time and facilitate large-scale banking of biomedical products including organs, tissues, and cell therapies. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the author discusses articles within the issue on topics including challenges of advanced biopreservation, biomedical applications, and applications in conservation biology and the food supply such as cryopreservation.

Transplantation has substituted dysfunctional organs with healthy organs from donors to significantly lower morbidity and mortality associated with end-stage organ disease. Since the advent of transplantation, the promise of functional replacement has attracted an exponential mismatch between organ supply and demand. Theoretical proposals to counter the increasing needs have either been to create a source through genetic engineering of porcine donors for xenotransplantation (with more potent immunosuppression protocols) or recreate one's organ in a pig using interspecies blastocyst complementation for exogenic organ transplantation (without immunosuppression). Another promising avenue has been organ banking through cryopreservation for transplantation. Although ice free preservation and acceptable early function following rewarming is critical for success in transplantation, the immunological response that predominantly defines short- and long-term graft survival has failed to captivate attention to date. It is well sorted that thermal and metabolic stress incurred at 4 °C during recovery and reperfusion of organs for clinical transplantation has varying impact on graft survival. Considering the magnitude of cellular imbalance and injury at sub-zero/ultralow temperatures in addition to the chemical toxicity of cryoprotective agents (CPA), it is essential to assess and address the immunological response associated following transplantation to maximize the success of cryopreservation. [ABSTRACT FROM AUTHOR]

Background: Infections are common in the general U.S. population, so it is inevitable that some persons with a potentially transmissible disease will become organ donors. There are numerous reports of viral, parasitic, fungal, and bacterial transmission through transplantation. At the same time, immunosuppression increases the risk of infection in organ recipients, so attribution of infectious diseases to the transplanted organ is often difficult.Method: Review of the English-language literature.Results: The Organ Procurement and Transplantation Network states that all potential deceased organ donors must be assessed for conditions that may influence donor acceptance. The infections most often transmitted knowingly to organ recipients are cytomegalovirus and hepatitis C virus. There was a 43% increase in the number of potential donor-derived transmission events between 2012 and 2013, but this affected only 3% of transplants; and the patterns of unexpected infection transmissions have remained fairly constant. The 2013 recognition of a case of raccoon rabies in a kidney recipient brought the risk of untested pathogens back into the general discussion of disease transmission. Also, unexpected transmissions of parasitic infection have resulted in highly visible recipient deaths.Conclusions: Organ transplantation has been an enormous advance in the treatment of chronic diseases, but the risk of unanticipated disease transmission has been gaining attention. The task for the organ donation community is to assess risk of transmission of clinically relevant diseases accurately without substantially diminishing organ availability. [ABSTRACT FROM AUTHOR]

Reviews major U.S. studies of passive immunization against hepatitis B (HB) virus recurrence in recipients of orthotopic liver allografts. Difficulties encountered with using anti-HB titers; Role of immunosuppression in liver transplantation for HB; Survey on the effect of retransplantation of patients who suffer allograft failure.

In recent decades, considerable advances have been made in assuring the safety of blood transfusion and organ transplantation. However, with the increasing movement of medical products of human origin across international boundaries, there is a need to enhance global norms and governance. These products, which include blood, organs, tissues, cells, human milk and faecal microbiota, are today crucial for health care but they also pose unique risks due to their human origin, such as disease transmission and graft failure. Moreover, the demand for medical products of human origin often exceeds supply, leading to dependence on international supply chains, and emerging technologies like cell and gene therapy present further challenges because of their unproven efficacy and long-term risks. Current regulatory mechanisms, especially in low- and middle-income countries, are insufficient. The World Health Organization (WHO) has both the mandate and experience to lead the development of international quality and safety standards, consistent product nomenclature, and robust traceability and biovigilance systems. An international, multistakeholder approach is critical for addressing the complexities of how medical products of human origin are used globally and for ensuring their safety. This approach will require promoting uniform product descriptions, enhancing digital communication systems and leveraging existing resources to support countries in establishing regulations for these products. As illustrated by World Health Assembly resolution WHA77.4 on transplantation in 2024, WHO's ongoing efforts to ensure the safe, efficient and ethical use of medical products of human origin worldwide provide the opportunity to galvanize international cooperation on establishing norms. [ABSTRACT FROM AUTHOR]

This article presents a framework of ethical analysis for anticipatory evaluation of advanced biopreservation technologies and employs the framework illustratively in three domains. The framework features four clusters of general ethical considerations: (1) Producing Benefits, Minimizing Harms, Balancing Benefits, Risk, and Costs; (2) Justice, Fairness, Equity; (3) Respect for Autonomy; and (4) Transparency, Trustworthiness, and Public Trust. [ABSTRACT FROM AUTHOR]

Research on advanced biopreservation — technologies that include, for example, partial freezing, supercooling, and vitrification with nanoparticle infusion and laser rewarming — is proceeding at a rapid pace, potentially affecting many areas of medicine and the life sciences, food, agriculture, and environmental conservation. Given the breadth and depth of its medical, scientific, and corresponding social impacts, advanced biopreservation is poised to emerge as a disruptive technology with real benefits, but also ethical challenges and risks. Early engagement with potentially affected groups can help navigate possible societal barriers to adoption of this new technology and help ensure that emerging capabilities align with the needs, desires, and expectations of a broad range of interested parties. [ABSTRACT FROM AUTHOR]

Total pancreatectomy with islet autotransplant (TPIAT) can improve quality of life for individuals with pancreatitis but creates health risks including diabetes, exocrine insufficiency, altered intestinal anatomy and function, and asplenia. We studied survival and causes of death for 693 patients who underwent TPIAT between 2001 and 2020, using the National Death Index with medical records to ascertain survival after TPIAT, causes of mortality, and risk factors for death. We used Kaplan Meier curves to examine overall survival, and Cox regression and competing-risks methods to determine pre-TPIAT factors associated with all-cause and cause-specific post-TPIAT mortality. Mean age at TPIAT was 33.6 years (SD = 15.1). Overall survival was 93.1% (95% CI 91.2, 95.1%) 5 years after surgery, 85.2% (95% CI 82.0, 88.6%) at 10 years, and 76.2% (95% CI 70.8, 82.3%) at 15 years. Fifty-three of 89 deaths were possibly related to TPIAT; causes included chronic gastrointestinal complications, malnutrition, diabetes, liver failure, and infection/sepsis. In multivariable models, younger age, longer disease duration, and more recent TPIAT were associated with lower mortality. For patients undergoing TPIAT to treat painful pancreatitis, careful long-term management of comorbidities introduced by TPIAT may reduce risk for common causes of mortality. [ABSTRACT FROM AUTHOR]

The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3months post-TPIAT. Here, we report 2-year diabetes outcomes and perioperative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90 mg/kg IV x6 doses, n = 13), etanercept (50 mg then 25 mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2 years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucosepotentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFα differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2 years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period. [ABSTRACT FROM AUTHOR]

Introduces a series of articles about advances in the treatment of recurrent hepatitis B after liver transplantation. Review of the use of hepatitis B immunoglobulin (HBIg) in passive immunization in the U.S.; Factors that affect the degree to which HBIg is employed against hepatitis B virus infection in liver grafts; Challenges associated with approaches to preventing hepatitis B in liver grafts.

The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3months post-TPIAT. Here, we report 2-year diabetes outcomes and perioperative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90 mg/kg IV x6 doses, n = 13), etanercept (50 mg then 25 mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2 years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucosepotentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFa differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2 years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period. [ABSTRACT FROM AUTHOR]

Background and Aims: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. Methods: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. Results: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. Conclusions: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies. [ABSTRACT FROM AUTHOR]

Advanced age has been shown to be a risk factor for survival in primary liver transplantation. We sought to determine the independent influence of recipient age on retransplantation survival. The UNOS dataset was analyzed for adult, nonstatus 1, liver retransplantations since February 27, 2002. The univariate effect of age on 90-day and 1-year survival was analyzed. Multivariate survival models were used to determine 90-day, 1-year, and overall survival. Recipient age, donor age, model for end-stage liver disease (MELD) score, and hepatitis C status were used to construct multivariable survival models. Some 2141 liver retransplantations were analyzed. Overall, increasing recipient age was independently predictive of increasing mortality after liver retransplantation. In recipients between 18 and 60, there remained a direct relationship between age and mortality. However, in recipients aged over 60, increasing age was not independently associated with 90-day mortality ( P = 0.88) and 1-year mortality ( P = 0.74), despite adjusting for donor age, MELD score, and viral hepatitis status, suggesting that their original liver condition, their co-morbidities or perioperative condition plays an important role in retransplantation survival. Increasing recipient age up to 60, adversely affects liver retransplantation survival. After 60, there are no additional risks. Advanced age alone should not be an exclusionary factor when considering liver retransplantation; only the overall ability of the patient to tolerate a major surgery should be the determining factor. [ABSTRACT FROM AUTHOR]

Background: The Kidney Allocation System (KAS) includes a scoring system to match transplant candidate life expectancy with expected longevity of the donor kidney, and a backdating policy that gives waitlist time credit to patients waitlisted after starting dialysis treatment (post‐dialysis). We estimated the effect of the KAS on employment among patient subgroups targeted by the policy. Methods: We used a sample selection model to compare employment after transplant before and after KAS implementation among patients on the kidney‐only transplant waitlist between December 4, 2011 and December 31, 2017. Results: Post‐dialysis transplant recipients aged 18–49 were significantly more likely to be employed 1‐year post transplant in the post‐KAS era compared to the pre‐KAS era. Transplant recipients aged 35–64 with no dialysis treatment were significantly less likely to be employed 1 year after transplant in the post‐KAS era compared to the pre‐KAS era. Conclusions: This study provides the first assessment of employment after DDKT under the KAS and provides important information about both the methods used to measure employment after transplant and the outcome under the KAS. Changes in employment after DDKT among various patient subgroups have important implications for assessing long‐term patient and societal effects of the KAS and organ allocation policy. [ABSTRACT FROM AUTHOR]

The effect of obesity on outcomes following liver transplantation remains unclear. We reviewed our experience with 302 liver transplants in 277 patients from September 1989 to September 1996 to determine the effect of body mass on outcome. Two-hundred and seventeen transplants were performed in patients with a body mass index (BMI) < 30 kg/m², 55 in patients with a BMI of 30-40 kg/m² (obese), and 30 in patients with a BMI > 35 kg/m² (severely obese). Non-weight related pre-operative demographics were similar between groups with the exception of an increased frequency of cryptogenic cirrhosis among the obese and severely obese patients. Intra-operative transfusion requirements were greater for the severely obese group (16.2 ± 3.5 units versus 9.1 ± 0.8 units for the non-obese, p = 0.0004), though not when normalized to body weight (0.14 ± 0.03 units/kg versus 0.13 ± 0.01 units/kg, p > 0.05). Post-operatively, severely obese patients had a higher rate of wound infection (20 versus 4%, p = 0.0001) and death attributed to multisystem organ failure (15 versus 2%, p = 0.0001), although overall mortality prior to discharge and total complications were not different between groups. Actual 1-yr graft survival showed a negative trend in the severely obese group (67 versus 81% for non-obese, p = 0.07), but both 3-yr graft survival and patient survival were similar to non-obese patients (p = 0.12 and 0.17, respectively by the Cox-Mantel test). Liver transplantation in severely obese patients is associated with wound infection and early death from multisystem organ failure, but has similar long-term outcomes when compared to non-obese controls. [ABSTRACT FROM AUTHOR]

Hepatic steatosis (HS) beyond a certain degree can jeopardize living donor (LD) safety, particularly in right lobe (RL) donors, making it a major obstacle for donor pool expansion in adult‐to‐adult living donor liver transplantation (ALDLT). From July 2004 to June 2016, 58 LDs donated their RLs despite having moderate HS (30%‐50% steatosis) determined by intraoperative biopsy at a single center. We performed greedy matching to compare the outcomes of the donors and recipients of this group with those of LDs with no HS. The mean left lobe (LL) HS value in the 58 cases was 20.9 ± 12.4%, which was significantly lower than the mean RL HS value (38.8 ± 6.7%, P < 0.001). The mean ratio of the remnant LL to the total liver volume was 37.8 ± 2.2. No differences were observed in the postoperative liver function and donor and recipient morbidity and mortality rates. The liver regeneration rates in recipients and donors at 1 month, 6 months, and 1 year postoperatively did not differ significantly. The patient and graft survival rates of the recipients showed no differences. The use of well‐selected RL grafts with moderate steatosis does not impair graft function, recipient outcomes, or donor safety. [ABSTRACT FROM AUTHOR]

Background: The Igls criteria for assessing islet function after allotransplantation cannot be directly applied to islet autotransplantation (IAT) patients due to differences in baseline characteristics of IAT patients (insulin independent and C-peptide positive). Methods: We tested modified criteria (Auto-Igls) for assessing islet function in a large cohort of total pancreatectomy-IAT (TPIAT) patients from 2010-2018 (n=379). Metabolic outcomes post-IAT were assessed (Table 1). We assigned an Auto-Igls class to each patient as able, and evaluated the utility, validity, and perioperative predictors of Auto-Igls at 1 year post-IAT. We associated Auto-Igls with independent measures of islet graft function where available: continuous glucose monitoring (CGM) data or acute c-peptide response to glucose (ACRglu) from intravenous glucose tolerance tests. Results: Auto-Igls class was assigned to 264 patients (69%). Of the 115 patients who could not be classified, most (74%) were missing exact insulin u/kg/day. The only significant predictor of Auto-Igls class was the islet mass transplanted (p<0.0001). Higher percent time in range (70-140 mg/dL) on CGM and higher ACRglu were associated with a better Auto-Igls class (p=0.02 and p<0.0001, respectively). Discussion: The modified Igls criteria for IAT permit a simple, comprehensive assessment of metabolic outcomes after TPIAT, and is associated with other measures of islet function. Disclosure: K.R. McEachron: None. Y. Yang: None. T.L. Pruett: None. M. Bellin: Research Support; Self; Dexcom, Inc., Viacyte, Inc. Other Relationship; Self; Insulet Corporation. Funding: National Institutes of Health (T32DK108733, R01DK109124) [ABSTRACT FROM AUTHOR]

Summary: The Igls criteria assess islet function after islet allotransplant, based on C‐peptide, insulin use, hemoglobin A1c, and severe hypoglycemia. However, these criteria as currently defined cannot be applied to total pancreatectomy islet autotransplant (TPIAT) patients. We tested modified criteria for assessing islet function in a large cohort of TPIAT patients (n = 379). Metabolic outcomes were assessed. We assigned Auto‐Igls class to each patient as able and evaluated the utility, validity, and perioperative risk factors of Auto‐Igls at 1‐year post‐IAT. We tested the association of Auto‐Igls with independent measures of islet graft function, specifically continuous glucose monitoring (CGM) data or acute C‐peptide response to glucose (ACRglu) from intravenous glucose tolerance tests. An Auto‐Igls class was assigned to 264 patients (69%). Among patients who could not be classified, most were missing exact insulin dose. Seventy‐three percent of TPIAT recipients were classified as optimal or good at 1 year. The only significant predictor of Auto‐Igls class was islet mass transplanted (P < 0.0001). Auto‐Igls class was associated with percent time in range (70–140 mg/dl) on CGM (P = 0.02) and ACRglu (P < 0.0001). Modified Igls classification for IAT permits simple, comprehensive assessment of metabolic outcomes after TPIAT and is associated with other islet functional measures. [ABSTRACT FROM AUTHOR]

Islet yield is an important predictor of acceptable glucose control after total pancreatectomy with islet autotransplantation (TP‐IAT). We assessed if pancreas volume calculated with preoperative MRI could assess islet yield and postoperative outcomes. We reviewed dynamic MRI studies from 154 adult TP‐IAT patients (2009‐2016), and associations between calculated volumes and digest islet equivalents (IEQs) were tested. In multivariate regression analysis, pancreas volume (P <.001) and preoperative HbA1c levels (P =.009) were independently associated with digest IEQs. The IEQ prediction formula was calculated according to each preoperative HbA1c level, (a) pancreas volume × 5800 for HbA1c ≥ 6.5, (b) pancreas volume × 10 000 for HbA1c ≥5.7/<6.5 and (iii) pancreas volume × 11 400 for HbA1c < 5.7. The formula was internally validated with 28 TP‐IAT patients between 2017 and 2018 (r2 =.657 and r2 =.710 when restricted to 24 patients without prior pancreatectomy). An estimated IEQs/Body Weight (kg) ≥3700 predicted HbA1c ≤6.5 and insulin independence at 1 year after TP‐IAT with 77% and 88% sensitivity and 55% and 43% specificity, respectively. The combination of pancreas volume and preoperative HbA1c levels may be useful to estimate islet yield. Estimated IEQs were reasonably sensitive to predict acceptable glucose control at 1 year. [ABSTRACT FROM AUTHOR]

Background: A total pancreatectomy and intraportal islet cell autotransplant (TPIAT) is increasingly being offered to patients with chronic pancreatitis (CP). The benefits include removal of the root cause of pain and amelioration of diabetes. However, the long-term durability of this operation remains unclear.Study Design: Of the 742 patients who have undergone a TPIAT at our center, 215 who did so between 1998 and 2008 now have at least 10 years of follow-up time and were eligible for this single-center observational study. Our outcomes measures included abdominal pain relief, narcotic use, islet graft function (subdivided into 3 groups: insulin independence; partial graft function, defined by C-peptide level > 0.6 mg/dL; and no function, defined by C-peptide level < 0.6 mg/dL), and health-related quality of life.Results: The 10-year actuarial survival rate was 72%. A BMI > 30 kg/m2 (p = 0.04) predicted 10-year mortality. The rates of pain relief were 82% at 10 years and 90% at 15 years. Narcotic use declined with time: the rates were 50% at 5 years and 37% at 10 years. At 10 years, the rate of insulin independence was 20%; the rate of partial graft function, 32%. Transplantation of islet equivalents/kg > 4,000 was the strongest predictor of islet graft function at 10 years. Pediatric patients were more likely to have islet function than adults (p = 0.01). Health-related quality of life continued to improve at 10 years, even in patients on narcotics.Conclusions: This represents the first and largest series to examine long-term outcomes (10 years or more) in TPIAT patients. In our series, this dual procedure produced durable pain relief and sustained islet graft function, even past 10 years postoperatively. [ABSTRACT FROM AUTHOR]

Abstract: With increasing organ demand, living kidney donation from older donors (>60‐years‐old) has become more common. Between 1975 and 2014, 3752 donor nephrectomies (DN) were performed at University of Minnesota; 167 (4.5%) were >60‐years‐old Short‐ and long‐term outcomes were compared between contemporaneous >60‐years‐old and <60‐years‐old donors. On univariate analysis, >60‐years‐old were more likely to have had prior abdominal surgery and hypertension; and less likely to smoke. Baseline estimated glomerular filtration rate (eGFR) was lower in >60‐years‐old (80 ± 16 vs 101 ± 26 mL/min/1.73 m2; P < .001). Intraoperative and postoperative complications were similar, except a higher prevalence of <30 day ileus (3% vs 7%; P = .021) and longer postoperative length of stay (LOS) (4.2 vs 4.6 days; P = .005). On multivariate analysis, <30 day ileus and LOS continued to be significantly greater for >60‐years‐old After >20 years post‐DN, systolic blood pressure was significantly higher among >60‐years‐old (142 vs 125 mm Hg; P < .001) and HTN was diagnosed earlier (9 vs 14 years). After donation, eGFR was significantly lower for >60‐years‐old but slope of eGFR and rates of end‐stage renal disease (ESRD) were not significantly different >20 years post‐DN. Thus, kidney donation among carefully selected >60‐years‐old poses minimal perioperative risks and no added risk of long‐term ESRD. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes distress (DD), or psychological fatigue associated with diabetes management, is common in type 1 and 2 diabetes mellitus and is associated with poor glycemic control. Diabetes distress has never been evaluated in patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for chronic pancreatitis. We analyzed DD after TPIAT in 260 patients (average age 34.3 [standard deviation 15], 75.5% F) undergoing TPIAT between 2006 and 2014. Each patient completed 1 or more diabetes distress scale (DDS) questionnaires from 1 to 7 years post‐TPIAT (631 total). We examined changes in DD over 7 years and also patient characteristics associated with DD 1 year post‐TPIAT (n = 189). One year after TPIAT, 151 of 189 (80%) reported no or low distress (DD<2). Diabetes distress increased over time by an average of 0.084 (SE 0.017) points per year, an average 0.59 point increase from years 1 to 7 (P < .0001). Insulin‐dependent patients had significantly greater DD 1 year post‐TPIAT compared to insulin‐independent patients (P < .0001). Higher DD was associated with poorer glycemic control as indicated by HbA1c (P < .0001). Prevalence of DD is low but increases over time after TPIAT. Insulin dependence and poorer glycemic control are associated with higher levels of DD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pancreatic fat may adversely affect β‐cell mass and function, possibly via local release of non‐esterified fatty acids, and proinflammatory and vasoactive factors released by adipose tissue. However, the effects of intrapancreatic fat in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplantation (TPIAT) have not been studied. This study investigated whether pancreatic fatty infiltration has a negative effect on metabolic outcomes following TPIAT. Methods: The association between pancreatic fatty infiltration and diabetes outcomes was studied in 79 patients with low or high pancreatic fat content (LPF [n = 53] and HPF [n = 26], respectively) undergoing TPIAT. Pancreatic fatty infiltration was stratified using gross examinations during isolation and validated with histomorphometry of archived histology samples. Results: Fat area percentage in histology samples differed significantly between the LPF and HPF groups (2.1% ± 4.3% vs 10.6% ± 8.9%, respectively; P = 0.0009). Insulin dependence was more common in the HPF group, whereas more patients in the LPF group were insulin independent or on partial insulin supplementation at 1 year (P = 0.022). Furthermore, 1‐ and 2‐h glucose concentrations during mixed‐meal tolerance tests were significantly higher in the HPF group (P = 0.032 and 0.027, respectively) and β‐scores (a composite measure of islet function and metabolic control) were significantly greater in the LPF than HPF group (6.1 ± 1.7 vs 4.6 ± 2.0; P = 0.034). Conclusions: Patients with HPF were more likely to be insulin dependent, with higher postprandial glucose excursion, suggesting that intrapancreatic fat may lead to β‐cell dysfunction with detrimental effects on diabetes outcomes after TPIAT. [ABSTRACT FROM AUTHOR]

Abstract: The Organ Procurement Transplant Network (OPTN) listing criteria for simultaneous liver‐kidney transplant (SLK) are not well defined. Concerns remain about rising numbers of SLKs, which divert quality kidneys from candidates awaiting kidney transplants (KT). We performed a retrospective review of liver transplants (LTs) at our center from 2004 to 2014; 127 recipients (liver transplant alone; 102 LTA, 25 SLK) were identified with short‐term preoperative kidney dysfunction (creatinine >4 mg/dL or preoperative hemodialysis [HD] for <6 weeks). Both cohorts had comparable baseline demographic characteristics with the exception of higher model for end‐stage liver disease (MELD) score in the LTA group (41.4 vs 32.9, P < .0001) and higher incidence of pre‐LT diabetes in the SLK cohort (52% vs 26.5%, P = .0176). Duration of pre‐LT HD was higher in SLK recipients, but the difference was not statistically significant (P = .39). Renal nonrecovery (RNR) rate in LTA cohort was low (<5%). No significant difference was noted in 1‐year mortality, liver graft rejection/failure, or length of stay (LOS) between the cohorts. Thus, it appears that liver recipients with short‐term (<6 weeks) HD or AKI without HD have comparable outcomes between LTA and SLK. With provisions for a KT safety net, as proposed by OPTN, LTA may be the most adequate option for these patients. [ABSTRACT FROM AUTHOR]

Background: Diarrhea is a common condition after solid organ transplant (SOT); Clostridium difficile-associated colitis (CDAC) is one of the most common infections after SOT. We documented previously that some types of enteritis are associated with an elevation of tacrolimus (TAC) trough concentrations by interfering with the drug's complex metabolism.Patients and Methods: Tacrolimus concentrations of 25 SOT recipients including 12 renal and 13 liver recipients before, during, and after CDAC were analyzed retrospectively.Results: Median age of the 25 patients was 54 y (range, 36-71), there were 15 males and 10 females. Clostridium difficile-associated colitis developed at a median of 55 d (range 2-4551) post-SOT. Median TAC concentrations prior to the outbreak of CDAC were 6.9 ng/mL (range, <1.5-17.2), 5.6 ng/mL (range, <1.5-13.2) during diarrhea, and 7.4 ng/mL (range, <1.5-24.3) after resolution of diarrhea (p > 0.05, NS). Treatment of CDAC consisted of metronidazole for 14 d in all cases. All patients recovered from CDAC but seven patients had CDAC relapse.Conclusions: In contrast to other types of infectious diarrhea such as rotavirus enteritis and cryptosporidiosis, CDAC is not associated with an increase in TAC concentrations. This is because C. difficile causes primarily colitis as opposed to other organisms, which are associated with enteritis. [ABSTRACT FROM AUTHOR]

Background: Post-transplant malignancy (PTM) remains a concern among pediatric kidney transplant (PKT) recipients.Study Design: Between 1963 and 2015, 884 pediatric (age 0 to 17 years old) patients received 1,055 PKTs at our institution. Cox proportional hazards models were constructed to identify risk factors for PTM after PKT with time-to-first-PTM as a primary outcome. Secondly, the hazard of death or graft loss was calculated in patients who developed PTM.Results: Median patient survival was 33 years (interquartile range [IQR] 18.7 to 47 years); 260 patients died during the study period and 47 had been diagnosed with PTM. There were 235 PTMs that occurred in 136 (15.4%) recipients at a median age of 29 years (IQR 17.8 to 37 years). The percentages of patients with PTM were 13% at 20 years post-PKT and 26% at 30 years post-PKT. Of PTM patients who died, 63.8% died of PTM. Among those who developed PTM, there was a higher hazard of death or graft loss (hazard ratio [HR] 1.62; 95% CI 1.11 to 2.38). In multivariable proportional hazards models, factors associated with PTM were increasing age at PKT (adjusted HR [AHR] 3.14; 95% CI 1.80 to 5.48 for 14 to 17 year-olds compared with children less than 3 years), having a living unrelated donor (LURD; AHR 3.25; 95% CI 1.27 to 8.35 compared with a living related donor), or implanting an Epstein-Barr virus (EBV)-positive allograft in an EBV-negative recipient (AHR 5.66; 95% CI 1.11 to 29.0). Compared with the general population, the cancer rate for PKT recipients was 6 times higher (126 vs 21 per 100,000 person-years).Conclusions: Pediatric kidney transplant recipients are at increased risk of PTM, which adversely affects survival. Children receiving transplants at an older age, from a LURD, or who receive an EBV-positive organ, should be monitored closely for the development of PTM. [ABSTRACT FROM AUTHOR]

The authors reflect on globally consistent coding systems for medical products of human origin. They suggest that medical products of human origin, including blood, organs and bone marrow, provide important and often irreplaceable therapies. They argue that a globally consistent coding system for the products needs to be developed and that organizational governance must guarantee traceability and transparency if the products are to be managed safely.

Background: Among postsurgical and critically ill patients, malglycemia is associated with increased complications. Continuous glucose monitoring (CGM) in the inpatient population may enhance glycemic control. CGM reliability may be compromised by postsurgical complications such as edema or vascular changes. We utilized Clarke Error Grid (CEG) and Surveillance Error Grid (SEG) analysis to evaluate CGM performance after total pancreatectomy with islet autotransplantation.Materials and Methods: This subanalysis evaluated Medtronic Enlite 2 CGM values against YSI serum glucose in seven post-transplant patients (86% female; 38.6 ± 9.4 years) on artificial pancreas for 72 h at transition from intravenous to subcutaneous insulin. Sensor recalibration occurred for absolute relative difference (ARD) ≥20% x2, ≥30% x1, or by investigator discretion based on trend.Results: Sensor analysis showed mean absolute relative difference (MARD) of 11.0% ± 11.5%. The sensors were recalibrated 8.3 times/day; active sensor was switched 1.4 times/day. Calibration factor was 7.692 ± 3.786 mg/nA·dL (target = 1.5-20 mg/nA·dL). CEG analysis showed 86.1% of pairs in Zone A (clinically accurate zone) and 99.4% of pairs in Zones A + B (low risk of error). SEG analysis of hypoglycemia/hyperglycemia risk showed 92.22% of pairs in the "no risk" zone, 5.96% of pairs in the "slight lower" risk zone, 1.01% of pairs in the "slight higher" risk zone, and only 0.81% of pairs in the "moderate lower" risk zone.Conclusions: Overall performance of the Medtronic Enlite 2 CGM in the post-transplant population was reasonably good with "no risk" or "slight lower" risk by SEG analysis and high CGM-YSI agreement by CEG analysis; however, frequent recalibrations were required in this intensive care population. [ABSTRACT FROM AUTHOR]

Background: Chronic pancreatitis is a painful and often debilitating disease. Total pancreatectomy with intra-portal islet autotransplantation (TP-IAT) is a treatment option that allows for pain relief and preservation of beta-cell mass, thereby minimizing the complication of diabetes mellitus. Cultures of harvested islets are often positive for bacteria, possibly due to frequent procedures prior to TP-IAT, such as endoscopic retrograde cholangiopancreatography (ERCP), stenting, or other operative drainage procedures. It is unclear if these positive cultures contribute to post-operative infections. Hypothesis: We hypothesized that positive cultures of transplant solutions will not be associated with increased infection risk. Methods: We reviewed retrospectively the sterility cultures from both the pancreas preservation solution used to transport the pancreas and the final islet preparation for intra-portal infusion of patients who underwent TP-IAT between April 2006 and November 2012. Two hundred fifty-one patients underwent total, near-total, or completion pancreatectomy with IAT and had complete sterility cultures. All patients received prophylactic peri-operative antibiotics. Patients with positive pancreas preservation solution or islet sterility cultures received further antibiotics for 5-7 d. Patients' medical records were reviewed for post-operative infections and causative organisms. Results: Of the 251 patients included, 151 (61%) had one or more positive bacterial cultures from the pancreas preservation solution or final islet product. Seventy-three of the 251 patients (29%) had an infectious complication. Thirty-four of the 73 (22%) patients with a post-operative infectious complication also had positive cultures. Only seven of 151 patients with positive cultures (4.7%) had an infectious complication caused by the same organism as that isolated from their pancreas or islet cell preparation. Conclusions: In autologous islet preparations, isolation solutions frequently have positive cultures, but this finding is associated infrequently with clinical infection. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the role of sex on cytokine expression and mortality in critically ill patients. Design: A cohort of patients admitted to were enrolled and followed over a 5-year period. Setting: Two university-affiliated hospital surgical and trauma ICUs. Patients: Patients 18 years old and older admitted for at least 48 hours to the surgical or trauma ICU. Interventions: Observation only. Measurements and Main Results: Major outcomes included admission cytokine levels, prevalence of ICU-acquired infection, and mortality during hospitalization conditioned on trauma status and sex. The final cohort included 2,291 patients (1,407 trauma and 884 nontrauma). The prevalence of ICU-acquired infection was similar for men (46.5%) and women (44.5%). All-cause in-hospital mortality was 1 2.7% for trauma male patient and 9.1 % for trauma female patient (p = 0.065) and 22.9% for nontrauma male patients and 20.6% for nontrauma female patients (p = 0.40). Among trauma patients, logistic regression analysis identified female sex as protective for all-cause mortality (odds ratio, 0.57). Among trauma patients, men had significantly higher admission serum levels of interleukin-2, interleukin-12, interferon-y, and tumor necrosis factor-a, and among nontrauma patients, men had higher admission levels of interleukin-8 and tumor necrosis factor-a. Conclusions: The relationship between sex and outcomes in critically ill patients is complex and depends on underlying illness. Women appear to be better adapted to survive traumatic events, while sex may be less important in other forms of critical illness. The mechanisms accounting for this gender dimorphism may, in part, involve differential cytokine responses to injury, with men expressing a more robust proinflammatory profile. [ABSTRACT FROM AUTHOR]

Background: Chronic pancreatitis is a debilitating disease resulting from many causes. The subset with hereditary/genetic pancreatitis (HGP) not only has chronic pain, but also an increased risk for pancreatic cancer. Long-term outcomes of total pancreatectomy (TP) and islet autogeneic transplantation (IAT) for chronic pancreatitis due to HGP are not clear. Study Design: We reviewed a prospectively maintained database of 484 TP-IATs from 1977 to 2012 at a single center. The outcomes (eg, pain relief, narcotic use, β-cell function, health-related quality of life measures) of patients who received TP-IAT for HGP (protease trypsin 1, n = 38; serine protease inhibitor Kazal type 1, n = 9; cystic fibrosis transmembrane conductance regulator, n = 14; and familial, n = 19) were evaluated and compared with those with non−hereditary/nongenetic causes. Results: All 80 patients with HGP were narcotic dependent and failed endoscopic management or direct pancreatic surgery. Post TP-IAT, 90% of the patients were pancreatitis pain free with sustained pain relief; >65% had partial or full β-cell function. Compared with nonhereditary causes, HGP patients were younger (22 years old vs 38 years old; p ≤ 0.001), had pancreatitis pain of longer duration (11.6 ± 1.1 years vs 9.0 ± 0.4 years; p = 0.016), had a higher pancreas fibrosis score (7 ± 0.2 vs 4.8 ± 0.1; p ≤ 0.001), and trended toward lower islet yield (3,435 ± 361 islet cell equivalent vs 3,850 ± 128 islet cell equivalent; p = 0.28). Using multivariate logistic regression, patients with non-HGP causes (p = 0.019); lower severity of pancreas fibrosis (p < 0.001); shorter duration of years with pancreatitis (p = 0.008); and higher transplant islet cell equivalent per kilogram body weight (p ≤ 0.001) were more likely to achieve insulin independence (p < 0.001). There was a significant improvement in health-related quality of life from baseline by RAND 36-Item Short Form Health Survey and in physical and mental component health-related quality of life scores (p < 0.001). None of the patients in the entire cohort had cancer of pancreatic origin in the liver or elsewhere develop during 2,936 person-years of follow-up. Conclusions: Total pancreatectomy and IAT in patients with chronic pancreatitis due to HGP cause provide long-term pain relief (90%) and preservation of β-cell function. Patients with chronic painful pancreatitis due to HGP with a high lifetime risk of pancreatic cancer should be considered earlier for TP-IAT before pancreatic inflammation results in a higher degree of pancreatic fibrosis and islet cell function loss. [ABSTRACT FROM AUTHOR]

Our institution explored using allografts from donors with Hepatitis C virus (HCV) for elderly renal transplantation (RT). Thirteen HCV– elderly recipients were transplanted with HCV+ allografts (eD+/R–) between January 2003 and April 2009. Ninety HCV– elderly recipients of HCV– allografts (eD–/R–), eight HCV+ recipients of HCV+ allografts (D+/R+) and thirteen HCV+ recipients of HCV– allografts (D–/R+) were also transplanted. Median follow-up was 1.5 (range 0.8–5) years. Seven eD+/R– developed a positive HCV viral load and six had elevated liver transaminases with evidence of hepatitis on biopsy. Overall, eD+/R– survival was 46% while the eD–/R– survival was 85% (P = 0.003). Seven eD+/R– died during follow-up. Causes included multi-organ failure and sepsis (n = 4), cancer (n = 1), failure-to-thrive (n = 1) and surgical complications (n = 1). One eD+/R– died from causes directly related to HCV infection. In conclusion, multiple eD+/R– quickly developed HCV-related liver disease and infections were a frequent cause of morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Total pancreatectomy (TP) with intraportal islet autotransplantation (IAT) can relieve pain and preserve β-cell mass in patients with chronic pancreatitis (CP) when other therapies fail. We report on a >30-year single-center series. Study Design: Four hundred and nine patients (including 53 children, 5 to 18 years) with CP underwent TP-IAT from February 1977 to September 2011 (etiology: idiopathic, 41%; Sphincter of Oddi dysfunction/biliary, 9%; genetic, 14%; divisum, 17%; alcohol, 7%; and other, 12%; mean age was 35.3 years, 74% were female; 21% has earlier operations, including 9% Puestow procedure, 6% Whipple, 7% distal pancreatectomy, and 2% other). Islet function was classified as insulin independent for those on no insulin; partial, if known C-peptide positive or euglycemic on once-daily insulin; and insulin dependent if on standard basal–bolus diabetic regimen. A 36-item Short Form (SF-36) survey for quality of life was completed by patients before and in serial follow-up since 2007, with an integrated survey that was added in 2008. Results: Actuarial patient survival post TP-IAT was 96% in adults and 98% in children (1 year) and 89% and 98% (5 years). Complications requiring relaparotomy occurred in 15.9% and bleeding (9.5%) was the most common complication. IAT function was achieved in 90% (C-peptide >0.6 ng/mL). At 3 years, 30% were insulin independent (25% in adults, 55% in children) and 33% had partial function. Mean hemoglobin A1c was <7.0% in 82%. Earlier pancreas surgery lowered islet yield (2,712 vs 4,077/kg; p = 0.003). Islet yield (<2,500/kg [36%]; 2,501 to 5,000/kg [39%]; >5,000/kg [24%]) correlated with degree of function with insulin-independent rates at 3 years of 12%, 22%, and 72%, and rates of partial function 33%, 62%, and 24%. All patients had pain before TP-IAT and nearly all were on daily narcotics. After TP-IAT, 85% had pain improvement. By 2 years, 59% had ceased narcotics. All children were on narcotics before, 39% at follow-up; pain improved in 94%; and 67% became pain-free. In the SF-36 survey, there was significant improvement from baseline in all dimensions, including the Physical and Mental Component Summaries (p < 0.01), whether on narcotics or not. Conclusions: TP can ameliorate pain and improve quality of life in otherwise refractory CP patients, even if narcotic withdrawal is delayed or incomplete because of earlier long-term use. IAT preserves meaningful islet function in most patients and substantial islet function in more than two thirds of patients, with insulin independence occurring in one quarter of adults and half the children. [Copyright &y& Elsevier]

Background. Cryptococcosis occurring ⩽30 days after transplantation is an unusual event, and its characteristics are not known. Methods. Patients included 175 solid-organ transplant (SOT) recipients with cryptococcosis in a multicenter cohort. Very early-onset and late-onset cryptococcosis were defined as disease occurring ⩽30 days or >30 days after transplantation, respectively. Results. Very early-onset disease developed in 9 (5%) of the 175 patients at a mean of 5.7 days after transplantation. Overall, 55.6% (5 of 9) of the patients with very early-onset disease versus 25.9% (43 of 166) of the patients with late-onset disease were liver transplant recipients (P = .05). Very early cases were more likely to present with disease at unusual locations, including transplanted allograft and surgical fossa/site infections (55.6% vs 7.2%; P < .001). Two very early cases with onset on day 1 after transplantation (in a liver transplant recipient with Cryptococcus isolated from the lung and a heart transplant recipient with fungemia) likely were the result of undetected pretransplant disease. An additional 5 cases involving the allograft or surgical sites were likely the result of donor-acquired infection. Conclusions. A subset of SOT recipients with cryptococcosis present very early after transplantation with disease that appears to occur preferentially in liver transplant recipients and involves unusual sites, such as the transplanted organ or the surgical site. These patients may have unrecognized pretransplant or donor-derived cryptococcosis. [ABSTRACT FROM AUTHOR]

Introduction: Acute cellular rejection (ACR) post-liver transplantation (LT) can usually be reversed with pulse dose steroids. Anti-thymocyte globulin (ATG) is used to treat steroid-resistant rejection (SRR).Patients and Methods: We report 15 male and five female LT recipients with a median age of 48.3 (range 14.3-71.7) years, who received ATG for biopsy-proven steroid-resistant rejection (n =13), severe rejection (6), and severe rejection/recurrent autoimmune hepatitis (n = 1) median 42 (range 6-2,456) days following LT.Results: Underlying liver diseases included HCV (n = 7), alcoholic cirrhosis (n = 3), NASH (n = 2), HBV (n = 2), autoimmune hepatitis (n =1), PSC (n = 1), miscellaneous (n = 4) including three re LTs. All patients responded to treatment (median AST declined from 172 to 34U/l, median total bilirubin from 9.1 to 1.3 mg/dl; p < 0.001). Three patients developed recurrent ACR, and none chronic rejection. All HCV patients developed recurrence with significant rises in HCV RNA levels. Infections included pneumonia, sepsis, intraabdominal infection, chronic diarrhea, wound infection, EBV, and CMV disease. After a median follow-up of 65.5 (range 4.3-101.7) months post-ATG and median 67.7 (range 9.3-306.3) months post-LT, 17 patients are alive, two died from sepsis/multi-organ failure and one from HCV recurrence.Conclusion: ATG effectively reversed severe and SSR; HCV recurrence and infections remain significant complications. [ABSTRACT FROM AUTHOR]

Organ donors are screened for the hepatitis C antibody (anti-HCV) and those with positive tests can be used under extended criteria donation. However, there is still a question of long-term organ viability. The aim of this study was to assess the long-term outcomes of anti-HCV positive (HCV+) liver grafts. The US Organ Procurement and Transplantation Network Scientific Registry was reviewed for the period from April 1994 to February 6, 2008 and 56 275 liver transplantations were analyzed. In total, there were 19 496 HCV+ recipients and 934 HCV+ donors. Patient and graft survival were assessed accounting for both donor and recipient anti-HCV status. Multivariable proportional hazards survival models were developed to adjust for factors known to affect post-transplant survival. With anti-HCV negative (HCV−) recipient/HCV− donor as the reference, the adjusted hazard ratio for death was similar for HCV+ recipient/HCV− donor compared with HCV+ recipient/HCV+ donor (1.176 vs. 1.165, P = 0.91). Our results suggest that HCV+ liver donors do not subject the HCV+ recipient to an increased risk for death over the HCV− donor, keeping in mind that careful donor and recipient selection is critical for the proper use of these extended criteria donors. [ABSTRACT FROM AUTHOR]

Background. Whether outcome of central nervous system (CNS) cryptococcosis in solid organ transplant recipients treated with lipid formulations of amphotericin B is different from the outcome of the condition treated with amphotericin B deoxycholate (AmBd) is not known. Methods. We performed a multicenter study involving a cohort comprising consecutive solid organ transplant recipients with CNS cryptococcosis. Results. Of 75 patients treated with polyenes as induction regimens, 55 (73.3%) received lipid formulations of amphotericin B and 20 (26.7%) received AmBd. Similar proportions of patients in both groups had renal failure at baseline (P = .94). Overall, mortality at 90 days was 10.9% in the group that received lipid formulations of amphotericin B and 40.0% in the group that received AmBd. In univariate analysis, nonreceipt of calcineurin inhibitors (P = .034), renal failure at baseline (P = .016), and fungemia (P = .003) were significantly associated with mortality. Compared with AmBd, lipid formulations of amphotericin B were associated with a lower mortality (P = .007). Mortality did not differ between patients receiving lipid formulations of amphotericin B with or without flucytosine (P = .349). In stepwise logistic regression analysis, renal failure at baseline (odds ratio [OR], 4.61; 95% confidence interval [CI], 1.02-20.80; P = .047) and fungemia (OR, 10.66; 95% CI, 2.08-54.55; P = .004) were associated with an increased mortality, whereas lipid formulations of amphotericin B were associated with a lower mortality (OR, 0.11; 95% CI, 0.02-0.57; P = .008). Conclusions. Lipid formulations of amphotericin B were independently associated with better outcome and may be considered as the first-line treatment for CNS cryptococcosis in these patients. [ABSTRACT FROM AUTHOR]

With the implementation of the Model for End-Stage Liver Disease (MELD) scoring system, the number of combined liver–kidney transplants (CLKT) has increased dramatically. The United Network for Organ Sharing (UNOS) dataset was analysed for adult recipients with renal failure for the period between February 2002 and April 2006. This group was subdivided into patients on hemodialysis (HD) and to those not on HD prior to transplantation. All recipients in renal failure (serum creatinine ≥2.5 mg/dl) at the time of transplantation were included. A total of 1397 subjects were in renal failure but not on HD (18% received a CLKT, 82% underwent LT alone). Another 1740 subjects were on HD prior to transplantation (41% received a CLKT while 59% received a LT). In dialysis-dependent recipients, Cox regression analysis demonstrated CLKT had an independent protective effect. In subjects on HD, CLKT had improved survival at 1 year (79.4 vs. 73.7%, P = 0.004). In patients in renal failure without HD, CLKT was not protective.  CLKT subjects had a nonsignificant difference in survival as compared with patients who had undergone liver transplantation alone, at 1 year (81.0% vs. 78.8%, P > 0.10). In subjects undergoing CLKT, there was improved survival at 1 year as compared with LT-alone patients on hemodialysis; however, in patients with renal failure, but not on hemodialysis, there was no difference in survival when comparing CLKT to LT-alone. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding adenoviral graft-nephritis.

Background: The definition of "high risk" in intra-abdominal infections remains vague. The purpose of this study was to investigate patient characteristics associated with a high risk of isolation of resistant pathogens from an intra-abdominal source.Methods: All complicated intra-abdominal and abdominal organ/space surgical site infections treated over a ten-year period in a single hospital were analyzed. Infections were categorized by pathogen(s). Organisms designated "resistant" were those that had a reasonable probability of being resistant to the broad-spectrum agents imipenem/cilastatin and piperacillin/tazobactam, and included non-fermenting gram-negative bacilli (e.g., Pseudomonas aeruginosa), resistant gram-positive pathogens, vancomycin-resistant enterococci, and fungi. Patient characteristics were analyzed to define associations with the risk of isolation of "resistant" pathogens.Results: A total of 2,049 intra-abdominal infections were treated during the period of study, of which 1,182 had valid microbiological data. The two genera of pathogens isolated from more than 25% of health care-associated infections and more commonly than from community-acquired infections were Enterococcus spp. (29%) and Candida spp. (33%). Health care association, corticosteroid use, organ transplantation, liver disease, pulmonary disease, and a duodenal source all were associated with resistant pathogens. By multivariable analysis, several acute and chronic measures of disease were predictive of death, with a strong interaction between solid organ transplantation, resistant pathogens, and death. Other links between specific pathogens and patient characteristics were documented, for example, between fungal infection and a gastric, duodenal, or small bowel source, and between liver transplantation and vancomycin-resistant enterococci.Conclusions: On the basis of clinical characteristics, it may be possible to identify patients with intra-abdominal infections caused by pathogens that are potentially resistant to broad-spectrum antibacterial agents. Under these circumstances, and if warranted clinically, broadened coverage probably ought to include specific anti-enterococcal and anti-candidal therapy. [ABSTRACT FROM AUTHOR]

Background: The burden of infection with antibiotic-resistant gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), continues to increase, leading to substantial morbidity and high mortality rates, particularly in intensive care units (ICUs). Creative interventions may be required to reverse or stabilize this trend.Methods: The efficacy of empiric cycling of antibiotics active against gram-positive organisms was tested in a before-after intervention in a single surgical ICU. Four years of baseline data were compared with two years of data compiled after the implementation of a strategy where the empiric antibiotic of choice for the treatment of gram-positive infections (linezolid or vancomycin) was changed every three months. Whatever the initial choice of drug, if possible, the antibiotic was de-escalated after final culture results were obtained. The rates of all gram-positive infections were analyzed, with a particular focus on MRSA and VRE. Concurrently, similar outcomes were followed for patients treated on the same services but outside the ICU, where cycling was not practiced.Results: During the four years prior to cycling, 543 infections with gram-positive organisms were acquired in the ICU (45.3/1,000 patient-days), including 105 caused by MRSA (8.8/1,000 patient days) and 21 by VRE (1.8/1,000 patient-days). In the two years after implementation of cycling, 169 gram-positive infections were documented (28.1/1,000 patient-days; p < 0.0001 vs. non-cycling period), including 11 caused by MRSA (1.8/1,000 patient-days; p < 0.0001 vs. non-cycling period). The percentage of S. aureus infections caused by MRSA declined from 67% to 36%. The rate of infection with VRE was unchanged. Outside the ICU, the yearly numbers of infections with both MRSA and VRE increased over time.Conclusion: Quarterly cycling of linezolid and vancomycin in the ICU is a promising method to reduce infections with MRSA. [ABSTRACT FROM AUTHOR]

Fungi cause severe infections in solid organ transplant (SOT) recipients. Recently, a shift towards non-Aspergillus filamentous fungal infections (nAFFI) was noticed. In a series of 2878 SOTs (kidney, pancreas, islets, liver, heart, lung, and bowel) performed between January 1995 and December 2006 at the Innsbruck medical university, eleven cases of nAFFI were diagnosed. The encountered species included Zygomyzetes ( n = 8), and Alternaria alternate, Pseudallescheria boydii, Trichoderma spp. (one each); there were three liver and three heart, one intestinal, pancreas, lung, bilateral forearm and renal recipient each. Five patients died from nAFFI (zygomycosis: 4, Pseudallerichia boydii: 1); four were diagnosed postmortem. In five cases infection was surgically treated in combination with antifungals. Risk factors for nAFFI were renal failure (73%) and intensified immunosuppression (73%); two cases were associated with post-transplant lymphoproliferative disorder, one with graft versus host disease. An increase in the incidence of nAFFI was observed parallel to introduction of caspofungin and voriconazole (three cases until 12/2003, seven cases thereafter). NAFFI are increasingly found in SOT recipients. If diagnosed in time, the outcome seems acceptable. Intensified immunosuppression and exposure to antifungals not active against zygomycetes may be risk factors. Surgical therapy may play an important role in these infections. [ABSTRACT FROM AUTHOR]

Background: Sepsis from bloodstream infection (BSI) is an important cause of morbidity and mortality among surgical patients. Our hypothesis was that fever and leukocytosis during BSI would be associated with gram-negative pathogens and worse outcomes among hospitalized surgical patients. Study design: A prospectively collected dataset of all infections diagnosed on the adult general and trauma surgery services between December 1996 and December 2005 at the University of Virginia Hospital was reviewed. Fever was considered a temperature of ≥ 38.5°C, and leukocytosis was defined as a white blood cell count ≥ 15,000/μL within 24 hours of treatment for infection. Logistic regression was used to identify predictors of fever and mortality. Results: Over 9 years, 823 BSIs were analyzed. One hundred forty-eight BSIs resulted in death (18.0%), and 541 (65.7%) patients were febrile at diagnosis; mortality for these two groups were 12.9% and 27.7%, respectively (p < 0.0001). Febrile patients had a trend toward fewer gram-negative infections (27.0% versus 31.9%, p = 0.13), 403 had a leukocytosis at diagnosis and 420 did not; mortality for the two groups was 19.1% and 16.9%, respectively (p = NS). Higher maximum temperature was protective against mortality in the logistic regression analysis (odds ratio = 0.60 per C°, p < 0.0001). Conclusions: Among surgical patients with sepsis, fever during BSI was not associated with a gram-negative cause and correlated with survival, although increasing WBC had little effect. Mortality after BSI appears associated more with an initially blunted physiologic response than with a robust, proinflammatory response. In addition, a threshold for blood culture other than temperature ≥ 38.5°C should be considered. [Copyright &y& Elsevier]

Variables influencing the risk of dissemination and outcome of Cryptococcus neoformans infection were assessed in 111 organ transplant recipients with cryptococcosis in a prospective, multicenter, international study. Sixty-one percent (68/111) of the patients had disseminated infection. The risk of disseminated cryptococcosis was significantly higher for liver transplant recipients (adjusted hazard ratio [HR], 6.65; P = .048). The overall P = .048 mortality rate at 90 days was 14% (16/111). The mortality rate was higher in patients with abnormal mental status (P = .023), renal failure at baseline (P = .028), fungemia (P = .006 ), and disseminated infection (P = .035 ) and was lower in those receiving a calcineurin-inhibitor agent (P = .003 ). In a multivariable analysis, the receipt of a calcineurin-inhibitor agent (P = .003) was independently associated with a lower mortality (adjusted HR, 0.21; P = .008), and renal failure at baseline with a higher mortality rate (adjusted HR, 3.14; P = .037). Thus, outcome in transplant recipients with cryptococcosis appears to be influenced by the type of immunosuppressive agent employed. Additionally, discerning the basis for transplant type-specific differences in disease severity has implications relevant for yielding further insights into the pathogenesis of C. neoformans infection in transplant recipients. [ABSTRACT FROM AUTHOR]

Abstract: Background: The role of Th1 and Th2 mediated cytokine responses in the pathogenesis of Cryptococcus neoformans infection in organ transplant recipients has not been defined. Methods: We assessed cytokine levels in the sera and CSF collected prospectively at the time of diagnosis of infection in 25 transplant recipients with cryptococcosis. Serum levels were compared with those in healthy individuals and transplant recipients without cryptococcosis. IFN-γ or IL-12 (Th1)/IL-10 (Th2) ratio <1.0 was considered a dominant Th2 response. Results: Cases had lower ratios of IFN-γ/IL-10 (p =0.03) and IL-12/IL-10 (p =0.03) compared to healthy individuals. Cytokine responses, however, did not differ significantly for cases vs. transplant controls. Cases with fungemia compared to those without fungemia tended to have higher serum IL-10 levels (p =0.07) and lower IL-12/IL-10 ratios (p =0.06). CSF ratios of IFN-γ/IL-10 (p =0.04) and IL-12/IL-10 (p =0.04) were lower in cases with cryptococcal meningitis compared to those without meningitis; 80% (8/10) of the cases with cryptococcal meningitis vs. 0% (4/4) of those without meningitis had CSF IFN-γ/IL-10 ratio of <1.0 (p =0.015). The levels of IL-10 (p =0.04) and IFN-γ (p =0.04) in the CSF in cases with cryptococcal meningitis were significantly higher than those in their serum, respectively. Conclusions: High expression of Th2 phenotype in cryptococcal meningitis and in fungemia suggests that Th dysregulation may contribute to the pathogenesis of cryptococcosis in organ transplant recipients. [Copyright &y& Elsevier]

Background: Hepatitis C (HCV) is a worldwide health problem, affecting nearly 170 million people. Current models for studying Hepatitis C have focused primarily on the use of poorly permissive cell lines and viral constructs, because of the lack of a suitable animal model or an in vitro system for studying functional infection. As hepatocytes are the primary reservoir for the virus in vivo, we report on a model using primary human hepatocytes cultured in spheroid formation. Materials and methods: The hepatocytes were harvested from uninfected liver resections and cultured as spheroids (that promotes a differentiated phenotype) or monolayers. Spheroids expressed the putative receptors CD81 and human scavenger receptor B1 in a variable pattern throughout the culture period. Samples were inoculated with infectious HCV serum, and HCV RNA was detected using RT-PCR. RNA was detected in the cells and culture medium by 3 days and 5 days after inoculation, respectively. Selection of HVR1 variants occurred in a differential pattern based on culture technique, suggesting that viral selection was dependent on host phenotype. Detection of NS5A by Western blot analysis of infected samples and immunofluorescence for HCV core protein was seen only in infected spheroids. Conclusion: The use of spheroid formation to study Hepatitis C is associated with the establishment of HVR1 selection and functional infection. This represents a promising alternative model to study Hepatitis C. [Copyright &y& Elsevier]