Lessons From Pancreas Transplantation in Type 1 Diabetes: Recurrence of Islet Autoimmunity.

Type 1 diabetes recurrence (T1DR) affecting pancreas transplants was first reported in recipients of living-related pancreas grafts from twins or HLA identical siblings; given HLA identity, recipients received no or minimal immunosuppression. This observation provided critical evidence that type 1 diabetes (T1D) is an autoimmune disease. However, T1DR is traditionally considered very rare in immunosuppressed recipients of pancreas grafts from organ donors, representing the majority of recipients, and immunological graft failures are ascribed to chronic rejection. We have been performing simultaneous pancreas-kidney (SPK) transplants for over 25 years and find that 6-8 % of our recipients develop T1DR, with symptoms usually becoming manifest on extended follow-up. T1DR is typically characterized by (1) variable degree of insulitis and loss of insulin staining, on pancreas transplant biopsy (with most often absent), minimal to moderate and rarely severe pancreas, and/or kidney transplant rejection; (2) the conversion of T1D-associated autoantibodies (to the autoantigens GAD65, IA-2, and ZnT8), preceding hyperglycemia by a variable length of time; and (3) the presence of autoreactive T cells in the peripheral blood, pancreas transplant, and/or peripancreatic transplant lymph nodes. There is no therapeutic regimen that so far has controlled the progression of islet autoimmunity, even when additional immunosuppression was added to the ongoing chronic regimens; we hope that further studies and, in particular, in-depth analysis of pancreas transplant biopsies with recurrent diabetes will help identify more effective therapeutic approaches.

Effects of a Brief Case Management Intervention Linking People With HIV to Oral Health Care: Project SMILE.

Objectives. Although people with HIV experience significant oral health problems, many consistently identify oral health as an unmet health care need. We conducted a randomized controlled trial to evaluate the impact of a dental case management intervention on dental care use. Methods. We evaluated the intervention according to self-reported dental care use at 6-, 12-, and 18-month follow-ups. Multivariable logistic models with generalized estimating equations were used to assess the effects of the intervention over time. Results. The odds of having a dental care visit were about twice as high in the intervention group as in the standard care group at 6 months (adjusted odds ratio [OR] = 2.52; 95% confidence interval [CI] = 1.58, 4.08) and 12 months (adjusted OR = 1.98; 95% CI = 1.17, 3.35), but the odds were comparable in the 2 groups by 18 months (adjusted OR = 1.07; 95% CI = 0.62, 1.86). Factors significantly associated with having a dental care visit included frequent physician visits and dental care referrals. Conclusions. We demonstrated that a dental case management intervention targeting people with HIV was efficacious but not sustainable over time. Barriers not addressed in the intervention must be considered to sustain its use over time.

Dentists' willingness to provide expanded HIV screening in oral health care settings: results from a nationally representative survey.

OBJECTIVES: Using a nationally representative survey, we determined dentists' willingness to provide oral rapid HIV screening in the oral health care setting. METHODS: From November 2010 through November 2011, a nationally representative survey of general dentists (sampling frame obtained from American Dental Association Survey Center) examined barriers and facilitators to offering oral HIV rapid testing (n = 1802; 70.7% response). Multiple logistic regression analysis examined dentists' willingness to conduct this screening and perceived compatibility with their professional role. RESULTS: Agreement with the importance of annual testing for high-risk persons and familiarity with the Centers for Disease Control and Prevention's recommendations regarding routine HIV testing were positively associated with willingness to conduct such screening. Respondents' agreement with patients' acceptance of HIV testing and colleagues' improved perception of them were also positively associated with willingness. CONCLUSIONS: Oral HIV rapid testing is potentially well suited to the dental setting. Although our analysis identified many predictors of dentists' willingness to offer screening, there are many barriers, including dentists' perceptions of patients' acceptance, that must be addressed before such screening is likely to be widely implemented.

Use of an indirect sampling method to produce reference intervals for hematologic and biochemical analyses in psittaciform species.

As with other animal species, comprehensive reference intervals (RI) for psittaciform species are rare and plagued by common issues, including sparse information regarding methods used to analyze specimens, low sample sizes, and improper statistical analyses. The purpose of this study was to examine the use of an indirect sampling method of RI generation from several years of data collected from specimens of multiple psittaciform species submitted to a veterinary diagnostic laboratory. These data were unselected for health status. A previously published method for indirect RI generation was applied to data collected for routine hematologic and biochemical analyses. Seven species groups were examined, and sample size ranged from 346 to 2358. Results showed that RI varied by species and appeared to represent a broader range than expected compared with other RI and traditional clinical expectations for core health assessments, such as total white blood cell count and white blood cell differential results. Some biochemical results reflected more narrow ranges, and a few were consistent with other published ranges. The intervals were likely influenced by changes related to stress and underlying disease. The results of the current study reflect the imprecision of this method related to data obtained from the population served by this laboratory. Overall, this method is not suitable for the production of comprehensive RI, although it may provide rough estimates for some limited analyses until traditional RI can be generated.

Comparison of Glycemic Control Between In-Person and Virtual Diabetes Consults in Hospitalized Patients With Diabetes.

BACKGROUND: There is limited evidence that the diabetes in-person consult in hospitalized patients can be replaced by a virtual consult. During COVID-19 pandemic, the diabetes in-person consult service at the University of Miami and Miami Veterans Affairs Healthcare System transitioned to a virtual model. The aim of this study was to assess the impact of telemedicine on glycemic control after this transition. METHODS: We retrospectively analyzed glucose metrics from in-person consults (In-person) during January 16 to March 14, 2020 and virtual consults during March 15 to May 14, 2020. Data from virtual consults were analyzed by separating patients infected with COVID-19, who were seen only virtually (Virtual-COVID-19-Pos), and patients who were not infected (Virtual-COVID-19-Neg), or by combining the two groups (Virtual-All). RESULTS: Patient-day-weighted blood glucose was not significantly different between In-person, Virtual-All, and Virtual-COVID-19-Neg, but Virtual-COVID-19-Pos had significantly higher mean ± SD blood glucose (mg/dL) compared with others (206.7 ± 49.6 In-person, 214.6 ± 56.2 Virtual-All, 206.5 ± 57.2 Virtual-COVID-19-Neg, 229.7 ± 51.6 Virtual-COVID-19-Pos; P = .015). A significantly less percentage of patients in this group also achieved a mean ± SD glucose target of 140 to 180 mg/dL (23.8 ± 22.5 In-person, 21.5 ± 20.5 Virtual-All, 25.3 ± 20.8 Virtual-COVID-19-Neg, and 14.4±18.1 Virtual-COVID-19-Pos, P = .024), but there was no significant difference between In-person, Virtual-All, and Virtual-COVID-19-Neg. The occurrence of hypoglycemia was not significantly different among groups. CONCLUSIONS: In-person and virtual consults delivered by a diabetes team at an academic institution were not associated with significant differences in glycemic control. These real-world data suggest that telemedicine could be used for in-patient diabetes management, although additional studies are needed to better assess clinical outcomes and safety.

Needles in a Haystack: Finding Qualitative and Quantitative Collaborators in Academic Medical Centers.

Translational research is a data-driven process that involves transforming scientific laboratory- and clinic-based discoveries into products and activities with real-world impact to improve individual and population health. Successful execution of translational research requires collaboration between clinical and translational science researchers, who have expertise in a wide variety of domains across the field of medicine, and qualitative and quantitative scientists, who have specialized methodologic expertise across diverse methodologic domains. While many institutions are working to build networks of these specialists, a formalized process is needed to help researchers navigate the network to find the best match and to track the navigation process to evaluate an institution's unmet collaborative needs. In 2018, a novel analytic resource navigation process was developed at Duke University to connect potential collaborators, leverage resources, and foster a community of researchers and scientists. This analytic resource navigation process can be readily adopted by other academic medical centers. The process relies on navigators with broad qualitative and quantitative methodologic knowledge, strong communication and leadership skills, and extensive collaborative experience. The essential elements of the analytic resource navigation process are as follows: (1) strong institutional knowledge of methodologic expertise and access to analytic resources, (2) deep understanding of research needs and methodologic expertise, (3) education of researchers on the role of qualitative and quantitative scientists in the research project, and (4) ongoing evaluation of the analytic resource navigation process to inform improvements. Navigators help researchers determine the type of expertise needed, search the institution to find potential collaborators with that expertise, and document the process to evaluate unmet needs. Although the navigation process can create a basis for an effective solution, some challenges remain, such as having resources to train navigators, comprehensively identifying all potential collaborators, and keeping updated information about resources as methodologists join and leave the institution.

Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial.

CONTEXT: Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. OBJECTIVE: To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. DESIGN, SETTING, AND PATIENTS: One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. INTERVENTION: Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. MAIN OUTCOME MEASURES: The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. RESULTS: Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) CONCLUSION: Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00658073.

Immune profiling by multiple gene expression analysis in patients at-risk and with type 1 diabetes.

There is a need for biomarkers to monitor the development and progression of type 1 DM. We analyzed mRNA expression levels for granzyme B, perforin, fas ligand, TNF-α, IFN-γ, Foxp3, IL-10, TGF-ß, IL-4, IL-6, IL-17, Activation-induced cytidine deaminase (AID) and Immunoglobulin G gamma chain (IgG) genes in peripheral blood of at-risk, new-onset and long-term type 1 DM , and healthy controls. The majority of the genes were suppressed in long-term type 1 DM compared to controls and new-onset patients. IFN-γ, IL-4 and IL-10 mRNA levels were significantly higher in new-onset compared to at-risk and long-term groups. There was decreased mRNA expression for AID and IgG and up-regulation of IFN-γ with age in controls. Data suggest an overall depressed immunity in long-term type 1 DM. Increased gene expression levels for IFN-γ, IL-4 and IL-10 in new-onset patients from at-risk patients might be used as potential markers for progression of the disease.

Utilization of dental care services among low-income HIV-positive persons receiving primary care in South Florida.

We investigated the use of dental care services among a population of low-income persons living with HIV/AIDS who had not seen a dental care provider during the 12 months prior to study enrollment. A total of 593 participants were recruited from five HIV primary care clinics in two South Florida counties and interviewed regarding past utilization of dental care services, HIV primary care service utilization, and barriers to care. Multivariate logistic regression analysis was used to determine correlates of oral care utilization within the preceding two years. One-third of respondents reported seeing a dentist in the preceding two years. The odds of having seen a dentist were greater for respondents with stable housing, more than a high school education, and who had received help in getting dental care; black respondents (compared to Hispanics and non-Hispanic whites) were less likely to have seen a dentist in the preceding two years. Despite the availability of dental services for low-income HIV-positive persons, utilization of dental care remains low. This study reinforces the need to provide assistance to HIV-positive persons in obtaining dental care. In particular, it indicates that such assistance should be targeted toward Black Americans, persons with low income and unstable housing situations, and those with limited help to navigate the health care system.

2007 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on perioperative cardiac evaluation are usually incorrectly applied by anesthesiology residents evaluating simulated patients.

BACKGROUND: The 2007 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on Perioperative Cardiac Evaluation and Care for Noncardiac Surgery is the accepted standard for perioperative cardiac evaluation. Anesthesiology training programs are required to teach these algorithms. We estimated the percentage of residents nationwide who correctly applied suggested testing algorithms from the ACC/AHA guidelines when they evaluated simulated patients in common clinical scenarios. METHODS: Anesthesiology resident volunteers at 24 training programs were presented with 6 scenarios characterized by surgical procedure, patient's risk factors, and patient's functional capacity. Scenarios and 5 possible recommendations per scenario were both presented in randomized orders. Senior anesthesiologists at 24 different United States training programs along with the first author of the 2007 ACC/AHA guidelines validated the appropriate recommendation to this web-based survey before distribution. RESULTS: The 548 resident participants, representing 12% of anesthesiology trainees in the United States, included 48 PGY-1s (preliminary year before anesthesia training), 166 Clinical Anesthesia Year 1 (CA-1) residents, 161 CA-2s, and 173 CA-3s. For patients with an active cardiac condition, the upper 95% confidence bound for the percent of residents who recommended evaluations consistent with the guidelines was 78%. However, for the remaining 5 scenarios, the upper 95% confidence bound for the percent of residents with an appropriate recommendation was 46%. CONCLUSIONS: The results show that fewer than half of anesthesiology residents nationwide correctly demonstrate the approach considered the standard of care for preoperative cardiac evaluation. Further study is necessary to elucidate the correct intervention(s), such as use of decision support tools, increased clarity of guidelines for routine use, adjustment in educational programs, and/or greater familiarity of responsible faculty with the material.

A conditional approach for the receiver operating characteristic curve construction to evaluate diagnostic test performance in a family-matched case-control design.

Receiver operating characteristic curves are widely used in medical research to illustrate biomarker performance in binary classification, particularly with respect to disease or health status. Study designs that include related subjects, such as siblings, usually have common environmental or genetic factors giving rise to correlated biomarker data. The design could be used to improve detection of biomarkers informative of increased risk, allowing initiation of treatment to stop or slow disease progression. Available methods for receiver operating characteristic construction do not take advantage of correlation inherent in this design to improve biomarker performance. This paper will briefly review some developed methods for receiver operating characteristic curve estimation in settings with correlated data from case-control designs and will discuss the limitations of current methods for analyzing correlated familial paired data. An alternative approach using conditional receiver operating characteristic curves will be demonstrated. The proposed approach will use information about correlation among biomarker values, producing conditional receiver operating characteristic curves that evaluate the ability of a biomarker to discriminate between affected and unaffected subjects in a familial paired design.

HIV transmission risk behaviors among HIV-infected persons who are successfully linked to care.

OBJECTIVES: We examined the relationship between receipt of medical care for human immunodeficiency virus (HIV) infection and HIV transmission risk behavior among persons who had received a recent diagnosis of HIV infection. METHODS: We enrolled 316 participants from 4 US cities and prospectively followed up participants for 1 year. Generalized estimating equations were used to examine whether having at least 3 medical care visits in a 6-month period was associated with unprotected vaginal or anal intercourse with an HIV-negative partner or partner with unknown HIV status. RESULTS: A total of 27.5% of the participants (84 of 305) self-reported having unprotected sex with an HIV-negative or unknown status partner at enrollment, decreasing to 12% (31 of 258) and 14.2% (36 of 254) at 6-month and 12-month follow-ups, respectively. At follow-up, people who had received medical care for HIV infection at least 3 times had reduced odds of engaging in risk behavior, compared with those with fewer visits. Other factors associated with reduced risk behavior were being >30 years of age, male sex, not having depressive symptoms, and not using crack cocaine. CONCLUSIONS: Being in HIV care is associated with a reduced prevalence of sexual risk behavior among persons living with HIV infection. Persons linked to care can benefit from prevention services available in primary care settings.

Nutritional status and behavior in subjects with type 1 diabetes, before and after islet transplantation.

BACKGROUND: To investigate whether changes of nutritional status and behavior are associated with islet transplantation (ITx) and to assess their possible mechanisms. METHODS: In this observational study, 52 subjects with type 1 diabetes, 30 of whom received ITx, underwent nutritional assessments. The study consisted of questionnaires complemented by a dietary intake recording, anthropometric measurements, and body composition analysis. Laboratory tests were also reviewed as part of the follow up. RESULTS: After ITx, significant reductions in body weight (3.7 kg; P<0.0001), body mass index (1.39 kg/m2; P<0.0001), waist circumference (3.96 cm; P=0.006), and fat weight (3.28 kg; P<0.01) were observed. The average consumption of carbohydrate and protein were also lower than pretransplant, together with some micronutrients (vitamins B12 and B6, zinc, and phosphorus). Insulin administration and changes in A1C were not associated with a significant change in anthropometric measurements. Subjects on exenatide after ITx showed significantly lower weight and body mass index than those not taking exenatide. CONCLUSIONS: ITx is associated with modifications in nutritional behavior and status. Drugs and health conditions are likely to be at least in part responsible for these changes, but a voluntary modification of eating habits by the patients also plays a role. Strict monitoring of nutritional parameters, counseling by experts in nutrition, and multivitamin/mineral supplement after ITx could be of benefit to the patients.

The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects.

BACKGROUND: A current limitation of islet transplantation is reduced long-term graft function. The glucagon-like peptide-1 receptor agonist, exenatide (Byetta, Amylin Pharmaceuticals, CA) has properties that could improve existing islet function, prevent further loss of islet mass and possibly even stimulate islet regeneration. METHODS: This prospective study evaluated the safety, efficacy, and metabolic effects of exenatide in subjects with type 1 diabetes mellitus and islet allograft dysfunction requiring exogenous insulin. RESULTS: Sixteen subjects commenced exenatide, 12 continue (follow-up 214+/-57 days; range 108-287), four (25%) discontinued medication because of side effects. At 6 months, exogenous insulin was significantly reduced with stable glycemic control (0.15+/-0.02 vs. 0.11+/-0.025 U/kg per day; P<0.0001); three subjects discontinued insulin from 4, 5, and 9 U/day, respectively, two sustained insulin independence with A1c reduction below graft dysfunction criteria. Postprandial capillary blood glucose was significantly decreased (129.4+/-3.8 vs. 118.7+/-4.6 mg/dL; P<0.001), C-peptide and C-peptide-to-glucose ratio increased significantly by 5th and 6th months of treatment (ratio, 1.09+/-0.15 vs. 1.52+/-0.18; P<0.05). Weight loss more than 3 kg occurred in 8 of 12 (67%) subjects. Stimulation testing demonstrated improved glucose disposal and C-peptide secretion (glucose area under the curve 52,332+/-3,219 vs. 42,072+/-1,965; P=0.002 mg x min x dL, mixed meal stimulation index 0.50+/-0.06 vs. 0.66+/-0.09; P=0.03 pmol x mL), with marked suppression of glucagon secretion and progressive increase in amylin secretion. Side effects were more frequent and severe compared with published reports in type 2 diabetes, tolerated doses were lower. CONCLUSIONS: Exenatide was tolerated in this patient population after appropriate dose titration and there appeared to be gradual but sustained positive effects on glycemic control and islet graft function.

Improved metabolic control and quality of life in seven patients with type 1 diabetes following islet after kidney transplantation.

BACKGROUND: The beneficial effects of glycemic control on both survival and function of transplanted kidneys in patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease (ESRD) have been recognized. METHODS: Herein, we present the clinical outcome of a single-center pilot trial of islet after kidney (IAK) transplantation in seven patients with T1DM. The immunosuppression protocol for the kidney graft was converted to sirolimus+tacrolimus regimen 6 months before islet transplantation to exclude negative effects on kidney graft function. Primary endpoint was achievement of insulin independence after transplantation. Clinical outcome, metabolic control, severe hypoglycemia, kidney function, Quality of Life (QOL) psychometric measures, and adverse events were monitored. RESULTS: Seven patients showed graft function with improved metabolic control (A1c, fasting glycemia, and metabolic tests) after IAK (14,779+/-3,800 IEQ/kg). One-year insulin independence was 30% with persistent graft function in 86% (C-peptide-positive). A1c reduction was 1.95+/-0.31% from baseline (P<0.0001). No episodes of severe hypoglycemia were observed, even after resuming insulin. The direct consequence of these benefits was a significant improvement in diabetes QOL. Adverse events included procedure-related pleural effusion (n=2), cholecystitis (n=1), and additional immunosuppression-related, all resolved without sequelae. Kidney function (by estimated glomerular filtration rate) remained stable during follow-up in six of seven patients. CONCLUSIONS: Islet transplantation represents a feasible therapeutic option for patients with T1DM bearing a stable kidney allograft. Insulin independence at 1 year is lower than what reported in islet transplant alone. Nevertheless, clear benefits in terms of optimal metabolic control and absence of severe hypoglycemia are invariably present.

Deterioration and variability of highly purified collagenase blends used in clinical islet isolation.

BACKGROUND: The quality and stability of enzyme blends used in islet cell processing are critical for successful human islet isolation. A wide variability in enzymatic activity among lots of Liberase HI has been reported. This study examines the interlot and intralot variability of Liberase HI and the over-time deterioration of enzyme quality based on the analysis of islet isolation outcomes. METHODS: The data of 169 human isolations processed for clinical islet transplantation, using five different lots of Liberase HI, were retrospectively analyzed. Inter- and intralot variables in the islet isolation were assessed over a 15-month period. RESULTS: The analysis revealed significant interlot differences in the digestion time, prepurification islet counts, percent recovery, viability, and glucose stimulation insulin index. Moreover, a significant decrease in the pre- and postpurification islet yield per pancreas weight (IEQ/g) in isolations processed by two different enzyme lots used over a 15-month period was observed, suggesting a progressive deterioration of enzyme quality. CONCLUSIONS: Our data demonstrate a significant lot-to-lot related variability in islet isolation outcomes. In addition, the over-time decline in isolation outcomes processed using a single enzyme lot was observed even when the enzyme blends were used within the expiration dating specified by the manufacturer.

Toward maximizing the success rates of human islet isolation: influence of donor and isolation factors.

In order to make islet transplantation a therapeutic option for patients with diabetes there is an urgent need for more efficient islet cell processing to maximize islet recovery. Improved donor management, organ recovery techniques, implementation of more stringent donor criteria, and improved islet cell processing techniques may contribute to enhance organ utilization for transplantation. We have analyzed the effects of donor and islet processing factors on the success rate of human islet cell processing for transplantation performed at a single islet cell processing center. Islet isolation outcomes improved when vasopressors, and in particular pitressin, and steroids were used for the management of multiorgan donors. Higher islet yields were obtained from adult male donors, BMI >25 kg/m2, adequate glycemic control during hospital stay, and when the pancreas was retrieved by a local surgical team. Successful isolations were obtained in 58% of the cases when > or = 4 donor criteria were met, and even higher success rates (69%) were observed when considering > or = 5 criteria. Our data suggest that a sequential, integrated approach is highly desirable to improve the success rate of islet cell processing.

A computer simulation model of diabetes progression, quality of life, and cost.

OBJECTIVE: To develop and validate a comprehensive computer simulation model to assess the impact of screening, prevention, and treatment strategies on type 2 diabetes and its complications, comorbidities, quality of life, and cost. RESEARCH DESIGN AND METHODS: The incidence of type 2 diabetes and its complications and comorbidities were derived from population-based epidemiologic studies and randomized, controlled clinical trials. Health utility scores were derived for patients with type 2 diabetes using the Quality of Well Being-Self-Administered. Direct medical costs were derived for managed care patients with type 2 diabetes using paid insurance claims. Monte Carlo techniques were used to implement a semi-Markov model. Performance of the model was assessed using baseline and 4- and 10-year follow-up data from the older-onset diabetic population studied in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). RESULTS: Applying the model to the baseline WESDR population with type 2 diabetes, we predicted mortality to be 51% at 10 years. The prevalences of stroke and myocardial infarction were predicted to be 18 and 19% at 10 years. The prevalences of nonproliferative diabetic retinopathy, proliferative retinopathy, and macular edema were predicted to be 45, 16, and 18%, respectively; the prevalences of microalbuminuria, proteinuria, and end-stage renal disease were predicted to be 19, 39, and 3%, respectively; and the prevalences of clinical neuropathy and amputation were predicted to be 52 and 5%, respectively, at 10 years. Over 10 years, average undiscounted total direct medical costs were estimated to be USD $53,000 per person. Among survivors, the average utility score was estimated to be 0.56 at 10 years. CONCLUSIONS: Our computer simulation model accurately predicted survival and the cardiovascular, microvascular, and neuropathic complications observed in the WESDR cohort with type 2 diabetes over 10 years. The model can be used to predict the progression of diabetes and its complications, comorbidities, quality of life, and cost and to assess the relative effectiveness, cost-effectiveness, and cost-utility of alternative strategies for the prevention and treatment of type 2 diabetes.

G-CSF and Exenatide Might Be Associated with Increased Long-Term Survival of Allogeneic Pancreatic Islet Grafts.

BACKGROUND: Allogeneic human islet transplantation is an effective therapy for the treatment of patients with Type 1 Diabetes (T1D). The low number of islet transplants performed worldwide and the different transplantation protocols used limit the identification of the most effective therapeutic options to improve the efficacy of this approach. METHODS: We present a retrospective analysis on the data collected from 44 patients with T1D who underwent islet transplantation at our institute between 2000 and 2007. Several variables were included: recipient demographics and immunological characteristics, donor and transplant characteristics, induction protocols, and additional medical treatment received. Immunosuppression was induced with anti-CD25 (Daclizumab), alone or in association with anti-tumor necrosis factor alpha (TNF-α) treatments (Etanercept or Infliximab), or with anti-CD52 (Alemtuzumab) in association with anti-TNF-α treatments (Etanercept or Infliximab). Subsets of patients were treated with Filgrastim for moderate/severe neutropenia and/or Exenatide for post prandial hyperglycemia. RESULTS: The analysis performed indicates a negative association between graft survival (c-peptide level ≥ 0.3 ng/ml) and islet infusion volume, with the caveat that, the progressive reduction of infusion volumes over the years has been paralleled by improved immunosuppressive protocols. A positive association is instead suggested between graft survival and administration of Exenatide and Filgrastim, alone or in combination. CONCLUSION: This retrospective analysis may be of assistance to further improve long-term outcomes of protocols for transplant of islets and other organs.

Fibroblast Growth Factor 23 and Risk of CKD Progression in Children.

BACKGROUND AND OBJECTIVES: Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1-16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites. RESULTS: At enrollment, median age was 11 years [interquartile range (IQR), 8-15], GFR was 44 ml/min per 1.73 m2 (IQR, 33-57), and FGF23 was 132 RU/ml (IQR, 88-200). During a median follow-up of 5.5 years (IQR, 3.5-6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P=0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P=0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses. CONCLUSIONS: High plasma FGF23 is an independent risk factor for CKD progression in children.