Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset.

AIMS/HYPOTHESIS: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. METHODS: In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. RESULTS: The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. CONCLUSIONS/INTERPRETATION: These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.

Total Pancreatectomy With Islet Autotransplantation as an Alternative to High-risk Pancreatojejunostomy After Pancreaticoduodenectomy: A Prospective Randomized Trial.

OBJECTIVE: To compare pancreaticoduodenectomy (PD) and total pancreatectomy (TP) with islet autotransplantation (IAT) in patients at high risk of postoperative pancreatic fistula (POPF). BACKGROUND: Criteria to predict the risk of POPF occurrence after PD are available. However, even when a high risk of POPF is predicted, TP is not currently accepted as an alternative to PD, because of its severe consequences on glycaemic control. Combining IAT with TP may mitigate such consequences. METHODS: Randomized, open-label, controlled, bicentric trial (NCT01346098). Candidates for PD at high-risk pancreatic anastomosis (ie, soft pancreas and duct diameter ≤3 mm) were randomly assigned (1:1) to undergo either PD or TP-IAT. The primary endpoint was the incidence of complications within 90 days after surgery. RESULTS: Between 2010 and 2019, 61 patients were assigned to PD (n=31) or TP-IAT (n=30). In the intention-to-treat analysis, morbidity rate was 90·3% after PD and 60% after TP-IAT ( P =0.008). According to complications' severity, PD was associated with an increased risk of grade ≥2 [odds ratio (OR)=7.64 (95% CI: 1.35-43.3), P =0.022], while the OR for grade ≥3 complications was 2.82 (95% CI: 0.86-9.24, P =0.086). After TP-IAT, the postoperative stay was shorter [median: 10.5 vs 16.0 days; P <0.001). No differences were observed in disease-free survival, site of recurrence, disease-specific survival, and overall survival. TP-IAT was associated with a higher risk of diabetes [hazard ratio=9.1 (95% CI: 3.76-21.9), P <0.0001], but most patients maintained good metabolic control and showed sustained C-peptide production over time. CONCLUSIONS: TP-IAT may become the standard treatment in candidates for PD, when a high risk of POPF is predicted.

Efficacy of flash glucose monitoring in pregnant women with poorly controlled pregestational diabetes (FlashMom): A randomized pilot study.

BACKGROUND AND AIMS: Good glycemic control is crucial to reduce the risk of adverse pregnancy outcomes. Our aim was to evaluate the efficacy of Flash Glucose Monitoring (FGM) on glucose control in women with pregestational diabetes. METHODS AND RESULTS: Forty women with inadequately controlled type 1 (T1D, n = 34) and type 2 (T2D, n = 6) diabetes at conception were randomly assigned to two arms: the Flash Glucose group (FG, n = 21) using FGM, and the control group (CG, n = 19) using self-monitoring of blood glucose (SMBG). Glycated hemoglobin (HbA1c, %), time in (TIR), below (TBR) and above (TAR) range, glucose variability as well as the occurrence of maternal and neonatal adverse outcomes, were evaluated. HbA1c decreased significantly (p < 0.01) and similarly (-0.65 ± 0.7 vs. -0.67 ± 0.8 for FG and CG, respectively; p = 0.89) in both groups during pregnancy. HbA1c reduction was positively associated with the number of daily FGM scans (p < 0.01). TBR (12.1 ± 2.0% vs. 19.6 ± 3.9%, p = 0.04) and the mean of the daily serum glucose difference (MODD) index (59.1 ± 5.4 vs. 77.7 ± 4.6, p = 0.02) were significantly lower in FG at second trimester. The rates of perinatal adverse outcomes were not different in the two studied groups. CONCLUSIONS: In women with pregestational diabetes, FGM and SMBG had similar efficacy on glucose control during pregnancy. FGM showed additional advantages in terms of TBR and glucose variability. Achievement of good metabolic results depended on the adequate use of glucose sensor. REGISTRATION: At ClinicalTrials.gov as NCT04666818 on December 14, 2020.

Antibody response to multiple antigens of SARS-CoV-2 in patients with diabetes: an observational cohort study.

AIMS/HYPOTHESIS: The aim of the study was to characterise the humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with diabetes. Demonstrating the ability to mount an appropriate antibody response in the presence of hyperglycaemia is relevant for the comprehension of mechanisms related to the observed worse clinical outcome of coronavirus disease 2019 (COVID-19) pneumonia in patients with diabetes and for the development of any future vaccination campaign to prevent SARS-CoV-2 infection. METHODS: Using a highly specific and sensitive measurement of antibodies by fluid-phase luciferase immunoprecipitation assays, we characterised the IgG, IgM and IgA response against multiple antigens of SARS-CoV-2 in a cohort of 509 patients with documented diagnosis of COVID-19, prospectively followed at our institution. We analysed clinical outcomes and antibody titres according to the presence of hyperglycaemia, i.e., either diagnosed or undiagnosed diabetes, at the time of, or during, hospitalisation. RESULTS: Among patients with confirmed COVID-19, 139 (27.3%) had diabetes: 90 (17.7%) had diabetes diagnosed prior to the hospital admission (comorbid diabetes) while 49 (9.6%) had diabetes diagnosed at the time of admission (newly diagnosed). Diabetes was associated with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leucocytosis and neutrophilia. Diabetes was independently associated with risk of death (HR 2.32 [95% CI 1.44, 3.75], p = 0.001), even after adjustment for age, sex and other relevant comorbidities. Moreover, a strong association between higher glucose levels and risk of death was documented irrespective of diabetes diagnosis (HR 1.14 × 1.1 mmol/l [95% CI 1.08, 1.21], p < 0.001). The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable, as for timing and antibody titres, to that of non-diabetic patients, with marginal differences, and was not influenced by glucose levels. Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike receptor-binding domain (RBD) was predictive of survival rate, both in the presence or absence of diabetes. CONCLUSIONS/INTERPRETATION: The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycaemia was not the result of an impaired humoral response against SARS-CoV-2. RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARs-COV-2 in people with diabetes. Graphical abstract.

Awareness about diabetes and pregnancy among diabetes specialists and fellows: The YoSID diabetes and pregnancy project.

BACKGROUND AND AIMS: Despite evidence that pregnancy planning improves outcomes, in Italy, as in many other countries worldwide, <50% of women with diabetes prepare their pregnancy. The aim of this study was to document training and knowledge on diabetes and pregnancy (D&P) among diabetes professionals. METHODS AND RESULTS: We administered an anonymous online questionnaire, focused on diabetes and pregnancy planning, to diabetes team members. Between Nov-2017 and Jul-2018, n = 395 professionals (60% diabetes/endocrinology/internal medicine specialists, 28% fellows) completed the survey. Fifty-nine percent of the specialists, mainly (78%) those completing their fellowship after 2006, reported having received training on D&P during fellowship. Considering specialists reporting training, 43% correctly identified fetal risks of inadequate preconceptional glucose control and 55% maternal risks, 38% identified risks associated with overweight/obesity, and 39% would prescribe hormonal contraception to women with diabetes only if glucose control is good. CONCLUSIONS: The results of our survey suggest the need to improve training and awareness of professionals in the area of diabetes and pregnancy.

Italian recommendations for the diagnosis of gestational diabetes during COVID-19 pandemic: Position statement of the Italian Association of Clinical Diabetologists (AMD) and the Italian Diabetes Society (SID), diabetes, and pregnancy study group.

AIM: In response to the COVID-19 pandemic, there is a need for substantial changes in the procedures for accessing healthcare services. Even in the current pandemic, we should not reduce our attention towards the diagnosis and treatment of GDM. The purpose of this document is to provide a temporary guide for GDM screening, replacing the current guidelines when it is not possible to implement standard GDM screening because of an unfavorable risk/benefit ratio for pregnant women or when usual laboratory facilities are not available. DATA SYNTHESIS: At the first visit during pregnancy, we must exclude the presence of "Overt diabetes" in all women. The criteria for the diagnosis of overt diabetes are either fasting plasma glucose ≥126 mg/dL, or random plasma glucose ≥200 mg/dL, or glycated hemoglobin ≥6.5%. When the screening procedure (OGTT) cannot be safely performed, the diagnosis of GDM is acceptable if fasting plasma glucose is ≥ 92 mg/dL. In order to consider the impaired fasting glucose as an acceptable surrogate for the diagnosis of GDM, the fasting glucose measurement should be performed within the recommended time windows for the risk level (high or medium risk). CONCLUSIONS: The changes to the screening procedure for GDM reported below are specifically produced in response to the health emergency of the COVID-19 pandemic. Therefore, these recommended changes should cease to be in effect and should be replaced by current national guidelines when the healthcare authorities declare the end of this emergency.

Diabetes-free survival after extended distal pancreatectomy and islet auto transplantation for benign or borderline/malignant lesions of the pancreas.

Islet autotransplant is particularly attractive to prevent diabetes after extended pancreatectomy for benign or borderline/malignant pancreas disease. Between 2008 and 2018, 25 patients underwent left extended pancreatectomy (>60%) and islet autotransplant for a neoplasm located in the pancreatic neck or proximal body. Overall, disease-free and diabetes-free survivals were estimated and compared with those observed in 68 nondiabetic patients who underwent distal pancreatectomy for pancreatic neoplasms without islet autotransplant. Median follow-up was 4 years. We observed no deaths and a low morbidity (nonserious procedure-related complications in 2 of 25 patients). Patient and insulin-independent survival rates at 4 years were 100% and 96%, respectively. Glucose homeostasis remained within a nondiabetic range at all times for 19 (73%) of 25 patients. Preoperative glycemic level and insulin resistance were major predictors of diabetes development in these patients. Patients undergoing islet autotransplant had a longer diabetes-free survival than did patients without islet autotransplant (P = .04). In conclusion, islet autotransplant after extended pancreatic resection for neoplasms is a safe and successful procedure for preventing diabetes.

Diabetes associated with pancreatic ductal adenocarcinoma is just diabetes: Results of a prospective observational study in surgical patients.

BACKGROUND: Identification of a specific diabetes signature associated to pancreatic ductal carcinoma (PDAC) could be a key to detect asymptomatic, early stage tumors. We aim to characterize the clinical signature and the pathogenetic factors of the different types of diabetes associated with PDAC, based on the time between diabetes and cancer diagnosis. METHODS: Prospective observational study on 364 PDAC patients admitted to a referral center for pancreatic disease. Hospital and/or outpatient medical records were reviewed. Blood biochemical values including fasting blood glucose, insulin and/or C-peptide, glycosylated hemoglobin and anti-islet antibodies were determined. Diabetes onset was assessed after surgery and during follow-up. RESULTS: The prevalence of diabetes in patients was 67%. Considering 174 patients (47.8%) already having diabetes when diagnosed with PDAC (long duration, short duration, concomitant), the clinical and biochemical profile was similar to that of patients with type 2 diabetes (T2D). Diabetes was associated with known risk factors (i.e., age, sex, family history for diabetes and increased BMI) and both beta-cell dysfunction and insulin resistance were present. Considering 70 patients (19.2%) with onset of diabetes after PDAC diagnosis (early and late onset), the strongest predictor was the loss of beta-cell mass following pancreatectomy in patients with risk factors for T2D. CONCLUSION: Different types of diabetes according to the time between diabetes and PDAC diagnosis are clinical entities widely overlapping with T2D. Therefore, the success of a strategy considering diabetes onset as a marker of asymptomatic PDAC will largely depend on our ability to identify new diabetes-unrelated biomarkers of PDAC.

Diabetes after pancreatic surgery: novel issues.

In the developed world, pancreatic surgery is becoming more common, with an increasing number of patients developing diabetes because of either partial or total pancreatectomy, with a significant impact on quality of life and survival. Although these patients are expected to consume increasing health care resources in the near future, many aspects of diabetes after pancreatectomy are still not well defined. The treatment of diabetes in these patients takes advantage of the therapies used in type 1 and 2 diabetes; however, no specific guidelines for its management, both immediately after pancreatic surgery or in the long term, have been developed. In this article, on the basis of both the literature and our clinical experience, we address the open issues and discuss the most appropriate therapeutic options for patients with diabetes after pancreatectomy.

The allocation of pancreas allografts on donor age and duration of intensive care unit stay: the experience of the North Italy Transplant program.

Starting in 2011, the North Italy Transplant program (NITp) has based on the allocation of pancreas allografts on donor age and duration of intensive care unit (ICU) stay, but not on donor weight or BMI. We analyzed the detailed allocation protocols of all NITp pancreas donors (2011-2012; n = 433). Outcome measures included donor characteristics and pancreas loss reasons during the allocation process. Twenty-three percent of the 433 pancreases offered for allocation were transplanted. Younger age, shorter ICU stay, traumatic brain death, and higher eGFR were predictors of pancreas transplant, either as vascularized organ or as islets. Among pancreas allografts offered to vascularized organ programs, 35% were indeed transplanted, and younger donor age was the only predictor of transplant. The most common reasons for pancreas withdrawal from the allocation process were donor-related factors. Among pancreas offered to islet programs, 48% were processed, but only 14.2% were indeed transplanted, with unsuccessful isolation being the most common reason for pancreas loss. Younger donor age and higher BMI were predictors of islet allograft transplant. The current allocation strategy has allowed an equal distribution of pancreas allografts between programs for either vascularized organ or islet transplant. The high rate of discarded organs remained an unresolved issue.

Gastroenteric neuroendocrine neoplasms classification: comparison of prognostic models.

BACKGROUND: Gastroenteric neuroendocrine neoplasms (GE-NENs) display highly variable clinical behavior. In an attempt to assess a better prognostic description, in 2010, the World Health Organization (WHO) updated its previous classification, and the European Neuroendocrine Tumors Society (ENETS) proposed a new grading and TNM-based staging system. In the current study, the authors evaluated the prognostic significance of these models and compared their efficacy in describing patients' long-term survival to assess the best prognostic model currently available for clinicians. METHODS: The study cohort was composed of 145 patients with extrapancreatic GE-NEN who were observed from 1986 to 2008 at a single center and were classified according to the WHO and ENETS classifications. Survival evaluations were performed using Kaplan-Meyer analyses on 131 patients. Only deaths from neoplasia were considered. A P value < .05 was considered significant. Prognostic efficacy was assessed by determining the Harrell concordance index (c-index). RESULTS: Both the 2010 WHO and the ENETS classification were able to efficiently divide patients into classes with different prognoses. According to the model comparison, the ENETS TNM-based staging system appeared to be the strongest. All combined models were effective prognostic predictors, but the model that included the 2010 WHO classification plus ENETS staging had a higher c-index. CONCLUSIONS: Both the 2010 WHO classification and the ENETS staging system are valid instruments for GE-NENs prognostic assessment, with TNM-based stage appearing to be the best available choice for clinicians, both alone and in association with other classifications.

Extending indications for islet autotransplantation in pancreatic surgery.

OBJECTIVE: To assess metabolic and oncologic outcomes of islet autotransplantation (IAT) in patients undergoing pancreatic surgery for either benign or malignant disease. BACKGROUND: IAT is performed to improve glycemic control after extended pancreatectomy, almost exclusively in patients with chronic pancreatitis. Limited experience is available for other indications or in patients with pancreatic malignancy. METHODS: In addition to chronic pancreatitis, indications for IAT were grade C pancreatic fistula (treated with completion or left pancreatectomy, as indicated); total pancreatectomy as an alternative to high-risk anastomosis during pancreaticoduodenectomy; and distal pancreatectomy for benign/borderline neoplasm of pancreatic body-neck. Malignancy was not an exclusion criterion. Metabolic and oncologic follow-up is presented. RESULTS: From November 2008 to June 2012, 41 patients were candidates to IAT (accounting for 7.5% of all pancreatic resections). Seven of 41 did not receive transplantation for inadequate islet mass (4 pts), patient instability (2 pts), or contamination of islet culture (1 pt). IAT-related complications occurred in 8 pts (23.5%): 4 bleeding, 3 portal thromboses (1 complete, 2 partial), and 1 sepsis. Median follow-up was 546 days. Fifteen of 34 patients (44%) reached insulin independence, 16 patients (47%) had partial graft function, 2 patients (6%) had primary graft nonfunction, and 1 patient (3%) had early graft loss. Seventeen IAT recipients had malignancy (pancreatic or periampullary adenocarcinoma in 14). Two of them had already liver metastases at surgery, 13 were disease-free at last follow-up, and none of 2 patients with tumor recurrence developed metastases in the transplantation site. CONCLUSIONS: Although larger data are needed to definitely exclude the risk of disease dissemination, the present study suggests that IAT indications can be extended to selected patients with neoplasm.

Alterations of the intestinal mucus layer correlate with dysbiosis and immune dysregulation in human Type 1 Diabetes.

BACKGROUND: In preclinical models of Type 1 Diabetes (T1D) the integrity of the gut barrier (GB) is instrumental to avoid dysregulated crosstalk between the commensal microbiota and immune cells and to prevent autoimmunity. The GB is composed of the intestinal epithelial barrier (IEB) and of the mucus layer containing mucins and antimicrobial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alterations of the GB primarily affect the mucus layer. In human T1D increased gut permeability and IEB damage have been demonstrated but the integrity of the mucus layer was never assessed. METHODS: We evaluated GB integrity by measuring serological markers of IEB damage (serological levels of zonulin) and bacterial translocation such as lipopolysaccharide binding protein (LBP) and myeloid differentiation protein 2 (MD2), and mRNA expression of tight junction proteins, mucins and AMPs in intestinal tissue of T1D patients and healthy controls (HC). Simultaneously, we performed immunological profiling on intestinal tissue and 16S rRNA analysis on the mucus-associated gut microbiota (MAGM). FINDINGS: Our data show a GB damage with mucus layer alterations and reduced mRNA expression of several mucins (MUC2, MUC12, MUC13, MUC15, MUC20, MUC21) and AMPs (HD4 and HD5) in T1D patients. Mucus layer alterations correlated with reduced relative abundance of short chain fatty acids (SCFA)-producing bacteria such as Bifidobacterium dentium, Clostridium butyricum and Roseburia intestinalis that regulate mucin expression and intestinal immune homeostasis. In T1D patients we also found intestinal immune dysregulation with higher percentages of effector T cells such as T helper (Th) 1, Th17 and TNF-α+ T cells. INTERPRETATION: Our data show that mucus layer alterations are present in T1D subjects and associated with dysbiosis and immune dysregulation. FUNDING: Research Grants from the Juvenile Diabetes Foundation (Grant 1-INO-2018-640-A-N to MF and 2-SRA-2019-680-S-B to JD) and from the Italian Ministry of Health (Grant RF19-12370721 to MF).

No Evidence of Long-Term Disruption of Glycometabolic Control After SARS-CoV-2 Infection.

PURPOSE: To assess whether dysglycemia diagnosed during severe acute respiratory syndrome coronavirus 2 pneumonia may become a potential public health problem after resolution of the infection. In an adult cohort with suspected coronavirus disease 2019 (COVID-19) pneumonia, we integrated glucose data upon hospital admission with fasting blood glucose (FBG) in the year prior to COVID-19 and during postdischarge follow-up. METHODS: From February 25 to May 15, 2020, 660 adults with suspected COVID-19 pneumonia were admitted to the San Raffaele Hospital (Milan, Italy). Through structured interviews/ medical record reviews, we collected demographics, clinical features, and laboratory tests upon admission and additional data during hospitalization or after discharge and in the previous year. Upon admission, we classified participants according to American Diabetes Association criteria as having (1) preexisting diabetes, (2) newly diagnosed diabetes, (3) hyperglycemia not in the diabetes range, or (4) normoglycemia. FBG prior to admission and during follow-up were classified as normal or impaired fasting glucose and fasting glucose in the diabetes range. RESULTS: In patients with confirmed COVID (n = 589), the proportion with preexisting or newly diagnosed diabetes, hyperglycemia not in the diabetes range and normoglycemia was 19.6%, 6.7%, 43.7%, and 30.0%, respectively. Patients with dysglycemia associated to COVID-19 had increased markers of inflammation and organs' injury and poorer clinical outcome compared to those with normoglycemia. After the infection resolved, the prevalence of dysglycemia reverted to preadmission frequency. CONCLUSIONS: COVID-19-associated dysglycemia is unlikely to become a lasting public health problem. Alarmist claims on the diabetes risk after COVID-19 pneumonia should be interpreted with caution.

Predictors of bone responsiveness to growth hormone (GH) replacement in adult GH-deficient patients.

Growth hormone (GH) replacement in adulthood results in variable bone responses as a function of the gonadic hormonal milieu. We performed a retrospective analysis of a large cohort of adult males and females with confirmed GH deficiency (GHD) prior to treatment and during 3 years of replacement therapy. Potential confounders and effect modifiers were taken into account. Sixty-four adult patients with GHD (20 females and 44 males; mean age 34 years, range 18-64) were included in the analysis. GH replacement induced a different effect on bone in males compared to females. Bone mineral content increased in males and decreased in females at the lumbar spine, total femur, and femoral neck; bone mineral density showed a similar trend at the lumbar spine and femoral neck. There was no significant gender difference in bone area at any measured bone site. In both sexes we observed a similar trend for serum markers of bone remodeling. Sex predicted bone outcome on multivariate analysis, as did age, onset of GHD (childhood/adulthood), pretreatment bone mass, baseline body mass index (BMI), and BMI change during GH replacement. Serum IGF-I levels during treatment did not show any relationship with bone outcome at any measured site. This study confirms that bone responsiveness to GH replacement in adult GHD varies as a function of sex even after controlling for potential confounders and highlights the importance of other cofactors that may affect the interaction between GH replacement therapy and bone remodeling.

Multiple outcomes associated with the use of metformin and sulphonylureas in type 2 diabetes: a population-based cohort study in Italy.

OBJECTIVE: To compare the effect of metformin and sulphonylureas on the risks of switching to insulin therapy, hospitalisation for macrovascular disease and all-cause mortality. METHODS: The 70,437 residents of the Italian Region of Lombardy aged 40 to 90 years who started diabetes treatment with metformin or sulphonylureas during 2001-2003 entered the study and were followed until July 2007. We estimated the effects of the first-line agent, early compliance, and persistence with first-line therapy on the risks of switching to insulin, hospitalisation for macrovascular disease and all-cause mortality, by fitting a multistate model and adjusting for age, gender and selected clinical factors. RESULTS: Compared with patients who started on metformin, those who started on sulphonylureas were at a higher risk of switching to insulin (adjusted hazard ratio and 95% CI, 1.55; 1.43, 1.68), hospitalisation (1.15; 1.08, 1.21), and death (1.37; 1.26, 1.49). Compared with patients who stayed on sulphonylureas for 3 months or less, those on sulphonylureas for more than 9 months had an adjusted hazard ratio of 1.24 (1.13, 1.35) for switching to insulin and 1.14 (1.05, 1.23) for hospitalisation. The risks of switching to insulin and hospitalisation were both increased among patients who switched from metformin to another oral hypoglycaemic agent or combined initial monotherapy with another agent. CONCLUSIONS: Our study provides evidence that the risks of switching to insulin, hospitalisation because of macrovascular events and death changes according to the first prescribed oral hypoglycaemic agent, as well as to the early compliance and persistence with such agent.

Impact of the 8th Edition of the AJCC-TNM Staging System on Estimated Cancer-Specific Survival in Patients Aged 45-54 Years at Diagnosis with Differentiated Thyroid Carcinoma: A Single Center Report.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system changed the age cutoff for risk stratification of differentiated thyroid carcinoma (DTC), downgrading patients between 45 and 54 years to stage I or II. The aim of our study was to assess cancer-specific survival (CSS) in patients aged 45-54 years, in order to document the prognostic capability of the last edition of the staging system. METHODS: We retrospectively reviewed the medical records of 172 patients that from January 1st, 2005, to May 31st, 2017, were diagnosed at our institution with DTC when aged 45-54 years. We restaged patients according to the 8th edition of the staging system and estimated CSS. RESULTS: 101 out of 172 patients (58.7%) were reallocated to a lower stage. Of the 101 downstaged patients, 88 (88.9%) showed a high or intermediate American Thyroid Association (ATA) risk of recurrence. We recorded no cancer-specific deaths. CONCLUSIONS: Risk of cancer-specific mortality in patients aged 45-54 years with DTC is low, supporting the prognostic capability of the 8th edition of the staging system. However, we recommend to consider carefully the significant proportion of patients at intermediate or high risk of recurrence in this group of patients.

Circulating CXCL10 and IL-6 in solid organ donors after brain death predict graft outcomes.

We tested the hypothesis that circulating CXCL10 and IL-6 in donor after brain death provide independent additional predictors of graft outcome. From January 1, 2010 to June 30, 2012 all donors after brain death managed by the NITp (n = 1100) were prospectively included in this study. CXCL10 and IL-6 were measured on serum collected for the crossmatch at the beginning of the observation period. Graft outcome in recipients who received kidney (n = 1325, follow-up 4.9 years), liver (n = 815, follow-up 4.3 years) and heart (n = 272, follow-up 5 years) was evaluated. Both CXCL-10 and IL-6 showed increased concentration in donors after brain death. The intensive care unit stay, the hemodynamic instability, the cause of death, the presence of risk factors for cardiovascular disease and the presence of ongoing infection resulted as significant determinants of IL-6 and CXCL10 donor concentrations. Both cytokines resulted as independent predictors of Immediate Graft Function. Donor IL-6 or CXCL10 were associated with graft failure after liver transplant, and acted as predictors of recipient survival after kidney, liver and heart transplantation. Serum donor IL-6 and CXCL10 concentration can provide independent incremental prediction of graft outcome among recipients followed according to standard clinical practice.

Structured self-monitoring of blood glucose is associated with more appropriate therapeutic interventions than unstructured self-monitoring: A novel analysis of data from the PRISMA trial.

AIMS: To investigate the relationship between single therapeutic interventions and indicatorsofglycemic control in the PRISMA trial, a large study comparing the effects of intensive structured SMBG (ISM) vs. active control (AC) in non-insulin-treated type 2 diabetes (T2D). METHODS: Information was collected at four time points, corresponding to months 3, 6, 9, and 12 and visits 2, 3, 4, and 5, respectively. Data on therapeutic interventions, HbA1c levels and the number of hypoglycemic episodes at each visit were analyzed. RESULTS: Intensification of drug therapy occurred in 20.3% vs. 15.6%, and no change in 71.8% vs. 78.7% of visits for the ISM and AC groups, respectively. On the other hand, de-intensification and redistribution of drugs and/or drug dose occurred in a similar proportion of visits. Intensification of drug therapy in both groups was associated with significant reductions in HbA1c vs. the previous visit, while de-intensification of therapy led to a significant increase in HbA1c in the AC group only. CONCLUSIONS: Our data strongly support that structured SMBG has clinical value in reducing HbA1c in non-insulin-treated T2D and suggest that this clinical benefit may be mediated by more appropriate and timely changes in drug therapy.