Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients:Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control

Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment

Exploring the effects of lifestyle on breast cancer risk, age at diagnosis, and survival: the EBBA-Life study

Purpose - Whether an unfavorable lifestyle not only affects breast cancer risk, but also influences age at onset of breast cancer and survival, is under debate. Methods - In a population-based cohort, the Energy Balance and Breast Cancer Aspects throughout life (EBBA-Life) study, a total of 17,145 women were included. During follow-up, 574 women developed invasive breast cancer. Breast cancer cases were followed for an additional 9.1 years. Detailed medical records were obtained. Cox’s proportional hazard regression models were used to study the association between pre-diagnostic lifestyle factors (weight, physical activity, alcohol use, smoking, and hypertension), breast cancer risk, age at diagnosis, and survival. Results - At study entry, 34.3% of the participating women were overweight and 30.7% were physically inactive. Mean age at breast cancer diagnosis was 58.0 years, and 78.9% of the tumors were estrogen receptor positive. Among menopausal women who did not use hormone therapy and had an unfavorable lifestyle (3–5 unfavorable factors), compared with women who had a favorable lifestyle, we observed a twofold higher risk for postmenopausal breast cancer (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.23–3.69), and they were 3.4 years younger at diagnosis (64.8 versus 68.2 years, P = 0.032). Breast cancer patients with an unfavorable lifestyle, compared with patients with a favorable lifestyle, had almost a two times higher overall mortality risk (HR 1.96, 95% CI 1.01–3.80). Conclusions - Our study supports a healthy lifestyle improving breast cancer prevention, postponing onset of disease, and extending life expectancy among breast cancer patients

Intraoperative Ultrasound: A Tool to Support Tissue-Sparing Curative Pancreatic Resection in Focal Congenital Hyperinsulinism

Background: Focal congenital hyperinsulinism (CHI) may be cured by resection of the focal, but often non-palpable, pancreatic lesion. The surgical challenge is to minimize removal of normal pancreatic tissue.Aim: To evaluate the results of intraoperative ultrasound-guided, tissue-sparing pancreatic resection in CHI patients at an international expert center.Methods: Retrospective study of CHI patients treated at Odense University Hospital, Denmark, between January 2010 and March 2017.Results: Of 62 consecutive patients with persistent CHI, 24 (39%) had focal CHI by histology after surgery. All patients had a paternal ABCC8 or KCNJ11 mutation and a focal lesion by 18F-DOPA-PET/CT. Intraoperative ultrasound localized the focal lesion in 16/20 patients (sensitivity 0.80), including one ectopic lesion in the duodenal wall. Intraoperative ultrasound showed no focal lesion in 11/11 patients with diffuse CH (specificity 1.0). The positive predictive value for focal histology was 1.0, negative predictive value 0.73.Tissue-sparing pancreatic resection (focal lesion enucleation, local resection of tail or uncinate process) was performed in 67% (n = 16). In 11/12 having tissue-sparing resection and intraoperative ultrasound, the location of the focal lesion was exactly identified. Eight patients had resection of the pancreatic head or head/body, four with Roux-en-Y, three with pancreatico-gastrostomy and one without reconstruction. None had severe complications to surgery. Cure of hypoglycaemia was seen in all patients after one (n = 21) or two (n = 3) pancreatic resections.Conclusion: In focal CHI, tissue-sparing pancreatic resection was possible in 67%. Intraoperative ultrasound was a helpful supplement to the mandatory use of genetics, preoperative 18F-DOPA-PET/CT and intraoperative frozen sections

The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

<p>Abstract</p> <p>Background</p> <p>The protein tyrosine phosphatase nonreceptor type 2 (<it>PTPN22</it>) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA_1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes.</p> <p>Methods</p> <p>The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA_1cand daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset.</p> <p>Results</p> <p>A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between <it>PTPN22 </it>and proinsulin (est.: 1.28, p = 0.03).</p> <p>Conclusions</p> <p>The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.</p

Mortality after Hospitalization for Pneumonia among Individuals with HIV, 1995–2008: A Danish Cohort Study

BACKGROUND: HIV-infected persons are at increased risk of pneumonia, even with highly active antiretroviral treatment (HAART). We examined the impact of pneumonia on mortality and identified prognostic factors for death among HIV-infected. METHODOLOGY/PRINCIPAL FINDINGS: In a nationwide, population-based cohort of individuals with HIV, we included persons hospitalized with pneumonia from the Danish National Hospital Registry and obtained mortality data from the Danish Civil Registration System. Comparing individuals with and without pneumonia, we used Poisson regression to estimate relative mortality and logistic regression to examine prognostic factors for death following pneumonia. From January 1, 1995, to July 1, 2008, we observed 699 episodes of first hospitalization for pneumonia among 4,352 HIV patients. Ninety-day mortality after pneumonia decreased from 22.4% (95% confidence interval [CI]: 16.5%-28.9%) in 1995-1996 to 8.4% (95% CI: 6.1%-11.6%) in 2000-2008. Mortality remained elevated for more than a year after hospitalization for pneumonia: adjusted mortality rate ratio 5.38 (95% CI: 4.27-6.78), 1.80 (95% CI: 1.36-2.37), and 1.62 (95% CI: 1.32-2.00) for days 0-90, 91-365, and 366+, respectively. The following variables predicted mortality within 90 days following hospitalization for pneumonia (adjusted Odds Ratios): male sex (3.77, 95% CI: 1.37-10.4), Charlson Comorbidity Index score > or = 2 (3.86, 95% CI: 2.19-6.78); no current HAART (3.58, 95% CI: 1.83-6.99); history of AIDS (2.46, 95% CI: 1.40-4.32); age per 10 year increase (1.43, 95% CI: 1.11-1.85); and CD4+ cell count < or = 200 (2.52, 95% CI: 1.37-4.65). CONCLUSIONS/SIGNIFICANCE: The first hospitalization for pneumonia among HIV-infected individuals was associated with elevated risk of death up to more than a year later. Use of HAART decreased the risk, independent of current CD4+ cell count. Prognosis following pneumonia improved over calendar time