-tailored intervention significantly improved CRC screening rates among low-income African American patients. This finding was largely driven by increasing SBT but the impact of the intervention on colonoscopy screening was strong. Implementation of a CRC screening quality improvement program in the VA site that included provision of stool blood test kits and follow-up likely contributed to the strong intervention effect observed at that site. The trial is registered at ClinicalTrials.gov as NCT00672828.Heart development relies on PTMs that control cardiomyocyte proliferation, differentiation and cardiac morphogenesis. We generated a map of phosphorylation sites during the early stages of cardiac postnatal development in mice; we quantified over 10,000 phosphorylation sites and 5000 proteins that were assigned to different pathways. Analysis of mitochondrial proteins led to the identification of PGC-1- and ERR-induced regulator in muscle 1 (PERM1), which is specifically expressed in skeletal muscle and heart tissue and associates with the outer mitochondrial membrane. We demonstrate PERM1 is subject to rapid changes mediated by the UPS through phosphorylation of its PEST motif by casein kinase 2. Ablation of Perm1 in mice results in reduced protein expression of lipin-1 accompanied by accumulation of specific phospholipid species. Isolation of Perm1-deficient mitochondria revealed significant downregulation of mitochondrial transport proteins for amino acids and carnitines, including SLC25A12/13/29/34 and CPT2. Consistently, we observed altered levels of various lipid species, amino acids, and acylcarnitines in Perm1-/- mitochondria. We conclude that the outer mitochondrial membrane protein PERM1 regulates homeostasis of lipid and amino acid metabolites in mitochondria.Genome-wide association studies identified Spen as a putative modifier of cardiac function, however, the precise function of Spen in the cardiovascular system is not known yet. Here, we analyzed for the first time the in vivo role of Spen in zebrafish and found that targeted Spen inactivation led to progressive impairment of cardiac function in the zebrafish embryo. In addition to diminished cardiac contractile force, Spen-deficient zebrafish embryos developed bradycardia, atrioventricular block and heart chamber fibrillation. Assessment of cardiac-specific transcriptional profiles identified Connexin 43 (Cx43), a cardiac gap junction protein and crucial regulator of cardiomyocyte-to-cardiomyocyte communication, to be significantly diminished in Spen-deficient zebrafish embryos. Similar to the situation in Spen-deficient embryos, Morpholino-mediated knockdown of cx43 in zebrafish resulted in cardiac contractile dysfunction, bradycardia, atrioventricular block and fibrillation of the cardiac chambers. Furthermore, ectopic overexpression of cx43 in Spen deficient embryos led to the reconstitution of cardiac contractile function and suppression of cardiac arrhythmia. Additionally, sensitizing experiments by simultaneously injecting sub-phenotypic concentrations of spen- and cx43-Morpholinos into zebrafish embryos resulted in pathological supra-additive effects. In summary, our findings highlight a crucial role of Spen in controlling cx43 expression and demonstrate the Spen-Cx43 axis to be a vital regulatory cascade that is indispensable for proper heart function in vivo.Alternative splicing is prevalent in the heart and implicated in many cardiovascular diseases, but not every alternative transcript is translated and detecting non-canonical isoforms at the protein level remains challenging. Here we show the use of a computation-assisted targeted proteomics workflow to detect protein alternative isoforms in the human heart. We build on a recent strategy to integrate deep RNA-seq and large-scale mass spectrometry data to identify candidate translated isoform peptides. A machine learning approach is then applied to predict their fragmentation patterns and design protein isoform-specific parallel reaction monitoring detection (PRM) assays. As proof-of-principle, we built PRM assays for 29 non-canonical isoform peptides and detected 22 peptides in a human heart lysate. The predictions-aided PRM assays closely mirrored synthetic peptide standards for non-canonical sequences. This approach may be useful for validating non-canonical protein identification and discovering functionally relevant isoforms in the heart.

This systematic review summarised the latest findings on differential composition of gut microbiota in T2DM.

Literature search was performed using electronic databases. Relevant studies were identified, extracted and assessed for risk of bias. The primary outcome of this systematic review was the composition of gut microbiota in healthy controls and T2DM while the secondary outcomes included the correlation of gut microbiota with metabolic parameters.

Thirteen case-control studies involving 575 T2DM and 840 healthy controls were included. T2DM patients exhibited a marked increase in lactobacilli. Six studies found lactobacilli to predominate the gut of T2DM patients; however, this could be confounded by the types of antihyperglyacemic medications. Conversely, butyrate producers dominate the gut of healthy controls. In T2DM patients, butyrate producers were surprisingly higher in those taking metformin intake than those not taking the drug. Whilst lactobacilli were found to be higher with increased plasma glucose, conflicting correlations were observed between various genera and anthropometric measurements, dietary intake, lipid profiles and inflammatory markers. There were moderate to strong significant positive correlations between the class Clostridia and phylum Firmicutes with pro-inflammatory IFN-γ as well as between Negativicutes and IL-6.

Altogether, butyrate-producing bacteria are negatively correlated to glycaemic parameters. Lactobacilli are higher in T2DM patients and Firmicutes is correlated with inflammation.

Altogether, butyrate-producing bacteria are negatively correlated to glycaemic parameters. Lactobacilli are higher in T2DM patients and Firmicutes is correlated with inflammation.

Fetal exposure to maternal GDM increases offspring risk for adult-onset metabolic syndromes. Epigenetic modifications such as DNA methylation are modulators for fetal metabolic programming and susceptibility to adult-onset disease. This study investigates genome-wide DNA methylation in GDM exposed cord blood and placenta.

Oral glucose tolerance testing between 24 and 28weeks of pregnancy was used to determine severity of glucose intolerance. We measured DNA methylation (DNAm) using the Illumina Infinium 450K array in 42 fetal cord blood and 36 placenta samples.

We identified 662 and 99 CpG sites in GDM placenta and cord blood, respectively at p-value <0.01 and a methylation difference >5% after adjustment for confounders. Annotated sites for AHRR and PTPRN2 were common to cord blood and placenta. Adding published GDM cord blood DNAm data we segregated patients based on treatment (Diet Only vs. +Insulin) and identified altered CpG sites to be unique to each GDM treatment group.

Consistency in findings with other studies provides evidence for the role of DNAm in placental and fetal responses to hyperglycemia. However, segregating DNAm analysis of GDM samples based on treatment may help delineate whether observed DNAm alterations are reflective of adaptive responses or treatment effects in utero.

Consistency in findings with other studies provides evidence for the role of DNAm in placental and fetal responses to hyperglycemia. However, segregating DNAm analysis of GDM samples based on treatment may help delineate whether observed DNAm alterations are reflective of adaptive responses or treatment effects in utero.

To evaluate the risk of all-cause and cardiovascular mortality, acute myocardial infarction, and stroke associated with insulin treatment in patients with type 2 diabetes.

A systematic review with meta-analysis of randomized clinical trials (RCTs) was performed. EMBASE, Cochrane, and PubMed databases were searched for RCTs reporting mortality or cardiovascular events and comparing basal insulin to any treatment in patients with type 2 diabetes. Data were summarized with Mantel-Haenzel relative risk (RR). Trial sequential analysis (TSA) was used to evaluate the reliability of the results considering a 20% relative risk difference between treatments. PROSPERO Registry CRD42018087336.

In total, 2351 references were identified, and 26 studies (24348 patients) were included. Most studies evaluated glargine insulin (69%), compared insulin to GLP-1 analogs (57%), and evaluated add-on therapy with metformin (77%). Insulin was not associated with increased all-cause mortality (RR 0.99; 95% confidence interval (CI) 0.92-1.06), cardiovascular mortality (RR 1.01; 95% CI 0.91-1.13), myocardial infarction (RR 1.02; 95% CI 0.92-1.15), or stroke (RR 0.87; 95% CI 0.68-1.12). Insulin treatment increased severe hypoglycemia risk (RR 2.98; 95% CI 2.47-3.61). All analyses had low statistical heterogeneity. TSA confirmed these findings optimal sample size (myocardial infarction), futility boundary (all-cause mortality, cardiovascular mortality, and stroke) and harm boundary (hypoglycemia) were reached.

Treatment with basal insulin of patients with type 2 diabetes does not increase the risk of cardiovascular events or death. Despite the increased risk of hypoglycemia, these findings reinforce that insulin is a safe option in the treatment of type 2 diabetes.

Treatment with basal insulin of patients with type 2 diabetes does not increase the risk of cardiovascular events or death. Despite the increased risk of hypoglycemia, these findings reinforce that insulin is a safe option in the treatment of type 2 diabetes.

Systemic inhibition of dipeptidyl peptidase 4 (DPP4) showed a protective effect in several transplant models. Here we assessed the specific role of extrarenal DPP4 in renal transplant rejection.

Kidneys from wildtype (wt) F344 rats were either transplanted in wt Dark Agouti or congenic rats not expressing DPP4. The remaining, not transplanted donor kidney served as healthy controls. To investigate early inflammatory events rats were sacrificed 3days after transplantation and kidneys were evaluated for inflammatory cells, capillary rarefaction, proliferation, apoptosis and myofibroblasts by immunohistochemistry.

Capillary ERG-1-positive endothelial cells were significantly more abundant in renal cortex when transplanted into DPP4 deficient compared to wt recipients. In contrast, TGF-ß and myofibroblasts were reduced by more than 25% in kidneys transplanted into DPP4 deficient compared to wt recipients. Numbers of CD161a-positive NK-cells were significantly lower in allografts in DPP4 deficient compared to wt recipients. Numbers of all other investigated immune cells were not affected by the lack of extrarenal DPP4.

In early transplant rejection extrarenal DPP4 is involved in the recruitment of NK-cells and early fibrosis. Beneficial effects were less pronounced than reported for systemic DPP4 inhibition, indicating that renal DPP4 is an important player in transplantation-mediated injury.

In early transplant rejection extrarenal DPP4 is involved in the recruitment of NK-cells and early fibrosis. Beneficial effects were less pronounced than reported for systemic DPP4 inhibition, indicating that renal DPP4 is an important player in transplantation-mediated injury.