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OBJECTIVE Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. RESULTS The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases]: 1.10 [1.06–1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = −0.05 [−0.06 to −0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35–2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12–1.70). CONCLUSIONS Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.

Aims/hypothesis Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. Methods We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. Results In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p 1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p p = 0.024). Conclusions/interpretation rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes. Graphical abstract

OBJECTIVES: Gamma-glutamyl transferase levels (GGT) are typically elevated in biliary atresia (BA), but normal GGT levels have been observed. This cohort of "normal GGT" BA has neither been described nor has the prognostic value of GGT level on outcomes in BA. We aimed to describe outcomes of a single-centre Australian cohort of infants with BA and assess the impact of GGT level at presentation on outcomes in BA. METHODS: Infants diagnosed with BA between 1991 and 2017 were retrospectively analysed. Outcomes were defined as survival with native liver, liver transplantation (LT), and death. Patients were categorized into normal (

BACKGROUND: Evidence suggests a positive association between sugar intake and colorectal cancer (CRC) outcomes. We sought to investigate inflammation and angiogenesis as underlying mechanisms behind increased sugar intake and worse CRC outcomes. METHOD: Pre-surgery serum samples were obtained from 191 patients diagnosed with primary invasive stage I-IV CRC. Biomarkers of inflammation (CRP, SAA, IL-6, IL-8, MCP-1, TNFα) and angiogenesis (VEGFA, VEGFD, sICAM-1 and sVCAM-1) were analyzed (Meso-Scale-Discovery). Fructose, glucose, sucrose, and total sugar intake (calories/day, % total calories) were assessed by FFQ. Pearson’s correlation and multiple linear regression analyses were performed. RESULTS: Patients were on average 64 years old, 64% were male, the majority was diagnosed with stage II-III (58%) cancers, and 67% were either overweight or obese. Among normalweight individuals (BMI

Background Bicuspid aortic valves (BAV) and related aortopathy remain an intriguing topic. Not all BAVs get diseased and around 40% would develop aortic dilatation in their lifetime. If haemodynamic theory is to be believed, then leaflet fusion pattern should have an impact. This study sought to compare the association of aortic morphologies and rate of growth in a set of 102 BAV acropathies operated at a single centre, based on the fusion patterns. Methods Data on aortic valve replacements over a 10-year period was analysed from a prospectively maintained database. Of the 198 BAV undergoing surgery, 102 had aortic dilatation above 40 mm on echocardiogram. These underwent computed tomography (CT) aortograms and were followed up as a part of a database. The impact of leaflet fusion patterns on aortic dilatation pattern and rate was analysed. Results Of the 102, two patients had type 0 pathology and one had left-noncoronary (LN) leaflet fusion. Seventy-four (74) had type 1A or left-right (RL) fusion and 25 had type 1B right-noncoronary (RN) fusion. RL fusion had more males, were taller, bigger and had more proportion of aortic stenosis (AS). Aortic diameters, angles and growth rates at root, ascending/descending aorta and arch were not different. Regression analyses for size or growth did not show any significant impact of fusion pattern. Conclusions Left-right fusion pattern comprised three-quarters of BAV in this cohort and these patients were bigger, taller and had a greater proportion of males with increased rate of aortic stenosis. Despite these differences, there was no significant impact of fusion pattern on aortic size or rate of growth.

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood ( 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p p p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend

MicroRNAs in biofluids are potential biomarkers for detecting kidney and other organ injuries. We profiled microRNAs in urine samples from patients with Russell’s viper envenoming or acute self-poisoning following paraquat, glyphosate, or oxalic acid [with and without acute kidney injury (AKI)] and on healthy controls. Discovery analysis profiled for 754 microRNAs using TaqMan OpenArray qPCR with three patients per group (12 samples in each toxic agent). From these, 53 microRNAs were selected and validated in a larger cohort of patients (Russell’s viper envenoming = 53, paraquat = 51, glyphosate = 51, oxalic acid = 40) and 27 healthy controls. Urinary microRNAs had significantly higher expression in patients poisoned/envenomed by different nephrotoxic agents in both discovery and validation cohorts. Seven microRNAs discriminated severe AKI patients from no AKI for all four nephrotoxic agents. Four microRNAs (miR-30a-3p, miR-30a-5p, miR-92a, and miR-204) had > 17 fold change (p 0.72. Pathway analysis of target mRNAs of these differentially expressed microRNAs showed association with the regulation of different nephrotoxic signaling pathways. In conclusion, human urinary microRNAs could identify toxic AKI early after acute injury. These urinary microRNAs have potential clinical application as early non-invasive diagnostic AKI biomarkers.

Type 2 diabetes mellitus is a major cause of morbidity and death worldwide. Women with gestational diabetes mellitus (GDM) have greater than a sevenfold higher risk of developing type 2 diabetes in later life. Accurate methods for postpartum type 2 diabetes risk stratification are lacking. Circulating microRNAs (miRNAs) are well recognised as biomarkers/mediators of metabolic disease. We aimed to determine whether postpartum circulating miRNAs can predict the development of type 2 diabetes in women with previous GDM. In an observational study, plasma samples were collected at 12 weeks postpartum from 103 women following GDM pregnancy. Utilising a discovery approach, we measured 754 miRNAs in plasma from type 2 diabetes non-progressors (n = 11) and type 2 diabetes progressors (n = 10) using TaqMan-based real-time PCR on an OpenArray platform. Machine learning algorithms involving penalised logistic regression followed by bootstrapping were implemented. Fifteen miRNAs were selected based on their importance in discriminating type 2 diabetes progressors from non-progressors in our discovery cohort. The levels of miRNA miR-369-3p remained significantly different (p

We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant.

With type 2 diabetes presenting at younger ages, there is a growing need to identify biomarkers of future glucose intolerance. A high (20%) prevalence of glucose intolerance at 18 years was seen in women from the Pune Maternal Nutrition Study (PMNS) birth cohort. We investigated the potential of circulating microRNAs in risk stratification for future pre-diabetes in these women. Here, we provide preliminary longitudinal analyses of circulating microRNAs in normal glucose tolerant (NGT@18y, N = 10) and glucose intolerant (N = 8) women (ADA criteria) at 6, 12 and 17 years of their age using discovery analysis (OpenArray™ platform). Machine-learning workflows involving Lasso with bootstrapping/leave-one-out cross-validation identified microRNAs associated with glucose intolerance at 18 years of age. Several microRNAs, including miR-212-3p, miR-30e-3p and miR-638, stratified glucose-intolerant women from NGT at childhood. Our results suggest that circulating microRNAs, longitudinally assessed over 17 years of life, are dynamic biomarkers associated with and predictive of pre-diabetes at 18 years of age. Validation of these findings in males and remaining participants from the PMNS birth cohort will provide a unique opportunity to study novel epigenetic mechanisms in the life-course progression of glucose intolerance and enhance current clinical risk prediction of pre-diabetes and progression to type 2 diabetes.

MicroRNAs are key regulators of the normal kidney function and development, and altered in acute kidney injury (AKI). However, there is a lack of studies comparing serum and urine miRNA expression in toxic AKI in humans. We aimed to compare the global signature of urinary and serum microRNAs, with and without kidney injury, after human oxalic acid poisoning. We profiled urinary microRNAs in patients who ingested oxalic acid and developed no injury (No AKI n = 3), moderate injury (AKIN2 n = 3) or severe injury (AKIN3 n = 3) and healthy controls (n = 3). We validated a signature of 30 urinary microRNAs identified in the discovery profiling, in a second cohort of individuals exposed to oxalic acid (No AKI n = 15, AKIN2 n=11 & AKIN3 n= 18) and healthy controls (n=-27) and we compared the results with previously published serum data. Global profiling in toxic AKI patients showed a higher expression of urinary microRNAs and lower expression of serum microRNAs. Most urine microRNA in the validation cohort were significantly upregulated (25/30, fold change >2.8 and p < 0.05) in AKIN2/3 patients compared to No AKI. Four urinary microRNAs (miR-191, miR-19b, miR-20a and miR-30b) had good diagnostic performance (AUC greater than 0.8) to predict AKIN2/3 between 4-8 hours post ingestion. Poisoning irrespective of AKI led to significantly lower expression of many microRNAs in serum but relatively few changes in urinary miRNA expression. In conclusion, urinary microRNA signature provides a stronger measure of AKI in oxalic acid poisoning compared to serum microRNA. Kidney injury has the greatest impact on urinary microRNA, while poisoning itself was better reflected in serum miRNA. Plasma and urinary microRNAs signatures provide complementary information in toxic kidney injury.

Lathosterolosis is a rare autosomal recessive disorder of cholesterol biosynthesis. It is caused by defects in the SC5D (sterol C5‐desaturase) gene which encodes for the 3‐beta‐hydroxysteroid‐delta‐5‐desaturase (also called sterol‐C5‐desaturase or lathosterol dehydrogenase). Only six cases have been described in the literature, but it is possible that a number of patients with milder forms of the condition might have been missed. Lathosterolosis manifests as microcephaly, bilateral cataracts, dysmorphism, limb anomalies, and developmental delay/intellectual disability. Liver involvement is variable and can range from normal liver function tests to portal fibrosis and cirrhosis. Diagnosis is made by demonstration of specific mutations in the SC5D gene and by plasma sterol analysis to confirm elevated lathosterol levels. In this report, we describe a girl with transaminitis in association with developmental delay/intellectual disability, facial dysmorphism, limb anomalies, and bilateral cataracts. Fibroscan showed severe liver fibrosis. Plasma sterol analysis and exome sequencing confirmed the diagnosis of lathosterolosis. Simvastatin treatment resulted in lowering of plasma lathosterol levels, improvement in transaminitis, and liver fibrosis grade, suggesting that children with this condition should be actively treated in order to prevent progression of liver disease.

B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5’-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r –0·33, Plinear < 0·0001), serum amyloid A (SAA) (r –0·23, Plinear = 0·003), IL-6 (r –0·39, Plinear < 0·0001), IL-8 (r –0·20, Plinear = 0·02) and TNFα (r –0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r –0·14), SAA (r –0·14) and TNFα (r –0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.

Introduction Changes in the coagulation profile in children with liver disease and extrahepatic portal vein obstruction or shunt result in both bleeding and thrombosis. Routine coagulation tests do not accurately predict bleeding risk, as they are not sensitive to changes in anticoagulant factors. The thrombin generation assay could be suitable for describing the overall balance of coagulation in children with liver disease. This study aims to characterise the mechanism of thrombin generation in this population, focusing on prothrombin conversion and thrombin inhibition. Methods Patients were categorised as: severe (paediatric end stage liver disease score > 15) and mild disease, or portal vein obstruction or shunt. Age and gender matched healthy controls were used. The thrombin generation assay was performed in plasma samples from patients and controls with and without exogenous thrombomodulin and the results were further analysed with the computational thrombin dynamics method. Results A total of 42 patients (severe, n = 5; mild, n = 29, obstruction/shunt, n = 8) and 20 controls were included in this study. The total prothrombin conversion, thrombin-antithrombin formation and the thrombin decay capacity, in the presence and absence of thrombomodulin were reduced in children with severe liver disease. The rate of prothrombin conversion was increased and thrombin decay capacity was decreased in patients with portal vein obstruction or shunt compared to controls. Conclusion This study demonstrates changes in the mechanism in thrombin generation seen in severe chronic liver disease. The changes vary in parenchymal versus non parenchymal liver disease and further study assessing the clinical significance of these variations in mechanism is required.

Oxalic acid-induced nephrotoxicity and acute kidney injury result from formation of calcium oxalate crystals. Oxalic acid-induced acute kidney injury is a significant problem in many parts of the world. Circulating biomarkers that can accurately and reproducibly detect acute kidney injury are highly desirable. We used a high sensitivity discovery platform to identify signature microRNAs to distinguish healthy individuals never exposed to oxalic acid (n = 4) from those who were exposed to oxalic acid but had no injury (NOAKI; n = 4), moderate injury (AKIN2; n = 4) or severe injury (AKIN3; n = 4). Longitudinal analyses identified 4–8 h post-ingestion as the best time to detect AKIN2/3. We validated a signature of 53 microRNAs identified in the discovery, in a second cohort of individuals exposed to oxalic acid (NOAKI = 11, AKIN2 = 8 and AKIN3 = 18) and healthy controls (n = 19). Thirteen microRNAs were significantly downregulated in acute kidney injury patients compared to NOAKI within 8-h post-ingestion. Five microRNAs (miR-20a, miR-92a, miR-93, miR-195, miR-451) had a highly significant correlation with normalized urinary albumin, serum creatinine at 24 h and creatinine clearance. Logistic regression of these microRNAs had AUC-ROC of 0.85 predicting AKIN2/3 and discriminated patients from healthy controls (AUC-ROC = 0.93). mRNA targets of these microRNAs identified oxidative stress pathways of nephrotoxicity in proximal tubule and glomeruli nephrotoxicity. In conclusion, the downregulation of multiple circulating microRNAs in patients correlated with the severity of oxalic acid-induced acute kidney injury. A set of microRNAs (miR-20a, miR-92a, miR-93, miR-195, miR-451) could be promising biomarkers for early detection of oxalic acid-induced acute kidney injury.

Background:Diabetes is positively associated with various cancers, but its relationship with tumors of the esophagus/esophagogastric junction remains unclear.Methods:Data were harmonized across 13 studies in the International Barrett's and Esophageal Adenocarcinoma Consortium, comprising 2309 esophageal adenocarcinoma (EA) cases, 1938 esophagogastric junction adenocarcinoma (EGJA) cases, 1728 Barrett's esophagus (BE) cases, and 16,354 controls. Logistic regression was used to estimate study‐specific odds ratios (ORs) and 95% CIs for self‐reported diabetes in association with EA, EGJA, and BE. Adjusted ORs were then combined using random‐effects meta‐analysis.Results:Diabetes was associated with a 34% increased risk of EA (OR, 1.34; 95% CI, 1.00‐1.80; I2 = 48.8% [where 0% indicates no heterogeneity, and larger values indicate increasing heterogeneity between studies]), 27% for EGJA (OR, 1.27; 95% CI, 1.05‐1.55; I2 = 0.0%), and 30% for EA/EGJA combined (OR, 1.30; 95% CI, 1.06‐1.58; I2 = 34.9%). Regurgitation symptoms modified the diabetes‐EA/EGJA association (P for interaction = .04) with a 63% increased risk among participants with regurgitation (OR, 1.63; 95% CI, 1.19‐2.22), but not among those without regurgitation (OR, 1.03; 95% CI, 0.74‐1.43). No consistent association was found between diabetes and BE.Conclusions:Diabetes was associated with increased EA and EGJA risk, which was confined to individuals with regurgitation symptoms. Lack of an association between diabetes and BE suggests that diabetes may influence progression of BE to cancer.

– Objective: Ovarian cancer, although not possessing a high incidence, is still the most common cancer-related deaths among women diagnosed with a gynecologic malignancy. The present study aims to highlight the epidemiology, risk factors of this disease and the significance of development of improved early detection strategies. Materials and Methods: This study was conducted using current published English studies by searching PubMed and Google Scholar. The search strategy included the keywords “ovarian cancer”, “diagnosis”, “risk factors”, “screening”, “epidemiology”. Studies on incidence and mortality were also considered. Case reports were excluded.Results: The highest incidence and mortality rates are observed in Central and Eastern Europe, while rates are relatively low in Asia and Africa. These rates are highest among the white population (14.3 per 100,000) and lowest among blacks (10 per 100,000) and Asians (9.7 per 100,000). The risk factors for this disease includes a family history, hormonal factors, nutrition and diet and physical activity, with some of them playing protective roles in reducing risk of ovarian cancers. There are no reliable screening methods for ovarian cancers. The most common diagnosis methods include a transvaginal ultrasound and a blood test to detect CA125 markers.Conclusions: The mortality rate of ovarian cancer is gradually increasing; thus, preventative measures are required to reduce lifetime risk of ovarian cancers and improve mortality rate.

Background HCV-specific DAAs have transformed treatment of chronic HCV, but few studies have evaluated these therapies in children. Methods Patients aged 12–17 years old with chronic GT1 HCV were enrolled into an open-label study to receive 12 weeks of LDV/SOF 90 mg/400 mg once daily, and those with HCV GT2 or GT3 to receive SOF (400 mg once daily) + RBV (15 mg/kg/day) for 12 (GT2) or 24 weeks (GT3), respectively. Primary efficacy endpoint was SVR12. Safety was assessed by adverse events and clinical/laboratory data. Pharmacokinetic (PK) sampling was conducted to confirm the appropriateness of the doses. Results 150 adolescents (100 GT1, 13 GT2 and 37 GT3) were enrolled and treated. The majority were female (56%), white (90%), treatment naive (81%), and vertically infected (80%). The mean age was 15 years (range 12–17). LDV, SOF and GS-331007 (primary metabolite) exposures were within the range of adult exposures observed in the SOF and LDV/SOF phase 2/3 studies. The SVR12 rate was 98% in GT1, 100% in GT2 and 97% in GT3; all 3 patients who were considered not to have achieved SVR12 were lost to follow-up. No adverse event (AE) leading to study drug discontinuation or serious AEs have been reported. Conclusion In adolescents, LDV/SOF for 12 weeks and SOF + RBV for 12 or 24 weeks, resulted in a SVR12 rate of 97–100% with no virologic failures. These regimens were well tolerated, demonstrating their potential as an important treatment option for children with HCV infection.

To determine whether continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) therapy from near-diagnosis of type 1 diabetes is associated with reduced glycaemic variability (GV) and altered microRNA (miRNAs) expression. Adolescents (74% male) within 3-months of diabetes diagnosis (n = 27) were randomized to CSII (n = 12) or MDI. HbA1c, 1-5-Anhydroglucitol (1,5-AG), high sensitivity C-peptide and a custom TaqMan qPCR panel of 52 miRNAs were measured at baseline and follow-up (median (LQ-UQ); 535 (519–563) days). There were no significant differences between groups in baseline or follow-up HbA1c or C-peptide, nor baseline miRNAs. Mean ± SD 1,5-AG improved with CSII vs. MDI (3.1 ± 4.1 vs. − 2.2 ± − 7.0 mg/ml respectively, P = 0.029). On follow-up 11 miRNAs associated with diabetes vascular complications had altered expression in CSII-users. Early CSII vs. MDI use is associated with lower GV and less adverse vascular-related miRNAs. Relationships with future complications are of interest.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (&lt, 50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.

Leukocyte telomere length (LTL) is a biomarker of biological aging, and has been associated with metabolic diseases such as type 2 diabetes (T2DM). Insufficient maternal vitamin D (25(OH)D) has also been associated with increased disease risk for many diseases and adverse later life outcomes. The association between maternal and cord blood total 25(OH)D and LTL was examined in mother-child pairs from the HAPO Hong Kong Field Centre, including 815 offspring at age (mean±SD) 6.96 ± 0.44 years. LTL was measured using real-time polymerase chain reaction and serum 25(OH)D2, 25(OH)D3 and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography-mass spectrometry. Children LTL at follow-up was significantly shorter in boys compared to girls (p Disclosure K. Wong: None. B. E. Metzger: None. W. Lowe: None. W. H. Tam: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. F. Cheng: None. D. Mao: None. C. K. P. Lim: Stock/Shareholder; Self; GemVCare Ltd. R. Wang: None. C. H. Tam: None. M. A. Joglekar: None. A. A. Hardikar: None. A. Jenkins: Advisory Panel; Self; Abbott Diabetes, Sanofi-Aventis, Other Relationship; Self; Amgen Inc., Research Support; Self; Abbott, International Diabetes Federation, JDRF, Medtronic, Mylan N. V.

Introduction: Multiple case studies have reported diabetic ketoacidosis (DKA) in recently-diagnosed cancer patients, especially those taking immune checkpoint inhibitors. The prevalence of DKA and other acute diabetes complications (ADC), including hypoglycemia and hyperosmolarity, and their relationship with the onset of systemic cancer therapy is unclear. Methods: This study utilized data from n=9,588 cancer patients from the Huntsman Cancer Institute, UT. Data on clinicodemographic characteristics, biomarkers, and cancer diagnoses were extracted from electronic medical records (EMR) and tumor registry. Patients included in this analysis received an ICD diagnosis of hypoglycemia, hyperosmolarity with or without coma, and/or DKA with or without coma. Systemic therapy was defined as any chemotherapy, immunotherapy or hormone therapy resulting from a specific first primary cancer diagnosis. Results: There were 243 instances of ADC within this cohort, occurring in 211 (2.2%) unique patients. Of these 211 unique patients with an ADC, 106 (50.0%) experienced their first ADC within one year after cancer diagnosis, with a median time to ADC diagnosis of 88 days. Forty-seven (44%) of these patients experienced the ADC following the onset of systemic therapy, with a median time from systemic therapy onset to ADC diagnosis of 120 days. In these 47 patients who received an ADC diagnosis following the onset of systemic therapy, 40 (85.1%) received chemotherapy (n=20 as monotherapy), 20 (42.6%) received immunotherapy (n=4 as monotherapy) and 12 (25.5%) received hormone therapy (n=2 as monotherapy). Only 54% of patients experiencing an ADC after cancer diagnosis had a history of diabetes prior to cancer, and on average their first diabetes diagnosis was 5.4 ± 4.4 years prior to their cancer diagnosis. Discussion: ADCs may be common following a cancer diagnosis, however a substantial number occurred prior to the onset of systemic cancer therapy and in patients with no prior history of diabetes. Disclosure R. Viskochil: None. S. Hardikar: None. S. Pauleck: None. M. Winn: None. K. Funai: None. M. L. Litchman: Research Support; Self; Abbott Diabetes. W. Akerley: None. H. Colman: Advisory Panel; Self; Adastra Pharmaceuticals, Orbus Therapeutics, Consultant; Self; Best Doctors/Teladoc. C. M. Ulrich: None. M. C. Playdon: None. Funding University of Utah Health/Larry H. Miller Family Wellness Initiative

Introduction: Cancer patients are more likely to develop hyperglycemia (HG) compared to cancer-free adults, and this increased risk is highest in the year following cancer diagnosis. The persistence of post-diagnosis HG and degree of glycemic control in this population is unclear. Methods: This study utilized data from n=9,588 cancer patients from the Huntsman Cancer Institute, UT. Clinicodemographic characteristics, biomarkers, and cancer diagnoses were extracted from electronic medical records (EMR) and tumor registry. Patients with a new HG diagnosis (ICD) of any kind between 30 days and 1 year after cancer diagnosis were included. Persistence of HG was determined through elevated Hemoglobin A1c (HbA1c) and/or new anti-HG medication prescription. Patients who did not survive >1 year after cancer diagnosis or were diagnosed with cancer Results: Of the 2,964 (30.9%) cancer patients with a HG diagnosis after cancer, 26.2% (n=777) were diagnosed with HG between 30 days and 1 year after cancer diagnosis, of these n=357 met criteria for HG evaluation. Data on HbA1c and/or anti-HG medication >1 but Discussion: Taken together, 82.5% of patients diagnosed with HG in the year following a cancer diagnosis still presented with HG between one and two years post-cancer diagnosis, and there was no difference by BMI among those that did and did not receive anti-HG medications. This suggests that HG post-cancer diagnosis is not a transient effect of cancer therapy (e.g., corticosteroids), and may have long-term health implications in cancer survivors. Disclosure R. Viskochil: None. S. Hardikar: None. S. Pauleck: None. M. Winn: None. K. Funai: None. M. L. Litchman: Research Support; Self; Abbott Diabetes. W. Akerley: None. H. Colman: Advisory Panel; Self; Adastra Pharmaceuticals, Orbus Therapeutics, Consultant; Self; Best Doctors/Teladoc. C. M. Ulrich: None. M. C. Playdon: None. Funding University of Utah Health/Larry H. Miller Family Wellness Initiative

Background Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. Methods This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. Results Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03–3.58) and high cholesterol (HR 1.76; CI 1.23–2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. Conclusion For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.

For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct‐acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir‐sofosbuvir in HCV‐infected children aged 3 to

Background Women with Polycystic Ovary Syndrome (PCOS) present a heterogeneous reproductive and metabolic profile with an increased lifetime risk of Type 2 Diabetes (T2D). Early biomarkers of these metabolic disturbances in PCOS women have not been identified. The abundance of circulating insulin gene promotor cell-free DNA (INS cfDNA) was shown to be valuable as a predictive biomarker of β-cell death in individuals with Type 1 diabetes (T1D) as well as with gestational diabetes. Since β-cell death is common to the development of T1D as well as in T2D, we aimed to investigate if insulin-coding DNA is more abundant in circulation of PCOS women (vs Controls) and if their levels change after 6 yr. follow-up as a potential measure to predict future T2D. Methods A cohort of 40 women diagnosed with PCOS according to Rotterdam 2003 criteria and eight healthy controls were examined at baseline and 6 years follow-up. Clinical measurements for evaluation of glucose homeostasis as well as blood/serum samples were obtained at each visit. Methylated and unmethylated INS cfDNA were quantified using droplet digital PCR. Differences between groups were assessed using Kruskall-Wallis test and Wilcoxon Signed rank test. Results At baseline, there was no detectable difference in copy number (copies/μL) of methylated (p = 0.74) or unmethylated INS cfDNA (p = 0.34) between PCOS and Control groups. At follow up, neither methylated (p = 0.50) nor unmethylated INScfDNA levels (p = 0.48) differed significantly between these groups. Likewise, when pooling the groups, there was no difference between baseline and follow up, in terms of copies of methylated or unmethylated INS cfDNA (p = 0.38 and p = 0.52, respectively). There were no significant correlations between counts of unmethylated or methylated cfDNA and the clinical measurements of β-cell function and pre-diabetes. Conclusion The circulating level of unmethylated and methylated INScfDNA is similar between PCOS and Controls and cannot be used to predict islet β-cell loss and progression to Type 2 diabetes in a 6-year follow-up. Trial registration The Danish Data Protection Agency (REG-31-2016. Approval: 01-12-2015) and by the Danish Scientific Ethical committee of Region Zealand (Journal no. SJ-525. Approval: 13-06-2016), Clinicaltrials.gov, (NCT03142633, registered 1. March, 2017, Retrospectively registered). Electronic supplementary material The online version of this article (10.1186/s12958-019-0478-7) contains supplementary material, which is available to authorized users.

Background Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood. Patients and Methods We examined associations between Fn abundance and clinicopathologic characteristics among 105 treatment-naive CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in preoperative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption, and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models. Results Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n = 22) were 3-fold more likely to be diagnosed with rectal versus colon cancer (odds ratio [OR] = 3.01; 95% confidence interval [CI], 1.06-8.57; P = .04) after adjustment for patient sex, age, BMI, and study site. Patients with high Fn abundance also had a 5-fold increased risk of being diagnosed with rectal cancer versus right-sided colon cancer (OR = 5.32; 95% CI, 1.23-22.98; P = .03). There was no statistically significant association between Fn abundance and overall survival. Conclusion Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naive CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.

Summary Background Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. Methods ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1–18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0–4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. Findings Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference –117 μmol/L, 95% CI –232 to –2). From baseline to week 48, sBA (–96 μmol/L, –162 to –31) and pruritus (–1·6 pts, –2·1 to –1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. Interpretation In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Funding Mirum Pharmaceuticals.

Few studies have investigated the relationship between rLTL and mortality in patients with type 2 diabetes in a large prospective study, particularly in the Asian population. This study investigates the relationship between rLTL and the risk of death in Chinese patients with type 2 diabetes.Consecutive Chinese patients with type 2 diabetes (N = 5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using a quantitative polymerase chain reaction. Mortality and clinical outcomes were obtained based on ICD-9 codes.The mean (SD) age of the subjects was 57.5 (13.3) years and mean (SD) follow-up duration was 13.4 (5.5) years. Baseline rLTL was significantly shorter in the 1925 subjects who subsequently died compared with the remaining subjects (4.3 ± 1.2 vs. 4.7 ± 1.2, P 0.001). Shorter rLTL was associated with a higher risk of mortality (HR: 1.19 (1.14-1.23), P 0.001), which remained significant after adjusting for traditional risk factors.Shorter rLTL was significantly associated with an increased risk of all-cause and CVD mortality in patients with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for mortality risk in patients with type 2 diabetes.

Summary: Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91–1.29; p = 0.4) and 1.01 (95% CI, 0.78–1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.

As part of the 2019 American Society of Preventative Oncology (ASPO) annual meeting, the Early Career Investigator Special Interest Group organized a session entitled “Strategies for Success: Landing Your First Academic Position and Navigating the Early Years.”* This session was designed to provide senior doctoral students and postdoctoral fellows with strategies for preparing successful faculty job applications. Furthermore, strategies and best practices to help guide early career faculty through the initial years of their academic positions were also discussed. This report summarizes the main themes of the session, including advice and recommendations from the panelists.

OBJECTIVE Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code. RESULTS Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P < 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P < 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P < 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195–1.311], P < 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084–1.200], P < 0.001). CONCLUSIONS rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.

Telomeres are regions of repetitive nucleotide sequences at the ends of chromosomes. Telomere length is a marker of DNA damage, which is often considered a biomarker for biological ageing, and has also been linked with cardiovascular disease, diabetes, and cancer. Emerging studies have highlighted the role of genetic and environmental factors, and explored the effect of modulating telomere length. We provide an overview of studies to date on diabetes and telomere length, and compare different methods and assays for evaluating telomere length and telomerase activity. We highlight the limitations of current studies and areas that warrant further research to unravel the link between diabetes and telomere length. The value of adding telomere length to clinical risk factors to improve risk prediction of diabetes and related complications also merits further investigation.

To determine associations between physical activity (PA), sedentary behavior (SB), and oxidative stress in colorectal cancer patients, ColoCare Study participants in Germany wore an accelerometer 6 and/or 12 months after surgery. Spearman partial correlations were used to assess associations between PA and urinary concentrations of oxidized guanine, a validated marker of oxidative stress. There were no significant associations between PA or SB and oxidized guanine in n = 76 measurements (ng/mg creatinine; r = 0.03, p = 0.76 for PA, r = –0.05, p = 0.69 for SB). Novelty Objectively measured PA was not associated with a marker of oxidative stress in colorectal cancer patients.

Introduction: Acute kidney injury after cardiopulmonary bypass surgery is associated with morbidity and mortality. This study aims to evaluate the role of low perfusion flow and pressure in the development of cardiopulmonary bypass–associated acute kidney injury, stroke and death, using multicentre registry data. Methods: We identified patients from the Australian and New Zealand Collaborative Perfusion Registry who underwent coronary artery bypass grafting and/or valvular surgery between 2008 and 2018. Primary predictor variables were the length of time the perfusion flow was 2 and the length of time perfusion pressure was < 50mmHg. The primary outcome was new postoperative acute kidney injury defined by the risk-injury-failure-loss-end stage criteria. Secondary outcomes were stroke and in-hospital death. The influence of perfusion flow and pressure during cardiopulmonary bypass on the primary and secondary outcomes was estimated using separate multivariate models. Results: A total of 16,356 patients were included. The mean age was 66 years and 75% were male. Acute kidney injury was observed in 1,844 patients (11%), stroke in 204 (1.3%) and in-hospital death in 286 (1.8%). Neither the duration of the time spent for perfusion flow (2) nor the duration of the time spent for perfusion pressure (Conclusions: Neither low perfusion pressure nor low perfusion flow during cardiopulmonary bypass were predictive of postoperative acute kidney injury, stroke or death.

Background: In the light of growing global epidemic of T2D and related microvascular complications, it is important to find early detection marker for the disease. Circulating miRNAs serve as a potential biomarker for monitering the progression to DR in diabetic individuals. Hypothesis and Aims: miRNAs play a substantial role in metabolic homeostasis through regulation of multiple genes, and could serve as a prognostic biomarker in DR. This study aims to assess a functional role of selected miRNAs in the Qatari population recruited for the Qatar Genome Project through Qatar BioBank. Methods: Plasma samples from 470 T2D subjects with and without DR and 500 matched-healthy controls has been included in this study. Total RNA was extracted and the expression profiling of 56 miRNA that previously reported as a player in the pathogenesis of DR was performed using custom open array panel. The miRNA expression data were normalized using ath-mir159a. Statistical analysis was performed to study the association between the phenotypes (HbA1c, C-peptide, age, BMI) and miRNA. Results: The patients and controls phenotypic and miRNA expression data were analyzed to interepret the differential expression of the miRNA in DR subjects. Initial analysis by applying the generalized additive model reveals that six miRNA (hsa-miR-27a, hsa-miR-376c, hsa-miR-92a, hsa-miR-1 hsa-miR-223, and mmu-miR-451) were found to be significantly associated with DR (p>0.05). Furthermore, two differentially expressed miRNAs, (hsa-miR-1274A and hsa-miR-24) found to be associated with higher level of C-peptide in DR patients, which suggest the correlation of these miRNAs with the glucose hemostasis and DR. Conclusion: The etiology of DR is unclear, and present treatments have limited effectiveness. The biomarkers and downstream functional studies are required to deepen the understanding of this chronic diseases and its complications. Disclosure A.S. Akil: None. S. Subash Padmajeya: None. L.A. Jerman: None. A. Al-Kurbi: None. A.M. Hussein: None. A. Hardikar: None. M. Joglekar: None. T. Habib: None. M. El Anbari: None. K. Fakhro: None.

Type 2 diabetes (T2D) is a major cause of morbidity and death worldwide. Women with gestational diabetes mellitus (GDM) have a seven-fold higher risk of developing T2D later in life. However, accurate methods for post-partum T2D risk stratification of GDM women, are lacking. MicroRNAs are now well recognised as circulating biomarkers or mediators of metabolic disease. We aimed to determine if post-partum circulating microRNAs can predict the devolvement of T2D in women with previous GDM. Participants were part of the GDM follow-up program at the Mercy Hospital for Women, Australia. Plasma samples were collected at 12-week post-partum from 103 women following an index GDM pregnancy. Women were followed for 10 years to assess development of T2D. In a discovery approach, we measured 754 miRNAs in plasma from T2D non-progressors (N=11) and in T2D progressors (N=10) using TaqMan-based real time PCR on an OpenArray platform. Data were analysed using penalised logistic regression followed by bootstrapping. Top 15 miRNAs with high frequencies in this discovery bootstrap analysis were selected for validation in the remaining samples (N=82; 71 non-progressors and 11 progressors). Validation data were normalized to spike-in control (ath-miR-172a). Four miRNAs (miR-543, miR-410, miR-491 and miR-369-3p) were significantly dysregulated (p Disclosure M. Joglekar: None. W.K. Wong: None. F. Ema: None. H.M. Georgiou: None. A. Hardikar: None. M. Lappas: None.

PURPOSE: BRAF mutation and DNA hypermethylation have linked sessile serrated adenomas/polyps (SSA/Ps) to serrated colorectal cancer (CRC) in cross-sectional studies, but they have not been evaluated in a longitudinal study. We aimed to evaluate the associations between molecular markers of serrated polyps and subsequent advanced colorectal neoplasia. METHODS: Study subjects included Kaiser Permanente Washington members aged 20–75 years who received an index colonoscopy between 1/1/1998 and 12/31/2007 and had hyperplastic polyps (HPs) or SSA/Ps according to study pathology review. Polyps from index colonoscopies were removed and assayed for BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 methylation. Pathology reports and biopsies from the subsequent lower gastrointestinal endoscopy through 1/1/2013 were reviewed for advanced colorectal neoplasia. We identified additional incident CRC cases through linkage to the Seattle-Puget Sound Surveillance Epidemiology and End Results registry. We used generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for subsequent advanced colorectal neoplasia, comparing index serrated polyps with different molecular markers. RESULTS: We included 553 individuals with index serrated polyps (420 HPs and 133 SSA/Ps) and 795 subsequent endoscopies. The prevalence of BRAF-mutant, CIMP-high, and MLH1-methylated serrated polyps were 51%, 4%, and 2%, respectively. BRAF and CIMP were not associated with subsequent advanced colorectal neoplasia. MLH1-methylated SSP/As were significantly more likely to have subsequent advanced neoplasia (OR = 4.66, 95% CI 1.06–20.51). CONCLUSION: Our results suggest that BRAF-mutant and CIMP-high serrated polyps are not associated with subsequent advanced colorectal neoplasia. Among SSA/Ps, MLH1 methylation may be an important marker to identify high-risk CRC precursors.

Background: Alagille syndrome (ALGS) is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical sodium-dependent bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in ALGS. Methods: ICONIC was a randomized, placebo-controlled, drug-withdrawal, Phase IIb study with open-label extension in children with ALGS (NCT02160782). Eligible participants had >3x normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once daily, participants were randomized 1:1 to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat to Week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice daily. The primary endpoint was the mean sBA change during the randomized withdrawal in participants with ≥50% sBA reduction by Week 18. Cholestasis was assessed using pruritus (observer-, patient- and clinician-rated; 0-4 scale), growth and liver function. Findings: Between October 2014 and August 2015, 31 participants (mean age: 5.4 years) were enrolled and 28 analyzed at Week 48. In the randomized-withdrawal period, participants switched to placebo experienced significant increases in sBA (+94 µmol/L; p=0.0130) and pruritus (+1.7 pts; p

Inappropriate insulin secretion from β-cells is considered as an early sign of impaired glucose tolerance and type 2 diabetes (T2D). Glucokinase (GCK) is an important enzyme that regulates glucose metabolism and ensures that the normal circulating glucose concentrations are maintained. GCK expression is induced by glucose and regulated via transcription factors and regulatory proteins. Recently, microRNA-206 (miR-206) was reported to regulate GCK and alter glucose tolerance in normal and high-fat diet-fed mice. Although the study findings have implications for human diabetes, studies in human islets are lacking. Here, we analyze human islets from individuals without or with T2D, using TaqMan-based real-time qPCR at the tissue (isolated islet) level as well as at single cell resolution, to assess the relationship between miR-206 and GCK expression in normal and T2D human islets. Our data suggest that, unlike mouse islets, human islets do not exhibit any correlation between miR-206 and GCK transcripts. These data implicate the need for further studies aimed toward exploring its potential role(s) in human islets.

Background: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. Methods: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer–specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. Results: The association between minor allele of rs7200950 (ACD) with colorectal cancer–specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer–specific survival in women but not in men. Conclusions: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. Impact: Our study found a gene–smoking and gene–sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.

ObjectiveTo determine if continuous subcutaneous insulin infusion (CSII) therapy is associated with lower glycated haemoglobin (HbA1c) variability (long-term glycaemic variability; GV) relative to multiple daily injection (MDI) treatment in adults with type 1 diabetes mellitus (T1DM).DesignRetrospective audit.Setting and participantsClinic records from 506 adults with T1DM from two tertiary Australian hospitals.Outcome measuresLong-term GV was assessed by HbA1c SD and coefficient of variation (CV) in adults on established MDI or CSII therapy, and in a subset changing from MDI to CSII.ResultsAdults (n=506, (164 CSII), 50% women, mean±SD age 38.0±15.3 years, 17.0±13.7 years diabetes, mean HbA1c 7.8%±1.2% (62±13 mmol/mol) on CSII, 8.0%±1.5% (64±16 mmol/mol) on MDI) were followed for 4.1±3.6 years. CSII use was associated with lower GV (HbA1c SD: CSII vs MDI 0.5%±0.41% (6±6 mmol/mol) vs 0.7%±0.7% (9±8 mmol/mol)) and CV: CSII vs MDI 6.7%±4.6% (10±10 mmol/mol) vs 9.3%±7.3% (14±13 mmol/mol), both pConclusionsIn clinical practice with T1DM adults relative to MDI, CSII therapy is associated with lower HbA1c GV.

Greater physical activity is associated with a decrease in risk of colorectal cancer for the general population; however, little is known about its relationship with colorectal cancer risk in people with Lynch syndrome, carriers of inherited pathogenic mutations in genes affecting DNA mismatch repair (MMR). We studied a cohort of 2,042 MMR gene mutations carriers (n = 807, diagnosed with colorectal cancer), from the Colon Cancer Family Registry. Self-reported physical activity in three age-periods (20-29, 30-49 and ≥50 years) was summarized as average metabolic equivalent of task hours per week (MET-hr/week) during the age-period of cancer diagnosis or censoring (near-term exposure) and across all age-periods preceding cancer diagnosis or censoring (long-term exposure). Weighted Cox regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the association between physical activity and colorectal cancer risk. Near-term physical activity was associated with a small reduction in the risk of colorectal cancer (HR ≥35 vs.

Background: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes. Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS). Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69–0.99] and 0.76 (95% CI, 0.63–0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (Pinteraction = 0.03). Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes. Impact: Our findings support further research on whether colon cancer survival may be enhanced by physical activity. Cancer Epidemiol Biomarkers Prev; 27(6); 696–703. ©2018 AACR.

Objectives A significant proportion of children with Crohn disease develop a secondary loss of response (LOR) to infliximab. Our aim was to study the impact of initial treatment strategies on secondary LOR. Methods We reviewed the medical records of children with Crohn disease who received scheduled maintenance infliximab therapy for at least 12 months. We compared children who developed LOR with those who did not; with regards to their clinical and laboratory parameters, disease phenotype, and treatment strategy before developing LOR. Results A total of 73 children (median age at diagnosis 11 (2-16) years, 41 boys) who had received a median duration of 33 (13-110) months of infliximab therapy were included in the final analysis. LOR was seen in 25(34.2%). Demographic variables, disease phenotype (age, disease location, and behavior), inflammatory parameters, and pediatric Crohn disease activity index at induction with infliximab were similar between both groups. Children with LOR had a significantly greater number of flares of the disease when compared to those who did not have LOR (4 [1-8] vs 2 [1-5] P = 0.03). The choice of the concomitant immunomodulator-methotrexate (11/29 [37.9%]) versus azathioprine (11/36 [30.5%]) (P = 0.6) did not affect LOR rates. The median time-lag between diagnosis and induction with infliximab was significantly longer in children with LOR as compared to those who did not have an LOR (28 [4-90] months vs 12.5 [1-121] months, P = 0.004). Conclusion Early use of infliximab in pediatric Crohn disease is associated with a decrease in secondary LOR. The type of concomitant immunomodulator used does not make a difference to LOR rates.

Background Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. Methods CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. Results At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). Conclusions Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. © 2017 American Cancer Society.

Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.