Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: A post-hoc analysis of a 52-week randomised trial.

AIMS: To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. METHODS: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean  ±â€¯SD age 60 ±â€¯8 years, HbA1c 7.5 ±â€¯0.9%, eGFR 86 ±â€¯16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. RESULTS: HbA1c-reductions were similar with exenatide (mean ±â€¯SEM -0.80 ±â€¯0.10%) and iGlar (-0.79 ±â€¯0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ±â€¯2.1 mL/min/1.73 m2; P = 0.069) and iGlar (-2.7 ±â€¯1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. CONCLUSIONS: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00097500.

Establishing the European diagnostic reference levels for interventional cardiology.

Interventional cardiac procedures may be associated with high patient doses and therefore require special attention to protect the patients from radiation injuries such as skin erythema, cardiovascular tissue reactions or radiation-induced cancer. In this study, patient exposure data is collected from 13 countries (37 clinics and nearly 50 interventional rooms) and for 10 different procedures. Dose data was collected from a total of 14,922 interventional cardiology procedures. Based on these data European diagnostic reference levels (DRL) for air kerma-area product are suggested for coronary angiography (CA, DRL = 35 Gy cm2), percutaneous coronary intervention (PCI, 85 Gy cm2), transcatheter aortic valve implantation (TAVI, 130 Gy cm2), electrophysiological procedures (12 Gy cm2) and pacemaker implantations. Pacemaker implantations were further divided into single-chamber (2.5 Gy cm2) and dual chamber (3.5 Gy cm2) procedures and implantations of cardiac resynchronization therapy pacemaker (18 Gy cm2). Results show that relatively new techniques such as TAVI and treatment of chronic total occlusion (CTO) often produce relatively high doses, and thus emphasises the need for use of an optimization tool such as DRL to assist in reducing patient exposure. The generic DRL presented here facilitate comparison of patient exposure in interventional cardiology.

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity.

BACKGROUND: Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics. METHODS: We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI >3 kg m-2, aged 23-36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines. RESULTS: We found 2108 genes differentially expressed (false discovery rate (FDR)<0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P<0.05) and upregulation of inflammation pathways (P<0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR<0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P<0.05). CONCLUSIONS: This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

Non-alcoholic fatty liver disease and risk of type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is commonly associated with features of the metabolic/insulin resistance syndrome ('Metabolic/Obese NAFLD') and may therefore predict type 2 diabetes (T2DM). For this review, we searched for prospective studies examining whether NAFLD predicts T2DM, and if so, whether this occurs independently of factors such as age and obesity. These studies included NAFLD diagnosed by ultrasonography (n = 6) or liver enzymes (n = 14). All ultrasonography studies found NAFLD to predict the risk of T2DM independently of age, and in 4 out of 6 studies NAFLD was also a predictor independently of BMI. NAFLD was a predictor of T2DM in all 14 studies where NAFLD was diagnosed by liver enzymes. In 12 of these studies, ALT or AST or GGT were significant predictors of T2DM risk, independently of age and BMI. NAFLD, however, is heterogeneous and may also be caused by common genetic variants. The I148M variant in PNPLA3 and the E167K variant in TM6SF2 are both associated with increased liver fat content, but not features of the metabolic/insulin resistance syndrome. These genetic forms of NAFLD predict NASH and cirrhosis but not T2DM. Taken together these data imply that 'Metabolic/Obese NAFLD' predicts T2DM independently of age and obesity and support the role of hepatic insulin resistance in the pathogenesis of this disease.

Efficacy and safety of linagliptin as add-on therapy to basal insulin and metformin in people with Type 2 diabetes.

AIM: To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin. METHODS: This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks. RESULTS: A total of 950 participants receiving background insulin and metformin were included in this subanalysis (linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (±se) change from baseline in HbA1c with linagliptin was -7 (±1) mmol/mol [-0.7 (±0.1) %; 95% CI -0.8, -0.6; P < 0.0001]. The overall frequency of drug-related adverse events (linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (±sd) body weight were noted in either group [week 52: linagliptin, -0.5 (±3.2) kg; placebo, 0.0 (±3.1) kg]. CONCLUSIONS: Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain.

Effectiveness of screening for colorectal cancer with a faecal occult-blood test, in Finland.

BACKGROUND: Screening for colorectal cancer (CRC) with guaiac-based faecal occult-blood test (FOBT) has been reported to reduce CRC mortality in randomised trials in the 1990s, but not in routine screening, so far. In Finland, a large randomised study on biennial FOB screening for CRC was gradually nested as part of the routine health services from 2004. We evaluate the effectiveness of screening as a public health policy in the largest population so far reported. METHODS: We randomly allocated (1:1) men and women aged 60-69 years to those invited for screening and those not invited (controls), between 2004 and 2012. This resulted in 180 210 subjects in the screening arm and 180 282 in the control arm. In 2012, the programme covered 43% of the target age population in Finland. RESULTS: The median follow-up time was 4.5 years (maximum 8.3 years), with a total of 1.6 million person-years. The CRC incidence rate ratio between the screening and control arm was 1.11 (95% CI 1.01 to 1.23). The mortality rate ratio from CRC between the screening and control arm was 1.04 (0.84 to 1.28), respectively. The CRC mortality risk ratio was 0.88 (0.66 to 1.16) and 1.33 (0.94 to 1.87) in males and females, respectively. CONCLUSIONS: We did not find any effect in a randomised health services study of FOBT screening on CRC mortality. The substantial effect difference between males and females is inconsistent with the evidence from randomised clinical trials and with the recommendations of several international organisations. Even if our findings are still inconclusive, they highlight the importance of randomised evaluation when new health policies are implemented. TRIAL REGISTRATION: 002_2010_august.

Characterisation of grids of point detectors in maximum skin dose measurement in fluoroscopically-guided interventional procedures.

PURPOSE: Point detectors are frequently used to measure patient's maximum skin dose (MSD) in fluoroscopically-guided interventional procedures (IP). However, their performance and ability to detect the actual MSD are rarely evaluated. The present study investigates the sampling uncertainty associated with the use of grids of point detectors to measure MSD in IP. METHOD: Chemoembolisation of the liver (CE), percutaneous coronary intervention (PCI) and neuroembolisation (NE) procedures were studied. Spatial dose distributions were measured with XR-RV3 Gafchromic(®) films for 176 procedures. These distributions were used to simulate measurements performed using grids of detectors such as thermoluminescence detectors, with detector spacing from 1.4 up to 10 cm. RESULTS: The sampling uncertainty was the highest in PCI and NE procedures. With 40 detectors covering the film area (36 cm × 44 cm), the maximum dose would be on average 86% and 63% of the MSD measured with Gafchromic(®) films in CE and PCI procedures, respectively. In NE procedures, with 27 detectors covering the film area (14 cm × 35 cm), the maximum dose measured would be on average 82% of the MSD obtained with the Gafchromic(®) films. CONCLUSION: Thermoluminescence detectors show good energy and dose response in clinical beam qualities. However the poor spatial resolution of such point-like dosimeters may far outweigh their good dosimetric properties. The uncertainty from the sampling procedure should be estimated when point detectors are used in IP because it may lead to strong underestimation of the MSD.

Characterization of XR-RV3 GafChromic(®) films in standard laboratory and in clinical conditions and means to evaluate uncertainties and reduce errors.

PURPOSE: To investigate the optimal use of XR-RV3 GafChromic(®) films to assess patient skin dose in interventional radiology while addressing the means to reduce uncertainties in dose assessment. METHODS: XR-Type R GafChromic films have been shown to represent the most efficient and suitable solution to determine patient skin dose in interventional procedures. As film dosimetry can be associated with high uncertainty, this paper presents the EURADOS WG 12 initiative to carry out a comprehensive study of film characteristics with a multisite approach. The considered sources of uncertainties include scanner, film, and fitting-related errors. The work focused on studying film behavior with clinical high-dose-rate pulsed beams (previously unavailable in the literature) together with reference standard laboratory beams. RESULTS: First, the performance analysis of six different scanner models has shown that scan uniformity perpendicular to the lamp motion axis and that long term stability are the main sources of scanner-related uncertainties. These could induce errors of up to 7% on the film readings unless regularly checked and corrected. Typically, scan uniformity correction matrices and reading normalization to the scanner-specific and daily background reading should be done. In addition, the analysis on multiple film batches has shown that XR-RV3 films have generally good uniformity within one batch (<1.5%), require 24 h to stabilize after the irradiation and their response is roughly independent of dose rate (<5%). However, XR-RV3 films showed large variations (up to 15%) with radiation quality both in standard laboratory and in clinical conditions. As such, and prior to conducting patient skin dose measurements, it is mandatory to choose the appropriate calibration beam quality depending on the characteristics of the x-ray systems that will be used clinically. In addition, yellow side film irradiations should be preferentially used since they showed a lower dependence on beam parameters compared to white side film irradiations. Finally, among the six different fit equations tested in this work, typically used third order polynomials and more rational and simplistic equations, of the form dose inversely proportional to pixel value, were both found to provide satisfactory results. Fitting-related uncertainty was clearly identified as a major contributor to the overall film dosimetry uncertainty with up to 40% error on the dose estimate. CONCLUSIONS: The overall uncertainty associated with the use of XR-RV3 films to determine skin dose in the interventional environment can realistically be estimated to be around 20% (k = 1). This uncertainty can be reduced to within 5% if carefully monitoring scanner, film, and fitting-related errors or it can easily increase to over 40% if minimal care is not taken. This work demonstrates the importance of appropriate calibration, reading, fitting, and other film-related and scan-related processes, which will help improve the accuracy of skin dose measurements in interventional procedures.

Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month extension.

AIMS: To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) over 12 months of treatment in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs (OADs). METHODS: EDITION 2 (NCT01499095) was a randomized, 6-month, multicentre, open-label, two-arm, phase IIIa study investigating once-daily Gla-300 versus Gla-100, plus OADs (excluding sulphonylureas), with a 6-month safety extension. RESULTS: Similar numbers of participants in each group completed 12 months of treatment [Gla-300, 315 participants (78%); Gla-100, 314 participants (77%)]. The reduction in glycated haemoglobin was maintained for 12 months with both treatments: least squares (LS) mean (standard error) change from baseline -0.55 (0.06)% for Gla-300 and -0.50 (0.06)% for Gla-100; LS mean difference -0.06 [95% confidence interval (CI) -0.22 to 0.10)%]. A significant relative reduction of 37% in the annualized rate of nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia was observed with Gla-300 compared with Gla-100: rate ratio 0.63 [(95% CI 0.42-0.96); p = 0.031], and fewer participants experienced ≥1 event [relative risk 0.84 (95% CI 0.71-0.99)]. Severe hypoglycaemia was infrequent. Weight gain was significantly lower with Gla-300 than Gla-100 [LS mean difference -0.7 (95% CI -1.3 to -0.2) kg; p = 0.009]. Both treatments were well tolerated with a similar pattern of adverse events (incidence of 69 and 60% in the Gla-300 and Gla-100 groups). CONCLUSIONS: In people with type 2 diabetes treated with Gla-300 or Gla-100, and non-sulphonylurea OADs, glycaemic control was sustained over 12 months, with less nocturnal hypoglycaemia in the Gla-300 group.

Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes.

AIMS: To conduct a patient-level meta-analysis of the EDITION 1, 2 and 3 studies, which compared the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) in people with type 2 diabetes (T2DM) on basal and mealtime insulin, basal insulin and oral antihyperglycaemic drugs, or no prior insulin, respectively. METHODS: The EDITION studies were multicentre, randomized, open-label, parallel-group, phase IIIa studies, with similar designs and endpoints. A patient-level meta-analysis of the studies enabled these endpoints to be examined over 6 months in a large population with T2DM (Gla-300, n = 1247; Gla-100, n = 1249). RESULTS: No significant study-by-treatment interactions across studies were found, enabling them to be pooled. The mean change in glycated haemoglobin was comparable for Gla-300 and Gla-100 [each -1.02 (standard error 0.03)%; least squares (LS) mean difference 0.00 (95% confidence interval (CI) -0.08 to 0.07)%]. Annualized rates of confirmed (≤3.9 mmol/l) or severe hypoglycaemia were lower with Gla-300 than with Gla-100 during the night (31% difference in rate ratio over 6 months) and at any time (24 h, 14% difference). Consistent reductions were observed in percentage of participants with ≥1 hypoglycaemic event. Severe hypoglycaemia at any time (24 h) was rare (Gla-300: 2.3%; Gla-100: 2.6%). Weight gain was low (<1 kg) in both groups, with less gain with Gla-300 [LS mean difference -0.28 kg (95% CI -0.55 to -0.01); p = 0.039]. Both treatments were well tolerated, with similar rates of adverse events. CONCLUSION: Gla-300 provides comparable glycaemic control to Gla-100 in a large population with a broad clinical spectrum of T2DM, with consistently less hypoglycaemia at any time of day and less nocturnal hypoglycaemia.

Indication-based national diagnostic reference levels for paediatric CT: a new approach with proposed values.

Indication-based national diagnostic reference levels (DRLs) for a few most common paediatric computed tomography (CT) examinations are proposed. Patient dose data (CTDI vol and dose length product) were collected for over 1000 patients in 4 university hospitals with best experiences in paediatric CT. Four indications for chest CT and two for abdomen (abdomen + pelvis), chest + abdomen and head CT were considered. The DRLs for the body examinations are proposed as exponential DRL-curves, where CTDI vol and dose length product are presented as a function of patient weight. The same DRL curve applies to all the indications studied. The basic 75 % level curve is supplemented by 50 % level curve to enable considerations on varying levels of technology. For head CT, DRLs are proposed for a few age groups (1, 1-5, 5-10 and 10-15 y), separately for routine CT and CT for ventricular size. The proposed DRLs are generally lower than the few published DRLs in other countries.

Collective effective dose in Europe from X-ray and nuclear medicine procedures.

Population doses from radiodiagnostic (X-ray and nuclear medicine) procedures in Europe were estimated based on data collected from 36 European countries. For X-ray procedures in EU and EFTA countries (except Liechtenstein) the collective effective dose is 547,500 man Sv, resulting in a mean effective dose of 1.06 mSv per caput. For all European countries included in the survey the collective effective dose is 605,000 man Sv, resulting in a mean effective dose of 1.05 mSv per caput. For nuclear medicine procedures in EU countries and EFTA (except Liechtenstein) countries the collective effective dose is 30,700 man Sv, resulting in a mean effective dose of 0.06 mSv per caput. For all European countries included in the survey the collective effective dose is 31,100 man Sv, resulting in a mean effective dose of 0.05 mSv per caput.

One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin: the EDITION 1 12-month randomized trial, including 6-month extension.

AIMS: To evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. METHODS: EDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. RESULTS: Of 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had ≥1 confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. CONCLUSION: During 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments.

Analysis of factors correlating with medical radiological examination frequencies.

The European Commission (EC) funded project Dose Datamed 2 (DDM2) had two objectives: to collect available data on patient doses from the radiodiagnostic procedures (X-ray and nuclear medicine) in Europe, and to facilitate the implementation of the Radiation Protection 154 Guidelines (RP154). Besides the collection of frequency and dose data, two questionnaires were issued to gather information about medical radiological imaging. This article analyses a possible correlation between the collected frequency data, selected variables from the results of the detailed questionnaire and national economic data. Based on a 35 countries dataset, there is no correlation between the gross domestic product (GDP) and the total number of X-ray examinations in a country. However, there is a significant correlation (p < 0.01) between the GDP and the overall CT examination frequency. High income countries perform more CT examinations per inhabitant. That suggests that planar X-ray examinations are replaced by CT examinations.

Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes.

AIM: To compare safety and efficacy of insulin glargine and liraglutide in patients with type 2 diabetes (T2DM). METHODS: This randomized, multinational, open-label trial included subjects treated for T2DM with metformin ± sulphonylurea, who had glycated haemoglobin (HbA1c) levels of 7.5-12%. Subjects were assigned to 24 weeks of insulin glargine, titrated to target fasting plasma glucose of 4.0-5.5 mmol/L or liraglutide, escalated to the highest approved clinical dose of 1.8 mg daily. The trial was powered to detect superiority of glargine over liraglutide in percentage of people reaching HbA1c <7%. RESULTS: The mean [standard deviation (s.d.)] age of the participants was 57 (9) years, the duration of diabetes was 9 (6) years, body mass index was 31.9 (4.2) kg/m(2) and HbA1c level was 9.0 (1.1)%. Equal numbers (n = 489) were allocated to glargine and liraglutide. Similar numbers of subjects in both groups attained an HbA1c level of <7% (48.4 vs. 45.9%); therefore, superiority of glargine over liraglutide was not observed (p = 0.44). Subjects treated with glargine had greater reductions of HbA1c [-1.94% (0.05) and -1.79% (0.05); p = 0.019] and fasting plasma glucose [6.2 (1.6) and 7.9 (2.2) mmol/L; p < 0.001] than those receiving liraglutide. The liraglutide group reported a greater number of gastrointestinal treatment-emergent adverse events (p < 0.001). The mean (s.d.) weight change was +2.0 (4.0) kg for glargine and -3.0 (3.6) kg for liraglutide (p < 0.001). Symptomatic hypoglycaemia was more common with glargine (p < 0.001). A greater number of subjects in the liraglutide arm withdrew as a result of adverse events (p < 0.001). CONCLUSION: Adding either insulin glargine or liraglutide to subjects with poorly controlled T2DM reduces HbA1c substantially, with nearly half of subjects reaching target levels of 7%.

Measurement of maximum skin dose in interventional radiology and cardiology and challenges in the set-up of European alert thresholds.

To help operators acknowledge patient dose during interventional procedures, EURADOS WG-12 focused on measuring patient skin dose using XR-RV3 gafchromic films, thermoluminescent detector (TLD) pellets or 2D TL foils and on investigating possible correlation to the on-line dose indicators such as fluoroscopy time, Kerma-area product (KAP) and cumulative air Kerma at reference point (CK). The study aims at defining non-centre-specific European alert thresholds for skin dose in three interventional procedures: chemoembolization of the liver (CE), neuroembolization (NE) and percutaneous coronary interventions (PCI). Skin dose values of >3 Gy (ICRP threshold for skin injuries) were indeed measured in these procedures confirming the need for dose indicators that correlate with maximum skin dose (MSD). However, although MSD showed fairly good correlation with KAP and CK, several limitations were identified challenging the set-up of non-centre-specific European alert thresholds. This paper presents preliminary results of this wide European measurement campaign and focuses on the main challenges in the definition of European alert thresholds.

Comparison of proctocolectomy and ileal pouch-anal anastomosis to colectomy and ileorectal anastomosis in familial adenomatous polyposis.

Prophylactic surgical options for familial adenomatous polyposis (FAP) are either colectomy and ileorectal anastomosis (IRA) or proctocolectomy and ileal pouch-anal anastomosis (IPAA). The aim of this study was to analyse the short-term and long-term outcomes of these two operative techniques. All patients with FAP in Finland have been prospectively recorded in a database since 1963 were retrospectively reviewed in this analysis. Altogether 140 (61%) colectomies with IRA and 88 (39%) proctocolectomies with IPAA have been performed. Complications occurred in 28 (21%) patients after IRA and in 26 (30%) patients after IPAA. There were 15 (11%) severe complications for IRA and 5 (6%) for IPAA. Twenty-one (15%) patients of the IRA group ended up in conventional ileostomy whereas 3 (3.4%) patients of the IPAA group had their ileal reservoir converted to an ileostomy (p = 0.01). Cumulative survival for IRA was lower than for the IPAA (p = 0.03), but if accounting only for operations made after the IPAA era had commenced, there was no significant difference. IPAA was associated with improved long-term survival without an increase in postoperative complications. The risk of death after colectomy and IRA seemed to be predominantly related to the remaining risk of rectal cancer. Therefore, we favour proctocolectomy with IPAA as the prophylactic surgical procedure for FAP with intermediate or severe polyposis.

Identification of 33 candidate oncogenes by screening for base-specific mutations.

BACKGROUND: Genes with recurrent codon-specific somatic mutations are likely drivers of tumorigenesis and potential therapeutic targets. Hypermutable cancers may represent a sensitive system for generation and selection of oncogenic mutations. METHODS: We utilised exome-sequencing data on 25 sporadic microsatellite-instable (MSI) colorectal cancers (CRCs) and searched for base-specific somatic mutation hotspots. RESULTS: We identified novel mutation hotspots in 33 genes. Fourteen genes displayed mutations in the validation set of 254 MSI CRCs: ANTXR1, MORC2, CEP135, CRYBB1, GALNT9, KRT82, PI15, SLC36A1, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1 and TTPAL. A database search found examples of the hotspot mutations in multiple cancer types. CONCLUSIONS: This work reveals a variety of new recurrent candidate oncogene mutations to be further scrutinised as potential therapeutic targets.

Risk of cancer and secondary proctectomy after colectomy and ileorectal anastomosis in familial adenomatous polyposis.

PURPOSE: The aim of our retrospective study was to review the outcome of patients undergoing colectomy with ileorectal anastomosis (IRA) due to familial adenomatous polyposis (FAP) in Finland during the last 50 years. METHODS: The cumulative risk of rectal cancer and the rate of anus preservation were analyzed. A total of 140 FAP patients with previous colectomy combined with ileorectal anastomosis were included. Kaplan-Meier analysis was performed to evaluate cumulative risks. RESULTS: Secondary proctectomy was performed for 39 (28 %) of 140 patients. The cumulative risk of secondary proctectomy was 53 % at 30 years after colectomy with IRA. A total of 17 (44 %) secondary proctectomies were performed due to cancer or suspicion of cancer, and another 17 (44 %) secondary proctectomies were performed due to uncontrollable rectal polyposis. During our study, the anus preservation rate in secondary proctectomies was 49 %. The cumulative risk of rectal cancer was 24 % at 30 years after colectomy with IRA. Therefore, the cumulative rectal cancer mortality 30 years after colectomy with IRA was 9 %. CONCLUSIONS: Proctocolectomy and ileal pouch-anal anastomosis (IPAA) should be favored as a primary operation for patients not having technical or medical contraindications for it because colectomy with IRA carried a rectal cancer risk of 13 % with a mortality of 7 % during our study, and because IPAA is likely to succeed better at earlier phase of the disease. Patients with attenuated FAP had no rectal cancer in our study, and they may form a group where IRA should still be the first choice as an exception.

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3.

AIMS/HYPOTHESIS: The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant ('PNPLA3 NAFLD' = PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity ('obese NAFLD'). METHODS: Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat ((1)H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2 ± 0.7 kg/m(2); non-obese 26.0 ± 0.4 kg/m(2)) or PNPLA3 genotype. All groups were similar with respect to age and sex. The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1 ± 1.3 kg/m(2); PNPLA3-148II, 31.2 ± 0.8 kg/m(2)), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR. RESULTS: Liver fat was similarly increased in obese NAFLD (9.5 ± 1.3% vs 5.1 ± 0.9%, obese vs non-obese, p = 0.007) and PNPLA3 NAFLD (11.4 ± 1.7% vs 5.3 ± 0.8%, PNPLA3-148MM vs PNPLA3-148II, p < 0.001). Fasting serum insulin was higher in the obese than the non-obese group (76 ± 6 vs 47 ± 6 pmol/l, p < 0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60 ± 8 vs 62 ± 5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups. CONCLUSIONS/INTERPRETATION: PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features.