Heterogeneity of glycaemic phenotypes in type 1 diabetes.

AIMS/HYPOTHESIS: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes. METHODS: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison. RESULTS: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.

Prevalence of sleep apnoea in patients with type 1 diabetes and its association with comorbidities and diabetic complications: A French nationwide prospective study.

AIM: To investigate sleep apnoea prevalence, factors influencing severity, and associations between sleep apnoea severity and micro-/macrovascular complications in a large population of patients with type 1 diabetes. MATERIALS AND METHODS: This French multicentre prospective cohort study was conducted between July 2016 and June 2020. Adults with type 1 diabetes using an insulin pump were eligible. Home care provider nurses collected demographic and clinical data and set up oximetry to determine the oxygen desaturation index (ODI). No, mild-moderate and severe sleep apnoea were defined as ODI <15 events/h, 15 to <30 events/h and ≥30 events/h, respectively. Univariate and multivariate analyses were performed to identify factors associated with sleep apnoea, and associations between sleep apnoea severity and micro-/macrovascular complications were determined using logistic regression. RESULTS: Of 769 participants, 12.4% and 3.4% had mild-to-moderate or severe sleep apnoea, respectively. Factors significantly associated with sleep apnoea on multivariate analysis were age, sex, body mass index (BMI) and hypertension. After adjustment for age, sex and BMI, presence of severe sleep apnoea was significantly associated with macrovascular complications (odds ratio vs. no sleep apnoea: 3.96 [95% confidence interval 1.43-11.11]; P < 0.01), while mild-to-moderate sleep apnoea was significantly associated with presence of diabetic retinopathy (odds ratio 2.09 [95% confidence interval 1.10-3.74]; P < 0.01). CONCLUSION: Sleep apnoea is a significant comorbidity in patients with type 1 diabetes, especially with respect to diabetic complications. This highlights the need for sleep apnoea screening and management in these individuals.

Distribution of Highly Prevalent Musculoskeletal Disorders and Their Association With Diabetes Complications in a Population of 140 Individuals With Type 1 Diabetes: A Retrospective Study in a French Diabetes Center.

Although they are usually not considered to be diabetes complications, musculoskeletal disorders (MSKDs) are common in individuals with type 1 or type 2 diabetes and can strongly interfere with daily diabetes care, especially in people using diabetes technologies. The authors of this retrospective study in a population of 140 patients with type 1 diabetes report the distribution of subtypes of MSKDs and speculate about the mechanisms involved. The authors emphasize the need for multidisciplinary care involving not only the diabetes care team but also orthopedic surgeons. This report should lead to large, prospective studies to increase knowledge about these under-studied complications.

The drugs that mostly frequently induce acute kidney injury: a case - noncase study of a pharmacovigilance database.

AIMS: Acute kidney injury (AKI) is associated with a high hospitalization rate, accelerated long-term decline in kidney function and a high mortality rate. Adverse drug reactions (ADRs) constitute one of the most important modifiable factors in the context of AKI. Most studies of drug-induced AKI have focused on a sole drug class. The objective of the present study was to establish a comprehensive overview of drug-induced AKI on the basis of spontaneously reported ADRs in the French national pharmacovigilance database (FPVD). METHODS: We performed a case-noncase study of drug-induced AKI. Cases corresponded to the reports of AKI recorded in the FPVD between 1 January 2015 and 31 December 2015. The noncases corresponded to all other spontaneously reported ADRs (excluding AKI) recorded in the FPVD during the same period. Data were expressed as the reporting odds ratio (ROR) and the 95% confidence interval. RESULTS: Of the 38 782 ADRs recorded in the FPVD during the study period, 3.2% were classified as cases of AKI. A total of 1254 patients experienced AKI (males: 55%; mean age ± standard deviation: 68.7 ± 15.0 years). Overall, 15.2% of the patients required renal replacement therapy. Two or more concomitantly administered drugs were involved in 66% of the cases of AKI. The most frequently implicated drug classes were antibacterial agents for systemic use (29.5%), diuretics (18.5%), agents acting on the renin-angiotensin system (16.3%), antineoplastic agents (10.2%) and anti-inflammatory agents (5.4%). Gentamicin, eplerenone, spironolactone, candesartan, cisplatin and acyclovir had the highest RORs (>10). CONCLUSION: A comprehensive study of a national pharmacovigilance database enabled us to identify the drug classes that most frequently induced AKI. Even though most of the identified drugs were already known to induce AKI, the present work should raise physicians' awareness of the compounds responsible for triggering this potentially life-threatening condition.

[Impact of a regional pharmacovigilance network on notification of adverse drug reactions: results at 3 years]. / Impact de la mise en place d'un réseau régional de pharmacovigilance sur la notification d'effets indésirables : bilan à 3 ans.

AIM: To stimulate spontaneous reporting of adverse drug reactions and to enable information sharing on drug's safety between Rennes Pharmacovigilance Regional Center and hospitals of its territory. METHODS: After having outlined objectives of the network to 11 major public institutions, the network was launched. It is coordinated by a dedicated pharmacist thanks to animation of monthly videoconference and diffusion of a quarterly newsletter. It relies on a local correspondent in each hospital who disseminates information to healthcare professionals and becomes their local contact for pharmacovigilance. RESULTS: The quality and usefulness of information sharing are emphasized by every one. We observed an increase in notifications and information requests multiplied by 3.4 and 2.4 % respectively between 2008 and 2013. CONCLUSIONS: The existence of a dedicated coordinator and implication of the correspondents are key elements enabling the network to be efficient. The increase of spontaneous notifications is noteworthy. The next step is to officially enlarge the network to private hospitals.

Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial.

BACKGROUND: In people with type 2 diabetes, a dipeptidyl peptidase-4 (DPP-4) inhibitor is one choice as second-line treatment after metformin, with basal insulin recommended as an alternative. We aimed to compare the efficacy, tolerability, and safety of insulin glargine and sitagliptin, a DPP-4 inhibitor, in patients whose disease was uncontrolled with metformin. METHODS: In this comparative, parallel, randomised, open-label trial, metformin-treated people aged 35-70 years with glycated haemoglobin A(1c) (HbA(1c)) of 7-11%, diagnosis of type 2 diabetes for at least 6 months, and body-mass index of 25-45 kg/m(2) were recruited from 17 countries. Participants were randomly assigned (1:1) to 24-week treatment with insulin glargine (titrated from an initial subcutaneous dose of 0·2 units per kg bodyweight to attain fasting plasma glucose of 4·0-5·5 mmol/L) or sitagliptin (oral dose of 100 mg daily). Randomisation (via a central interactive voice response system) was by random sequence generation and was stratified by centre. Patients and investigators were not masked to treatment assignment. The primary outcome was change in HbA(1c) from baseline to study end. Efficacy analysis included all randomly assigned participants who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable. This trial is registered at ClinicalTrials.gov, NCT00751114. FINDINGS: 732 people were screened and 515 were randomly assigned to insulin glargine (n=250) or sitagliptin (n=265). At study end, adjusted mean reduction in HbA(1c) was greater for patients on insulin glargine (n=227; -1·72%, SE 0·06) than for those on sitagliptin (n=253; -1·13%, SE 0·06) with a mean difference of -0·59% (95% CI -0·77 to -0·42, p<0·0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4·21 [SE 0·54] vs 0·50 [SE 0·09] events per patient-year; p<0·0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event. INTERPRETATION: Our results support the option of addition of basal insulin in patients with type 2 diabetes inadequately controlled by metformin. Long-term benefits might be expected from the achievement of optimum glycaemic control early in the course of the disease. FUNDING: Sanofi.

Occurrence and Diversity of Listeria monocytogenes Isolated from Two Pig Manure Treatment Plants in France.

The presence of Listeria monocytogenes in piggery effluents intended for irrigation crops may be a source of bacterial dissemination in agriculture. The occurrence and diversity of L. monocytogenes in the farm environment were examined in two pig manure treatment systems (S1 and S2). Samples collected over the course of one year consisted of manure, the liquid fraction of treated manure (lagoon effluent), and soil surrounding the lagoon. L. monocytogenes was enumerated using the Most Probable Number (MPN) method, serotyped by PCR, genotyped by pulsed-field gel electrophoresis (PFGE), and sequenced for multilocus sequence typing (MLST). L. monocytogenes was detected in 92% of manure samples and in approximately 50% of lagoon effluent and soil samples. Concentrations ranged between 5 and 103 MPN 100| |mL-1. Serogroups IIa, IIb, and IVb were identified. Diversity was high with 44 PFGE profiles (252 isolates) and 17 clonal complexes (CCs) (96 isolates) with higher diversity in manure at site S1 supplied by four farms. Some PFGE profiles and CCs identified in manure or in pig feces from a previous study were also detected in lagoons and/or soil, reflecting pig L. monocytogenes circulation throughout the manure treatment and in the vicinity of the sampling sites. However, some PFGE profiles and CCs were only found in the lagoon and/or in soil, suggesting an origin other than pigs. The present study highlights the limited ability of biological treatments to eliminate L. monocytogenes from pig manure. The persistence of some PFGE profiles and CCs throughout the year in the lagoon and soil shows the ability of L. monocytogenes to survive in this type of environment.

[Adverse drug reactions profiles for abiraterone and enzalutamide: A pharmacovigilance descriptive analysis]. / Profils d'effets indésirables sous abiratérone et enzalutamide : analyse descriptive des données de la base nationale de pharmacovigilance.

OBJECTIVE: The aim of this study was to describe the profile of adverse drug reactions (ADRs) observed with abiraterone and enzalutamide, based on cases registered in the French regional pharmacovigilance centres to identify potential pharmacovigilance signals. METHODS: We extracted from the French pharmacovigilance database all cases of ADRs or drug interactions involving abiraterone or enzalutamide from the time they market authorization date until December 31st, 2017. Signal detection results have been transmitted by the French Agency for Health Products (ANSM). The data were compared with those of the risk management plans for each drug and the literature. RESULTS: Among the 233 observations analyzed, nearly 62% involved abiraterone as a suspect drug and 38% involved enzalutamide; only 1 case involved both drugs. The ADRs profile is different between the drugs. Abiraterone is mostly associated with expected cardiac diseases (heart failure, and QT prolongation), expected with the drug. Also described, several cases of hepatotoxicity have been reported, however some cases with fatal outcome suggest that despite a follow-up of the liver function tests, it is difficult to anticipate this risk. Signals concerning acute renal failure and ischemic stroke have arisen. Enzalutamide is more particularly associated with various neurological disorders (convulsions, hallucinations, fatigue, and memory impairment) expected with the drug. While ischemic heart disease is also expected, signals of heart failure and atrial fibrillation have arisen. A potential hepatotoxicity of the molecule is discussed because of cases of cholestatic hepatitis. CONCLUSION: The analysis of the French pharmacovigilance database cases allows to confirm an expected and monitored risk profile in the risk management plan for both drugs. Several signals have arisen, some of which will be investigated through a pharmacoepidemiology study.

Early predictors of cardiac decompensation in experimental volume overload.

In humans, volume overload (VOL) increases the risk of sudden cardiac death, but there is also important inter-individual variability, presumably because of differences in genetic backgrounds. Although VOL has rapid effects on myocardial properties, it is not known to which extent the severity of these early responses correlate with the effect of sustained VOL on mortality. In order to test this question, we induced VOL in male rats from two genetically distinct strains [i.e., Sprague-Dawley (SD) and Wistar Kyoto-derived Hyperactive (WKHA) rats] by creating a surgical aorto-caval fistula (ACF). Only 36% of SD rats remained alive after 39 weeks of ACF, in contrast to 82% of the operated WKHA rats. We also monitored myocardial hemodynamic function, mitochondrial properties, left ventricular (LV) morphology and LV wall diastolic properties at different times ranging from 2 to 12 weeks after either ACF or sham surgery. ACF had a rapid impact on the LV walls of both rat strains, but the only variables that were affected to a greater extent in the mortality-prone SD strain were normalized LV weight, LV cavity area, and myocardial wall stiffness. In contrast, there were only marginal strain-related differences in the way ACF affected hemodynamic and mitochondrial functions. Thus, while early morphologic responses of LV walls to ACF (along with their downstream consequences on myocardial diastolic wall stress) correlated well with strain-dependent differences in late mortality, other functional changes showed no predictive effects. Close monitoring of early changes in cardiac geometry (as well as new methods to analyze myocardial diastolic strain) might, therefore, be helpful to further improve risk stratification in humans with volume overload cardiopathies.

[Pitch perception modification due to antiepileptics: A literature and pharmacovigilance databases review]. / Modification de la perception des sons sous antiépileptiques : une revue de la littérature et des bases de pharmacovigilance.

Pitch perception modifications are among the little-known adverse effects observed with antiepileptics, mainly affecting patients treated with carbamazepine (CBZ). Here, we describe an original French case of pitch perception modification due to CBZ resulting in perfect pitch loss. We also reviewed the literature as well as French and world health organisation global pharmacovigilance database. The case report concerns a 22-year-old patient with perfect pitch with untreated left temporal partial epilepsy. Following a generalized seizure, the introduction of CBZ prolonged release (200mg twice a day) is decided. As soon as CBZ is introduced, the patient notices a change in pitch perception, about a semitone lower. This adverse effect persisted despite a gradual decrease in doses. The patient reported a total recovery of his perfect pitch when CBZ stopped completely 11 years later. In the French pharmacovigilance database, only one other case of pitch perception modification under CBZ was recorded (no cases were found with oxcarbazepine, lacosamide, sodium valproate, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, ethosuximide, vigabatrine, felbamate, gabapentin, tiagabine and topiramate). In the literature, 27 cases of pitch perception modification have been published with CBZ, 1 case with oxcarbazepine and 1 case with lacosamide. Pitch perception modification is a very rare adverse effect of CBZ, oxcarbazepine and lacosamide, identified in the literature mainly in the Japanese population, in experienced musicians. A rapid onset after the introduction of treatment, a complete resolution of symptoms, in most cases upon discontinuation of treatment, is observed, with no sequelae reported. Due to the impact on quality of life, especially in patients whose profession is related to music, knowledge of this adverse event seems important to evoke this diagnosis.

Optimization of Insulin Regimen and Glucose Outcomes with Short-Term Real-Time Continuous Glucose Monitoring in Adult Type 1 Diabetes Patients with Suboptimal Control on Multiple Daily Injections: The Adult DIACCOR Study.

BACKGROUND: The impact of a 7-day real-time continuous glucose monitoring (RT-CGM) on type 1 diabetes (T1D) management remains unclear in patients suboptimally controlled by multiple daily injections (MDI). The DIACCOR Study aimed to describe treatment decisions and glucose outcomes after a short-term RT-CGM sequence. PATIENTS AND METHODS: This French multicenter longitudinal observational study included T1D patients with HbA1c >7.5% or history of severe hypoglycemia (SH) or recurrent documented hypoglycemia. A sensor was inserted at the inclusion visit, treatment changes were proposed by the investigator within 7-15 days ("INT" = MDI intensification, "CSII" = switch to continuous insulin infusion, or "ER" = educational reinforcement with no change in insulin regimen), and a 4-month follow-up visit (M4) was scheduled. RESULTS: Four hundred fifty-nine patients were recruited by 155 diabetologists, 17.0% had SH history, and 24.2% had recurrent hypoglycemia. Baseline HbA1c was 8.34% ± 1.21% (>7.5% in 79.6%). Overall, 253 (64.4%), 64 (16.3%), and 76 patients (19.3%) were, respectively, included in the "INT," "CSII," and "ER" subgroups. The number of patients who experienced SH or recurrent hypoglycemia dropped dramatically (7.9% vs. 17.0% and 10.8% vs. 24.2%, respectively). The same trend was observed for ketoacidosis and ketosis (0.3% vs. 3.3% and 2.2% vs. 4.8%). At M4, HbA1c was significantly reduced in the whole cohort to 7.98% ± 1.01% (P < 0.0001). The adjusted differences in HbA1c level in the INT, CSII, and ER subgroups were, respectively, -0.32%, -0.69%, and -0.50% (P < 0.0001 for all). CONCLUSION: In real-life setting, a 1-week diagnostic RT-CGM supports appropriate treatment changes in patients with uncontrolled T1D resulting in better glucose control and less hypoglycemia.

Cardiac mass and cardiomyocyte size are governed by different genetic loci on either autosomes or chromosome Y in recombinant inbred mice.

Left ventricular hypertrophy is one of the main risk factors for cardiovascular mortality and morbidity. It has been proposed that hypertrophic stimuli act in great part by increasing the size of cardiomyocytes, and that the latter characteristic is a necessary condition to differentiate left ventricular hypertrophy from other benign forms of cardiac enlargement. To test whether the same genetic loci control the size of cardiomyocytes and left ventricular mass, we performed whole genome linkage analyses in a panel of 24 recombinant inbred AXB/BXA mouse strains. Whereas one major locus was linked to left ventricular mass in both males and females, loci linked to the size of cardiomyocytes were clearly distinct and showed sex-specific linkage. Moreover, the parental origin of chromosome Y had strong effects on the size of cardiomyocytes in male mice but did not affect left ventricular mass. In addition to showing that genetic loci that increase the size of cardiomyocytes are not necessarily linked to increased left ventricular mass, our findings have important consequences in evaluating cardiac phenotypes when performing genetic manipulations in mice, and in determining the cause of sex-specific differences when using models derived from C57BL/6J mice.

Dissolution of particulate phosphorus in pig slurry through biological acidification: A critical step for maximum phosphorus recovery as struvite.

Recycling phosphorus as struvite from pig slurry requires an acidification step to dissolve the inorganic solids containing most of the phosphorus. This study focused on the biological acidification of several pig slurries using sucrose as a model organic co-substrate. Lactic acid fermentation occurred systematically, dissolving 60-90% of TP (total phosphorus) and T-Mg (total magnesium) at pH 6 or lower. Optimal pH range for maximum P dissolution aimed at struvite recovery was 5.5-6. A simple model was developed correlating pH, sucrose and buffer capacity to optimize P dissolution and future recovery using real organic waste.

Polyamine derivatives as selective RNaseA mimics.

Site-selective scission of ribonucleic acids (RNAs) has attracted considerable interest, since RNA is an intermediate in gene expression and the genetic material of many pathogenic viruses. Polyamine-imidazole conjugates for site-selective RNA scission, without free imidazole, were synthesized and tested on yeast phenylalanine transfer RNA. These molecules catalyze RNA hydrolysis non-randomly. Within the polyamine chain, the location of the imidazole residue, the numbers of nitrogen atoms and their relative distances have notable influence on cleavage selectivity. A norspermine derivative reduces the cleavage sites to a unique location, in the anticodon loop of the tRNA, in the absence of complementary sequence. Experimental results are consistent with a cooperative participation of an ammonium group of the polyamine moiety, in addition to it's binding to the negatively charged ribose-phosphate backbone, as proton source, and the imidazole moiety as a base. There is correlation between the location of the magnesium binding sites and the RNA cleavage sites, suggesting that the protonated nitrogens of the polycationic chain compete with some of the magnesium ions for RNA binding. Therefore, the cleavage pattern is specific of the RNA structure. These compounds cleave at physiological pH, representing novel reactive groups for antisense oligonucleotide derivatives or to enhance ribozyme activity.

Fate of Viable but Non-culturable Listeria monocytogenes in Pig Manure Microcosms.

The fate of two strains of Listeria monocytogenes and their ability to become viable but non-culturable (VBNC) was investigated in microcosms containing piggery effluents (two raw manures and two biologically treated manures) stored for 2 months at 8 and 20°C. Levels of L. monocytogenes were estimated using the culture method, qPCR, and propidium monoazide treatment combined with qPCR (qPCRPMA). The chemical composition and the microbial community structure of the manures were also analyzed. The strains showed similar decline rates and persisted up to 63 days. At day zero, the percentage of VBNC cells among viable cells was higher in raw manures (81.5-94.8%) than in treated manures (67.8-79.2%). The changes in their proportion over time depended on the temperature and on the type of effluent: the biggest increase was observed in treated manures at 20°C and the smallest increase in raw manures at 8°C. The chemical parameters had no influence on the behavior of the strains, but decrease of the persistence of viable cells was associated with an increase in the microbial richness of the manures. This study demonstrated that storing manure altered the culturability of L. monocytogenes, which rapidly entered the VBNC state, and underlines the importance of including VBNC cells when estimating the persistence of the pathogens in farm effluents.

Comparisons of chromosome Y-substituted mouse strains reveal that the male-specific chromosome modulates the effects of androgens on cardiac functions.

BACKGROUND: The C57BL/6J.YA/J mouse strain is a chromosome-substituted line where the original male-specific portion of chromosome Y (MSY) from C57BL/6J mice was substituted for that from A/J mice. In hearts from male C57BL/6J.YA/J and C57BL/6J mice, orchidectomy (ORX) affected in a strictly strain-specific fashion the expression a subset of genes showing enrichment for functional categories, including that of circadian rhythms and cardiac contractility. We further tested whether: (1) there were strain-specific differences in cardiac circadian rhythms; (2) strain-dependent differences in the effects of ORX on contractility genes translated into differences in cardiac functions; and (3) differential contractility responses occurred preferentially at times when circadian rhythms also showed strain-specific differences. METHODS: In hearts from the two above strains, we (1) profiled the expression levels of 15 circadian genes at 4-h intervals across a 24 h period; (2) tested the effects of either ORX or androgen replacement on expression of cardiac contractility genes, and that of ORX on myocardial functional reserve; and (3) verified whether the effects of MSY variants on cardiac contractility-related responses showed synchronicity with differences in circadian rhythms. RESULTS: Among the 15 tested circadian genes, a subset of them were affected by strain (and thus the genetic origin of MSY), which interacted with the amplitude of their peak of maximal expression at 2:00 PM. At that same time-point, ORX decreased (and androgen supplementation increased) the expression of three contractility-related genes, and decreased myocardial relaxation reserve in C57BL/6J.YA/J, but not in C57BL/6J mice. These effects were not detected at 10:00 AM, i.e., at another time-point when circadian genes showed no strain-specific differences. CONCLUSIONS: The results indicate that in mice, androgens have activational effects on cardiac circadian rhythms, contractile gene expression, and myocardial functional reserve. All effects occurred preferentially at the same time of the day, but varied as a function of the genetic origin of MSY. Androgens may therefore be necessary but not sufficient to impart male-specific characteristics to some particular cardiac functions, with genetic material from MSY being one other necessary factor to fully define their range of actions.

Evaluation of the Adherence to Continuous Glucose Monitoring in the Management of Type 1 Diabetes Patients on Sensor-Augmented Pump Therapy: The SENLOCOR Study.

BACKGROUND: Continuous glucose monitoring (CGM) and sensor-augmented pump (SAP) therapy improve glucose control provided good adherence. In France, not only diabetologists, nurses, and dieticians but also nurses employed by homecare providers (HCPNs) are together involved in the initiation and/or follow-up of continuous subcutaneous insulin injection (CSII) and SAP training. The SENLOCOR Study is an observational study designed to assess SAP adherence over 6 months (primary objective). Secondary objectives included the impact of SAP on metabolic control and patients' satisfaction. MATERIALS AND METHODS: CGM initiation (M0) was performed within 3 months after CSII. CGM adherence, defined by sensor wear >70% of the time, glycated hemoglobin (HbA1c) levels, and satisfaction questionnaires were collected at inclusion and at 3 (M3) and 6 (M6) months. RESULTS: The analysis population was 234 patients, including 27 children. Of the physicians, 88.0% were involved in SAP education for the whole cohort (median time, 45 min), whereas HCPNs were involved in CGM training for 190 patients (81.2%) (median time: at M0, 156 min; at M3, 20 min). Good adherence was obtained in 86.1% (M0-M3) and 68.9% (M3-M6) of the patients. The HbA1c level decreased from 8.16 ± 1.35% (M0) to 7.67 ± 1.01% (M6) in 189 patients (change, -0.48%; 95% confidence interval, -0.64, -0.33). The percentage of patients who experienced severe hypoglycemia decreased from 20.7% (M0) to 13.6% (M3) and 13.3% (M6). Satisfaction scores were high. CONCLUSIONS: In patients with type 1 diabetes, a 6-month training on SAP involving a multidisciplinary team, and especially HCPNs, improved metabolic control with a high level of adherence and satisfaction.

Association of a Network of Interferon-Stimulated Genes with a Locus Encoding a Negative Regulator of Non-conventional IKK Kinases and IFNB1.

Functional genomic analysis of gene expression in mice allowed us to identify a quantitative trait locus (QTL) linked in trans to the expression of 190 gene transcripts and in cis to the expression of only two genes, one of which was Ypel5. Most of the trans-expression QTL genes were interferon-stimulated genes (ISGs), and their expression in mouse macrophage cell lines was stimulated in an IFNB1-dependent manner by Ypel5 silencing. In human HEK293T cells, YPEL5 silencing enhanced the induction of IFNB1 by pattern recognition receptors and phosphorylation of TBK1/IKBKE kinases, whereas co-immunoprecipitation experiments revealed that YPEL5 interacted physically with IKBKE. We thus found that the Ypel5 gene (contained in a locus linked to a network of ISGs in mice) is a negative regulator of IFNB1 production and innate immune responses that interacts functionally and physically with TBK1/IKBKE kinases.

Triple combination of insulin glargine, sitagliptin and metformin in type 2 diabetes: the EASIE post-hoc analysis and extension trial.

AIM: We examined the effects of adding glargine to metformin-sitagliptin (MS+G) or sitagliptin to metformin-glargine (MG+S) therapy in type 2 diabetic persons uncontrolled after 24-week MS or MG dual therapy. METHODS: Subjects with A1c≥7% on MS or MG treatment were respectively given glargine (0.2U/kg starting dose) or sitagliptin (100mg daily) for 12weeks. The primary endpoint was number of subjects attaining A1c goal defined as <7%. RESULTS: After receiving 24-week MS or MG dual therapy in the original EASIE Study, 42% (104/248) on MS and 68% (152/224) on MG attained A1c<7% (p<0.0001). The reduction in A1c was negatively associated with baseline fasting blood glucose (FBG) only in the MG group. Reduction in A1c was not related to baseline postprandial blood glucose (PPBG) in either the MG or MS group. Amongst 194 eligible patients, 57.7% (n=111) entered the 12-week extension trial [MS+G:74/131, 57.3%; MG+S:37/63, 58.7%) with 55 (51.9%) subjects attaining goal [MS+G:59.2%; MG+S:37.1%] at week 12. The final insulin dosage was similar in both groups [MS+G: 0.46U/kg; MG+S: 0.45U/kg] with a higher rate of hypoglycemia in the MG+S (6.5 events/patient-year) than the MS+G group (3.2 events/patient-year), although neither group had severe hypoglycemia. CONCLUSION: In metformin-treated type 2 diabetes patients, high fasting BG predicted greater A1c reductions with the addition of glargine, but not with sitagliptin. In subjects uncontrolled with 6-month dual therapy of MS or MG, 50% attained A1c<7% with triple therapy of MS+G or MG+S in 12weeks. The increased rate of hypoglycemia with MG+S (but not with MS+G) underlines the need to take measures to avoid the hypoglycemia.