Long-acting exenatide does not prevent cognitive decline in mild cognitive impairment: a proof-of-concept clinical trial.

PURPOSE: According to preclinical evidence, GLP-1 receptor may be an actionable target in neurodegenerative disorders, including Alzheimer's disease (AD). Previous clinical trials of GLP-1 receptor agonists were conducted in patients with early AD, yielding mixed results. The aim was to assess in a proof-of-concept study whether slow-release exenatide, a long-acting GLP-1 agonist, can benefit the cognitive performance of people with mild cognitive impairment (MCI). METHODS: Thirty-two (16 females) patients were randomized to either slow-release exenatide (n = 17; 2 mg s.c. once a week) or no treatment (n = 15) for 32 weeks. The primary endpoint was the change in ADAS-Cog11 cognitive test score at 32 weeks vs baseline. Secondary endpoints herein reported included additional cognitive tests and plasma readouts of GLP-1 receptor engagement. Statistical analysis was conducted by intention to treat. RESULTS: No significant between-group effects of exenatide on ADAS-Cog11 score (p = 0.17) were detected. A gender interaction with treatment was observed (p = 0.04), due to worsening of the ADAS-Cog11 score in women randomized to exenatide (p = 0.018), after correction for age, scholar level, dysglycemia, and ADAS-Cog score baseline value. Fasting plasma glucose (p = 0.02) and body weight (p = 0.03) decreased in patients randomized to exenatide. CONCLUSION: In patients with MCI, a 32-week trial with slow-release exenatide had no beneficial effect on cognitive performance. TRIAL REGISTRATION NUMBER: NCT03881371, registered on 21 July, 2016.

Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience.

INTRODUCTION: Mitochondrial fatty acid oxidation disorders (FAODs) are a heterogeneous group of hereditary autosomal recessive diseases included in newborn screening (NBS) program in Italy. The aim of this study was to analyse FAODs cases, identified either clinically or by NBS,for clinical and genetic characterization and to evaluate a five years' experience of NBS, in the attempt to figure out the complexity of genotype-phenotype correlation and to confirm the clinical impact of NBS in our centre experience. MATERIALS AND METHODS: We analysed FAODs patients diagnosed either by NBS or clinically, followed since February 2014 to April 2019 at the Regional Screening Centre and Inherited Metabolic Diseases Unit of Verona. Diagnosis was confirmed by plasma acylcarnitines, urinary organic acids, enzymatic and genetic testing. For not clear genotypes due to the presence of variants of uncertain significance, in silico predictive tools have been used as well as enzymatic activity assays. Patients underwent clinical, nutritional and biochemical follow up. RESULTS: We diagnosed 30 patients with FAODs. 20 by NBS: 3 CUD, 6 SCADD, 5 MCADD, 4 VLCADD, 2 MADD. Overall incidence of FAODs diagnosed by NBS was 1:4316 newborns. No one reported complications during the follow up period. 10 patients were diagnosed clinically: 2 CUD, 2 CPT2D, 1 VLCADD, 5 MADD. Mean age at diagnosis was 29.3 years. Within this group, complications or symptoms were reported at diagnosis, but not during follow-up. 12 mutations not previously reported in literature were found, all predicted as pathogenic or likely pathogenic. DISCUSSION AND CONCLUSIONS: Our study highlighted the great phenotypic variability and molecular heterogeneity of FAODs and confirmed the importance of a tailored follow up and treatment. Despite the short duration of follow up, early identification by NBS prevented diseases related complications and resulted in normal growth and psycho-motor development as well.

Asthma diagnosis in infants and preschool children: a systematic review of clinical guidelines.

BACKGROUND AND AIM: The definition and diagnosis of asthma are the subject of controversy that is particularly intense in the case of individuals in the first years of life, due to reasons such as the difficulty of performing objective pulmonary function tests or the high frequency with which the symptoms subside in the course of childhood. Since there is no consensus regarding the diagnosis of asthma in preschool children, a systematic review has been carried out. MATERIALS AND METHODS: A systematic search was made of the clinical guidelines published in the last 10 years and containing information referred to the concept or diagnosis of asthma in childhood - including the first years of life (infants and preschool children). A series of key questions were established, and each selected guide was analyzed in search of answers to those questions. The review protocol was registered in the international prospective register of systematic reviews (PROSPERO), with registration number CRD42017074872. RESULTS: Twenty-one clinical guidelines were selected: 10 general guides (children and adults), eight pediatric guides and three guides focusing on preschool children. The immense majority accepted that asthma can be diagnosed from the first years of life, without requiring pulmonary function tests or other complementary techniques. The response to treatment and the exclusion of other alternative diagnoses are key elements for establishing the diagnosis. Only one of the guides denied the possibility of diagnosing asthma in preschool children. CONCLUSIONS: There is generalized although not unanimous agreement that asthma can be diagnosed in preschool children.

A Markov state modeling analysis of sliding dynamics of a 2D model.

Non-equilibrium Markov State Modeling (MSM) has recently been proposed by Pellegrini et al. [Phys. Rev. E 94, 053001 (2016)] as a possible route to construct a physical theory of sliding friction from a long steady state atomistic simulation: the approach builds a small set of collective variables, which obey a transition-matrix-based equation of motion, faithfully describing the slow motions of the system. A crucial question is whether this approach can be extended from the original 1D small size demo to larger and more realistic size systems, without an inordinate increase of the number and complexity of the collective variables. Here we present a direct application of the MSM scheme to the sliding of an island made of over 1000 harmonically bound particles over a 2D periodic potential. Based on a totally unprejudiced phase space metric and without requiring any special doctoring, we find that here too the scheme allows extracting a very small number of slow variables, necessary and sufficient to describe the dynamics of island sliding.

The surgical experience influences the safety of retrograde intrarenal surgery for kidney stones: a propensity score analysis.

The aim of this study is to evaluate if surgical experience could influence the outcomes of retrograde intrarenal surgery (RIRS) in terms of stone clearance and complication rate. Patients from five institutions were included in this study. Patients were divided into two groups. Group 1: patients treated by three surgeons in the early phase of learning curve (surgical experience <100 procedures); Group 2: cases operated by two surgeons with great endourological experience (>400 procedures). Patients and stone characteristics, outcome and complications were analyzed. Multivariable regression model was used. Differences between groups were estimated using propensity scores to adjust for the bias inherent to the different characteristics. 381 RIRS were analyzed (Group 1: 150 RIRS; Group 2: 231 RIRS). Clinical data and stone parameters were comparable. The SFR was 70 % in Group 1 and 77.9 % in Group 2 (p = 0.082). Operative time was significantly shorter in the Group 2 (76.3 vs. 53.1 min, p = 0.001). The overall complication rate was significantly lower in Group 2 (20.7 vs. 8.7, p = 0.001). At unadjusted analysis, a non-significant difference was found between centers on SFR (OR 1.51 95 % CI 0.95-2.41). Conversely, a significant difference was found on overall complications (OR 0.36 95 %CI 0.20-0.67) with lower overall complication in Group 2. This study shows that surgeon experience influences the outcomes of RIRS mainly in terms of safety. Further studies will be needed to assess the exact number of procedures necessary to obtain a plateau in the rate of complications and success.

Markov state modeling of sliding friction.

Markov state modeling (MSM) has recently emerged as one of the key techniques for the discovery of collective variables and the analysis of rare events in molecular simulations. In particular in biochemistry this approach is successfully exploited to find the metastable states of complex systems and their evolution in thermal equilibrium, including rare events, such as a protein undergoing folding. The physics of sliding friction and its atomistic simulations under external forces constitute a nonequilibrium field where relevant variables are in principle unknown and where a proper theory describing violent and rare events such as stick slip is still lacking. Here we show that MSM can be extended to the study of nonequilibrium phenomena and in particular friction. The approach is benchmarked on the Frenkel-Kontorova model, used here as a test system whose properties are well established. We demonstrate that the method allows the least prejudiced identification of a minimal basis of natural microscopic variables necessary for the description of the forced dynamics of sliding, through their probabilistic evolution. The steps necessary for the application to realistic frictional systems are highlighted.

Noncontact Atomic Force Microscope Dissipation Reveals a Central Peak of SrTiO_{3} Structural Phase Transition.

The critical fluctuations at second order structural transitions in a bulk crystal may affect the dissipation of mechanical probes even if completely external to the crystal surface. Here, we show that noncontact force microscope dissipation bears clear evidence of the antiferrodistortive phase transition of SrTiO_{3}, known for a long time to exhibit a unique, extremely narrow neutron scattering "central peak." The noncontact geometry suggests a central peak linear response coupling connected with strain. The detailed temperature dependence reveals for the first time the intrinsic central peak width of order 80 kHz, 2 orders of magnitude below the established neutron upper bound.

Clinically stable very low birthweight infants are at risk for recurrent tissue glucose fluctuations even after fully established enteral nutrition.

OBJECTIVE: In previous cases, we have observed occasional hypoglycaemic episodes in preterm infants after initial intensive care. In this prospective study, we determined the frequency and severity of abnormal tissue glucose (TG) in clinically stable preterm infants on full enteral nutrition. METHODS: Preterm infants born at <1000 g (n=23; G1) and birth weight 1000-1500 g (n=18; G2) were studied at a postmenstrual age of 32±2 weeks (G1) and 33±2 weeks (G2). Infants were fed two or three hourly, according to a standard bolus-nutrition protocol, and continuous subcutaneous glucose measurements were performed for 72 h. Normal glucose values were assumed at ≥2.5 mmol/L (45 mg/dL) and ≤8.3 mmol/L (150 mg/dL). Frequency, severity and duration of glucose values beyond normal values were determined. RESULTS: We observed asymptomatic low TG values in 39% of infants in G1 and in 44% in G2. High TG values were detected in 83% in G1 and 61% in G2. Infants in G1 experienced prolonged and more severe low TG episodes, and also more frequent and severe high TG episodes. In G1 and G2, 87% and 67% of the infants, respectively, showed glucose fluctuations characterised by rapid glucose increase followed by a rapid glucose drop after feeds. In more mature infants, glucose fluctuations were less pronounced and less dependent on enteral feeds. CONCLUSIONS: Clinically stable well-developing preterm infants beyond their initial period of intensive care show interstitial glucose instabilities exceeding values as low as 2.5 mmol/L and as high as 8.3 mmol/L. This novel observation may play an important role for the susceptibility of these high-risk infants for the development of the metabolic syndrome. TRIAL REGISTRATION NUMBER: German trial registration number DRKS00004590.

Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To evaluate whether cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels could predict the time to generalization (TTG) in amyotrophic lateral sclerosis (ALS). METHODS: Cerebrospinal fluid NFL levels of 37 cases of sporadic ALS were measured and the time of symptom spreading from spinal or bulbar localization to both (TTG) was evaluated in all patients. RESULTS: Kaplan-Meier analysis showed a short TTG in patients with high NFL levels (log-rank test chi-squared = 19.4, P < 0.0001). In a multivariate regression model patients with NFL levels above the median had an eight-fold higher risk of generalization (adjusted hazard ratio 7.9, 95% confidence interval 2.9-21.4, P < 0.0001) compared with those with NFL levels below the median. CONCLUSIONS: This study shows that in sporadic ALS NFL, a marker of neurodegeneration, is correlated with TTG, a clinical intermediate parameter of survivorship.

Metabolomics signature improves the prediction of cardiovascular events in elderly subjects.

AIMS: Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors. METHODS AND RESULTS: Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n = 67, mean age = 85 ± 3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models. At follow-up (median = 3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence = 7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR = 1.77 (95%CI = 1.11-2.81, p = 0.016) and HR = 2.18 (95%CI = 1.17-4.07, p = 0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 7%, p = 0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI = 0.79 (p = 0.005). CONCLUSIONS: Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors.

Severe hypoglycemia and ketoacidosis over one year in Italian pediatric population with type 1 diabetes mellitus: a multicenter retrospective observational study.

BACKGROUND AND AIMS: Evaluation of incidence and correlates of severe hypoglycemia (SH) and diabetes ketoacidosis (DKA) in children and adolescents with T1DM. METHODS AND RESULTS: Retrospective study conducted in 29 diabetes centers from November 2011 to April 2012. The incidence of SH and DKA episodes and their correlates were assessed through a questionnaire administered to parents of patients aged 0-18 years. Incidence rates and incident rate ratios (IRRs) were estimated through multivariate Poisson regression analysis and multilevel analysis. Overall, 2025 patients were included (age 12.4 ± 3.8 years; 53% males; diabetes duration 5.6 ± 3.5 years; HbA1c 7.9 ± 1.1%). The incidence of SH and DKA were of 7.7 and 2.4 events/100 py, respectively. The risk of SH was higher in females (IRR = 1.44; 95%CI 1.04-1.99), in patients using rapid acting analogues as compared to regular insulin (IRR = 1.48; 95%CI 0.97-2.26) and lower for patients using long acting analogues as compared to NPH insulin (IRR = 0.40; 95%CI 0.19-0.85). No correlations were found between SH and HbA1c levels. The risk of DKA was higher in patients using rapid acting analogues (IRR = 4.25; 95%CI 1.01-17.86) and increased with insulin units needed (IRR = 7.66; 95%CI 2.83-20.74) and HbA1c levels (IRR = 1.63; 95%CI 1.36-1.95). Mother's age was inversely associated with the risk of both SH (IRR = 0.95; 95%CI 0.92-0.98) and DKA (IRR = 0.94; 95%CI 0.88-0.99). When accounting for center effect, the risk of SH associated with the use of rapid acting insulin analogues was attenuated (IRR = 1.48; 95%CI 0.97-2.26); 33% and 16% of the residual variance in SH and DKA risk was explained by center effect. CONCLUSION: The risk of SH and DKA is mainly associated with treatment modalities and strongly depends on the practice of specialist centers.

Improving quality of care in people with Type 2 diabetes through the Associazione Medici Diabetologi-annals initiative: a long-term cost-effectiveness analysis.

AIMS: The Associazione Medici Diabetologi-annals initiative is a physician-led quality-of-care improvement scheme that has been shown to improve HbA1c concentration, blood pressure, lipid profiles and BMI in enrolled people with Type 2 diabetes. The present analysis investigated the long-term cost-effectiveness of enrolling people with Type 2 diabetes in the Associazione Medici Diabetologi-annals initiative compared with conventional management. METHODS: Long-term projections of clinical outcomes and direct costs (in 2010 Euros) were made using a published and validated model of Type 2 diabetes in people with Type 2 diabetes who were either enrolled in the Associazione Medici Diabetologi-annals initiative or who were receiving conventional management. Treatment effects were based on mean changes from baseline seen at 5 years after enrolment in the scheme. Costs and clinical outcomes were discounted at 3% per annum. RESULTS: The Associazione Medici Diabetologi-annals initiative was associated with improvements in mean discounted life expectancy and quality-adjusted life expectancy of 0.55 years (95% CI 0.54-0.57) years and 0.48 quality-adjusted life years (95% CI 0.46-0.49), respectively, compared with conventional management. Whilst treatment costs were higher in the Associazione Medici Diabetologi-annals arm, this was offset by savings as a result of the reduced incidence and treatment of diabetes-related complications. The Associazione Medici Diabetologi-annals initiative was found to be cost-saving over patient lifetimes compared with conventional management [€ 37,289 (95% CI 37,205-37,372) vs € 41,075 (95% CI 40,956-41,155)]. CONCLUSIONS: Long-term projections indicate that the physician-led Associazione Medici Diabetologi-annals initiative represents a cost-saving method of improving long-term clinical outcomes compared with conventional management of people with Type 2 diabetes in Italy.

The SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.

BACKGROUND/AIMS: The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association. METHODS: The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448). RESULTS: Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05). CONCLUSION: Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH.

Association of dietary patterns with insulin resistance and clinically silent carotid atherosclerosis in apparently healthy people.

BACKGROUND/OBJECTIVES: Dietary habits are important determinants of individual cardiovascular and metabolic risk. This study investigated the association between dietary patterns and asymptomatic carotid atherosclerosis, defined as the presence of plaques and/or increased intima-media thickness, and metabolic biomarkers of insulin resistance, including the homeostasis model assessment of insulin resistance (HOMA-IR) and the trygliceride/high-density lipoprotein (HDL)-cholesterol (Tg/HDL) ratio in a cohort of adults without known diabetes or atherosclerotic cardiovascular disease. SUBJECTS/METHODS: Nine hundred and twenty-nine randomly selected participants were cross-sectionally investigated. Each participant answered a food frequency questionnaire, and underwent high-resolution ultrasonographic evaluation of both carotid arteries. Laboratory blood measurements were obtained in a subsample of 507 participants. RESULTS: A dietary pattern that could be defined as unhealthy (high consumption of soft drinks, fried foods, seed oils, cured meats, butter, red meat and sweets) was identified in 21% of the cohort, whereas 34% of the cohort exhibited a dietary pattern that resembled the Mediterranean diet (high intakes of fruit, milk and cheese, olive oil, vegetables, pasta and bread). Intermediate habits characterized the remaining 45%. After adjusting for age, body mass index (BMI), waist circumference, glycated hemoglobin (HbA1c) and hypertension on treatment, the Mediterranean dietary pattern was associated with significantly lower HOMA-IR (ß-coefficient=-0.51; P=0.003). After adjusting for gender, BMI and HbA1c, the unhealthy dietary pattern was associated with a significantly higher Tg/HDL-cholesterol ratio (ß-coefficient=0.43; P=0.006). No significant association was found between dietary patterns and carotid atherosclerosis. CONCLUSIONS: This study suggests that, independent of measures of adiposity, a Mediterranean dietary pattern is associated with lower insulin resistance.

Role of obesity on all-cause mortality in whites with type 2 diabetes from Italy.

Mortality rate of diabetic patients is twice as much that of non-diabetic individuals. The role of obesity on mortality risk in patients with type 2 diabetes is controversial. Aim of our study was to address the relationship between obesity and all-cause mortality in a real-life set of white patients with type 2 diabetes from central-southern Italy from the Gargano Mortality Study (GMS). In addition, we used genetic data from genome-wide association studies (GWAs)-derived single nucleotide polymorphisms (SNPs) firmly associated with body mass index (BMI), in order to investigate the intrinsic nature of reduced mortality rate we, in fact, observed in obese patients. Study subjects with type 2 diabetes (n = 764) are part of the GMS, which is aimed at unraveling predictors of incident all-cause mortality. Time-to-death analyses were performed by Cox regression. Association between genotype risk score and obesity was tested by logistic regression. Of the 32 SNPs firmly associated with BMI, we investigated those with BMI ß value ≥0.10 kg/m(2) and allele frequency ≥10 %. Genotyping was performed by KBioscience (http://www.lgcgenomics.com/). In GMS, obesity predicted a 45 % reduction in all-cause mortality. Individuals with high "obesity genetic load" (i.e., those carrying >9 risk alleles) were 60 % more likely to be obese as compared to individuals with low "obesity genetic load." Most importantly, mortality rate was not different in individuals with high and low "obesity genetic load," thus indicating no role of obesity genes on all-cause mortality and speaking against a cause-effect relationship underlying the association between obesity and reduced mortality rate.

[Effects of dose of erythropoiesis stimulating agents on cardiovascular outcomes, quality of life and costs of haemodialysis. the clinical evaluation of the DOSe of erythropoietins (C.E. DOSE) Trial]. / Effetti della dose degli agenti stimolanti l'eritropoiesi su esiti cardio-cerebrovascolari, qualità di vita e costi in emodialisi.

BACKGROUND: Anaemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are the most used treatment option. In observational studies, higher haemoglobin (Hb) levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to Hb levels around 9-10 g/dL. Randomized studies found that targeting higher Hb levels with ESA causes an increased risk of death, mainly due to adverse cardiovascular outcomes. It is possible that this is mediated by ESA dose rather than haemoglobin concentration, although this hypothesis has never been formally tested. METHODS: We present the protocol of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial, which will assess the benefits and harms of a high versus a low ESA dose therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD). This is a randomized, prospective open label blinded end-point (PROBE) design trial due to enroll 900 haemodialysis patients. Patients will be randomized 1:1 to 4000 UI/week i. v. versus 18000 UI/week i. v. of epoetin alfa, beta or any other epoetin in equivalent doses. The primary outcome of the trial is a composite of cardiovascular events. In addition, quality of life and costs of these two strategies will be assessed. The study has been approved and funded by the Italian Agency of Drugs (Agenzia Italiana del Farmaco (AIFA)) within the 2006 funding plan for independent research on drugs (registered at www.clinicaltrials.gov (NCT00827021)).

The impact of neutralizing antibodies on the risk of disease worsening in interferon ß-treated relapsing multiple sclerosis: a 5 year post-marketing study.

The impact of neutralizing antibodies (NAbs) on interferon ß (IFNß) efficacy in MS patients is still an object of controversy. To evaluate the clinical response to IFNß during NAb-positive (NAb+) and NAb-negative (NAb-) statuses on a large population of relapsing remitting (RR) MS patients were followed up to 5 years. Sera from 567 RR MS patients treated with IFNß for 2-5 years were collected every 6-12 months and evaluated for NAb presence by a cytopathic effect assay. The relapse rate and expanded disability status scale (EDSS) score were assessed at baseline and every 6 months for each patient. A NAb+ status was defined after two consecutive positive titers of NAbs >/= 20 neutralizing units (NU)/mL. Multivariate models were used to analyze the relapse rate, the time to first relapse, the time to confirmed EDSS score 4 during NAb+ and NAb- statuses. A propensity score (PS) matching analysis was performed to assess the robustness of the multivariate models. Fourteen percent of patients became NAb+ during the follow-up. A significant increase of the relapse rate (IRR = 1.38; p = 0.0247) and decrease of the time to 1st relapse (IRR = 1.51; p = 0.0111) were found during NAb+ periods. The PS matching analysis, in a selected cohort of patients, demonstrated a negative trend of NAbs on the time to reach the milestone EDSS 4 (IRR = 2.94; p = 0.0879). This long-term post-marketing observational study further confirms that the occurrence of NAbs significantly affects the risk of disease worsening in IFNß- treated RRMS.

The ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K121Q polymorphism modulates the beneficial effect of weight loss on fasting glucose in non-diabetic individuals.

BACKGROUND AND AIMS: Several studies have reported that the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) K121Q polymorphism (rs1044498) interacts with increased adiposity in affecting glucose homeostasis and insulin sensitivity. Conversely, one would expect that the amelioration of glucose homeostasis observed after weight loss is modulated by the ENPP1 K121Q polymorphism. The aim of our study was to test such hypothesis, in non-diabetic overweight-obese individuals. METHODS AND RESULTS: Two hundred eleven non-diabetic overweight-obese individuals were studied. Body mass index (BMI), fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR index) and lipid levels were obtained before and after 6-week lifestyle intervention (LI; diet and exercise) and their changes calculated as baseline minus 6-week values. LI decreased BMI, glucose, HOMA-IR and triglyceride levels (p < 0.001 for all). No difference across genotype groups (160 KK and 51 KQ or QQ - named as XQ - individuals) was observed in these changes. In a multivariate model, BMI changes predicted fasting glucose changes (ß = 0.139 mmol/L (2.50 mg/dl) for 1 unit BMI change, p = 0.005). This correlation was not significant among KK individuals (ß = 0.082; p = 0.15), while much steeper and highly significant among XQ individuals (ß = 0.336; p = 0.00008) (p-value for Q121-by-weight loss interaction = 0.047). CONCLUSION: Individuals carrying the ENPP1 Q121 variant are highly responsive to the effect of weight loss on fasting glucose. This reinforces the previously suggested hypothesis that the Q121 variant interacts with adiposity in modulating glucose homeostasis.

Safety and efficacy of insulin aspart and soluble human insulin in Type 2 diabetes mellitus.

AIM: The UpGrade study evaluated the safety profile and effectiveness of insulin aspart (IAsp, NovoRapid®) and soluble human insulin (SHI) in patients with Type 2 diabetes mellitus, under current clinical practice conditions. METHODS: This 26-week, open-label, non-randomized, observational safety study recruited patients using insulin ± metformin and having received ≥ 2 injections of IAsp or SHI over a period of 3 months to 3 years. Data were collected via patient recall and treatment diaries, at baseline, 13- and 26-week visits. The number of major hypoglycemic episodes was the primary endpoint. Secondary endpoints were minor hypoglycemic episodes, HbA1c, fasting and post-prandial blood glucose. RESULTS: Overall, 4099 patients were included. At study end the incidence of major hypoglycemia was low (mean rate 0.117 ev/pt-y) and rates were lower in subjects using IAsp compared with those using SHI, for both major (0.115 vs. 0.121) and minor (6.648 vs. 9.530) episodes. IAsp correlated with a significantly lower risk of minor hypoglycemic episodes (IRR=0.64, P<0.0001). Overall, HbA1c levels decreased across 26 weeks (7.97% to 7.63%, P<0.0001); IAsp had greater HbA1c reduction than SHI (-0.39% and -0.22%, respectively) and was associated with a marginally significant likelihood (vs. SHI) of achieving HbA1c reduction of ≥ 0.5% (OR=1.22, P=0.059). CONCLUSION: Under current clinical practice conditions, treatment of patients with Type 2 diabetes mellitus using either IAsp or SHI resulted in low rates of major hypoglycemia after 26 weeks. Patients using IAsp had a better clinical safety profile and a greater reduction in HbA1c compared with patients using SHI.

Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry.

OBJECTIVE: The European Acquired Haemophilia registry (EACH2) collected data on the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcome of women with acquired haemophilia A (AHA), a rare and often severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII. DESIGN: Prospective, multi-centre, large-scale, pan-European registry. SETTING: A total of 117 haemophilia centres in 13 European countries. POPULATION: Pregnancy-associated AHA. METHODS: Data were reported using a web-based electronic case report form. Diagnosis was based on the presence of a prolonged activated partial thromboplastin time, reduced coagulation Factor VIII level and positive inhibitor assay. MAIN OUTCOME MEASURES: Presenting characteristics, time to diagnosis, haemostatic treatment and outcome, immunosuppressive treatment and outcome. RESULTS: The EACH2 registry (n = 501) documented 42 (8.4%) cases of AHA associated with the peripartum period, a median Factor VIII level at diagnosis of 2.5 (range 0-25) IU/dl and inhibitor titre of 7.8 (range 0.7-348) BU/ml. Antepartum inhibitors were evident in eight women. Time to diagnosis of AHA after delivery was 89 (range 21-120) days. First-line haemostatic treatment was successful in 20/23 (87%) women treated. Bleeding episodes resolved in 17/18 (94%) women treated with a bypassing agent and 29/39 (74%) women achieved complete remission with first-line immunosuppressive treatment. Two babies experienced postnatal bleeding, suggesting transplacental transfer of the antibody. All women were alive at last follow-up. CONCLUSIONS: Although rare, pregnancy-associated AHA may cause severe bleeding-related morbidity. Once diagnosed, women respond well to haemostatic treatment with bypassing agents and immunosuppression. Awareness of peripartum AHA requires improvement to facilitate rapid and appropriate management.