Weyl Consistency Conditions and γ_{5}.

The treatment of γ_{5} in dimensional regularization leads to ambiguities in field-theoretic calculations, of which one example is the coefficient of a particular term in the four-loop gauge beta functions of the standard model. Using Weyl consistency conditions, we present a scheme-independent relation between the coefficient of this term and a corresponding term in the three-loop Yukawa beta functions, where a semi-naïve treatment of γ_{5} is sufficient, thereby fixing this ambiguity. We briefly outline an argument by which the same method fixes similar ambiguities at higher orders.

Liraglutide and cardiovascular outcomes in adults with overweight or obesity: A post hoc analysis from SCALE randomized controlled trials.

The cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist approved for weight management at a dose of 3.0 mg, was evaluated post hoc using data from 5908 participants in 5 randomized, double-blind, placebo-controlled clinical trials. Participants were randomized to liraglutide or a comparator group (placebo or orlistat). The objective was to evaluate whether cardiovascular risk was increased with liraglutide treatment. The primary composite outcome of this time-to-event analysis was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. These cardiovascular events were adjudicated prospectively for three of the trials and retrospectively for two trials by an event adjudication committee. The primary outcome was analyzed using a Cox proportional hazards model, stratified by trial. With liraglutide 3.0 mg, 8 participants had positively adjudicated cardiovascular events (1.54 events/1000 person-years) compared to 10 participants in the comparators group (3.65 events/1000 person-years). The hazard ratio for liraglutide 3.0 mg compared to comparators was 0.42 (95% confidence interval, 0.17-1.08). In this analysis, liraglutide 3.0 mg treatment was not associated with excess cardiovascular risk. However, the wide confidence intervals and retrospective adjudication of events in two of the trials are limitations of the analysis.

Pancreatic stellate cells in pancreatic cancer: In focus.

Pancreatic stellate cells are stromal cells that have multiple physiological functions such as the production of extracellular matrix, stimulation of amylase secretion, phagocytosis and immunity. In pancreatic cancer, stellate cells exhibit a different myofibroblastic-like morphology with the expression of alpha-smooth muscle actin, the activated form is engaged in several mechanisms that support tumorigenesis and cancer invasion and progression. In contrast to the aforementioned observations, eliminating the stromal cells that are positive for alpha-smooth muscle actin resulted in immune-evasion of the cancer cells and resulted in worse prognosis in animal models. Understanding the cancer-stromal signaling in pancreatic adenocarcinoma will provide novel strategies for therapy. Here we provide an updated review of studies that handle the topic "pancreatic stellate cells in cancer" and recent experimental approaches that can be the base for future directions in therapy.

Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-SWITCH): a randomized, double-blind, double-dummy, active-controlled 26-week trial.

AIMS: To confirm superiority on glycaemic control by switching from sitagliptin to liraglutide 1.8 mg/d versus continued sitagliptin. MATERIALS AND METHODS: A randomized, multicentre, double-blind, double-dummy, active-controlled trial across 86 office- or hospital-based sites in North America, Europe and Asia. Subjects with type 2 diabetes who had inadequate glycaemic control (glycated haemoglobin [HbA1c] 7.5-9.5% on sitagliptin (100 mg/d) and metformin (≥1500 mg daily) for ≥90 days were randomized to either switch to liraglutide (n = 203) or continue sitagliptin (n = 204), both with metformin. The primary endpoint was change in HbA1c from baseline to week 26. Change in body weight was a confirmatory secondary endpoint. RESULTS: Greater reduction in mean HbA1c was achieved with liraglutide than with continued sitagliptin [-1.14% vs. -0.54%; estimated mean treatment difference (ETD): -0.61% (95% CI -0.82 to -0.40; p < 0.0001)], confirming superiority of switching to liraglutide. Body weight was reduced more with liraglutide [-3.31 kg vs. -1.64 kg; ETD: -1.67 kg (95% CI -2.34 to -0.99; p < 0.0001)]. Nausea was more common with liraglutide [44 subjects (21.8%)] than with continued sitagliptin [16 (7.8%)]. Three subjects (1.5%) taking sitagliptin reported a confirmed hypoglycaemic episode. CONCLUSIONS: Subjects insufficiently controlled with sitagliptin who switch to liraglutide can obtain clinically relevant reductions in glycaemia and body weight, without compromising safety. A switch from sitagliptin to liraglutide provides an option for improved management of type 2 diabetes while still allowing patients to remain on dual therapy.

Are allergic multimorbidities and IgE polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis.

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.

IFNγ and perforin cooperate to control infection and prevent fatal pathology during persistent gammaherpesvirus infection in mice.

Infection with murine gammaherpesvirus 68 has become an accepted model for studying the virus/host interactions with regard to gammaherpesvirus infections. Previous studies using gene-deficient mice have revealed that neither IFNγ nor perforin is essential in controlling the outcome of infection or the virus load during chronic infection in C57BL/6 mice. However, pronounced multiorgan fibrosis and splenic atrophy are observed in mice lacking IFNγ or the IFNγ receptor. To study the interplay between perforin and IFNγ in controlling the virus-induced pathology and the viral load during chronic gammaherpesvirus infection, we infected IFNγ/perforin double-deficient C57BL/6 mice and followed the course of infection. While absence of perforin prevented the splenic atrophy in IFNγ-deficient mice, fibrosis did not disappear. Moreover, double-deficient mice developed extreme splenomegaly, were unable to control the viral load and displayed chronic immune activation. Thus, IFNγ and perforin act in concert to minimize pathology and control the viral load in mice chronically infected with MHV68. Furthermore, while certain aspect of the virus-induced pathology in IFNγ-deficient mice may be alleviated in double-deficient mice, other aspects are exaggerated, and the normal architecture of the spleen is completely destroyed. We believe that these findings add to the understanding of the virus/host interaction during chronic gammaherpes virus infection.

Clinical bleeding diathesis, laboratory haemostatic aberrations and survival in dogs infected with Angiostrongylus vasorum: 180 cases (2005-2019).

OBJECTIVES: Bleeding diathesis is a complication in dogs infected with Angiostrongylus vasorum. This retrospective study investigated clinical and laboratory haemostatic differences in A. vasorum-positive dogs with and without signs of bleeding and impact of bleeding on survival. MATERIALS AND METHODS: Demographics, type of clinical bleeding, haematocrit and a range of haemostatic tests, including thromboelastography and derived velocity curves were retrospectively registered from A. vasorum-positive dogs. All parameters were compared between dogs with and without signs of bleeding using univariable analyses. Binomial and multinomial regression models were applied to examine specific indicators in the bleeding dogs. P-values were false discovery rate adjusted, and adjusted P<0.05 was considered significant. RESULTS: One hundred and eighty dogs entered the study, including 65 dogs (36.1%) presenting with bleeding diathesis. Different types of cutaneous and mucosal bleeding were the most common clinical findings. Twenty dogs presented with neurological signs associated with intracranial and intra-spinal bleeding. One hundred and thirty-seven dogs had haematological and/or haemostatic laboratory analyses performed. Haematocrit, platelet count, thromboelastographic angle, maximum amplitude, global clot strength, maximum rate of thrombin generation and total thrombin generation were decreased, while prothrombin time was prolonged in bleeding dogs. Survival rate of bleeding dogs was lower at hospital discharge (76.9%) and 1 month after diagnosis (66.0%) than in dogs without signs of bleeding (94.8% and 90.1% at discharge and at 1 month, respectively). CLINICAL SIGNIFICANCE: Several haemostatic aberrations were detected in A. vasorum-positive dogs with bleeding diathesis. Bleeding was identified as an important negative prognostic indicator in A. vasorum-positive dogs.

Cohabitation patterns among patients with severe psychiatric disorders in the entire Danish population.

BACKGROUND: Assortative mating has been demonstrated in mental disorders but the extent of cohabitation between patients with clinically diagnosed psychiatric disease has been poorly explored. Method We conducted a register-based study of all Danes between 18 and 70 years of age in a 13-year observational period, linking data on individuals' contacts with psychiatric services with data on individuals' cohabitation status. Two different Poisson regression analyses were performed: the first comparing the rates of commencing cohabitation with a psychiatric patient between individuals, depending on whether the individuals themselves had, or did not have, a psychiatric diagnosis; the second comparing the incidence rates of psychiatric diagnoses for individuals cohabitating with psychiatric patients with the similar rates for individuals living with unaffected cohabitants. RESULTS: In total, 159 929 (5.0%) out of 3 204 633 individuals were given a psychiatric diagnosis during the study period. Diagnosed individuals had an overall rate ratio (RR) of commencing cohabitation with a psychiatric patient of 1.95 [95% confidence interval (CI) 1.90-2.00] for women and 1.65 (95% CI 1.61-1.69) for men, when compared with unaffected individuals. The overall RR of receiving a psychiatric diagnosis while cohabitating with a psychiatric patient was 2.40 (95% CI 2.31-2.49) for women and 2.91 (95% CI 2.81-3.01) for men, when compared with those cohabitating with unaffected individuals. Individuals with schizophrenia and men with bipolar disorder had the highest RR of commencing cohabitation with a cohabitant with a similar diagnosis. CONCLUSIONS: Cohabitation among individuals with severe psychiatric disorders is increased. This has implications for research and for the clinical management of patients.

Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study.

AIMS: To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2 years in patients with type 2 diabetes. METHODS: In the 26-week the Liraglutide Effect and Action in Diabetes (LEAD)-2 core trial, patients (n = 1091) were randomized (2 : 2 : 2 : 1: 2) to liraglutide (0.6, 1.2 or 1.8 mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 18-80 years old with HbA1c 7.0-11.0% (previous monotherapy ≥3 months), or 7.0-10.0% (previous combination therapy ≥3 months), and body mass index ≤40 kg/m(2) . Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. RESULTS: HbA1c decreased significantly with liraglutide (0.4% with 0.6 mg, 0.6% with 1.2 and 1.8 mg) versus 0.3% increase with metformin monotherapy (p < 0.0001). HbA1c decrease with liraglutide was non-inferior versus 0.5% decrease with glimepiride. Liraglutide groups experienced significant weight loss (2.1, 3.0 and 2.9 kg with 0.6, 1.2 and 1.8 mg, respectively) compared to weight gain (0.7 kg) with glimepiride (p < 0.0001). Weight loss with liraglutide 1.2 and 1.8 mg was significantly greater than with metformin monotherapy (1.8 kg; p = 0.0185 and p = 0.0378 for 1.2 and 1.8 mg, respectively). The occurrence of minor hypoglycaemia was <5.0% in all liraglutide groups, significantly less than with glimepiride (24.0%; p < 0.0001). Liraglutide was well tolerated overall: gastrointestinal events were more common than with glimepiride or metformin monotherapy, but occurrence decreased with time. CONCLUSIONS: Liraglutide provided sustained glycaemic control over 2 years comparable to that provided by glimepiride. Liraglutide was well tolerated, and was associated with weight loss and a low rate of hypoglycaemia.

Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group.

The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.

New insights into the genetics of immune responses in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease with a strong genetic component. Numerous aberrant immune responses have been described during the evolution of the disease. In later years, the appearance of anti-citrullinated protein antibodies (ACPAs) has become a hallmark for the diagnosis and prognosis of RA. The post-translational transformation of arginine residues of proteins and peptides into citrulline (citrullination) is a natural process in the body, but for unknown reasons autoreactivity towards citrullinated residues may develop in disposed individuals. ACPAs are often found years before clinical manifestations. ACPAs are present in about 70% of RA patients and constitute an important disease marker, distinguishing patient groups with different prognoses and different responses to various treatments. Inside the human leukocyte antigen (HLA) region, some HLA-DRB1 alleles are strongly associated with their production. Genome-wide association studies in large patient cohorts have defined a great number of single nucleotide polymorphisms (SNPs) outside of the HLA region that are associated with ACPA positive (ACPA+) RA. The SNPs are generally located close to or within genes involved in the immune response or signal transduction in immune cells. Some environmental factors such as tobacco smoking are also positively correlated with ACPA production. In this review, we will describe the genes and loci associated with ACPA+ RA or ACPA- RA and attempt to clarify their potential role in the development of the disease.

Allergy, living and learning: diagnosis and treatment of allergic respiratory diseases in Europe.

BACKGROUND: Allergy Living and Learning (ALL) is a European initiative designed to increase knowledge and understanding of people living with allergies in order to improve respiratory allergy care. OBJECTIVES: To investigate diagnostic and treatment patterns associated with respiratory allergies, patients' perception of their treatment, and restrictions on daily activities. METHODS: Using a telephone-based randomized screening method, we recruited and analyzed 7004 patients (aged 16-60 years) with self-reported respiratory allergic disease from 10 European countries. Patients answered questions assessing their knowledge, experience, and perception of their condition and its treatment. Data analyses were descriptive. RESULTS: The most prevalent conditions were allergic rhinitis (66%) and asthma (26%), and the average duration of the symptoms of respiratory allergy was 14.5 years. Over 30% of patients had never had a specific diagnostic test. About 80% of patients used medication for their respiratory allergy, and 10% of those not receiving treatment had severe symptoms. One-third of patients were not satisfied with their treatment, and two-thirds experienced restrictions in daily activities. Medication was most commonlytaken in the form of tablets and nasal spray. Allergy-specific immunotherapy was received by 16% of patients. Knowledge of specific immunotherapy was low overall and varied widely by country: 30% of patients (country range, 10%-52%) had never heard of this treatment option. CONCLUSIONS: A notable proportion of individuals with respiratory allergy in Europe are underdiagnosed, undertreated, and dissatisfied with their treatment. Addressing these shortcomings may help to optimize respiratory allergy care and, ultimately, quality of life.

Danish military fatalities in international operations 2002-2018.

INTRODUCTION: This study describes deaths among Danish soldiers in international operations 2002-2018. Having been part of UN and later NATO forces in ex-Yugoslavia, in 2002 the first Danish contingent took part in the International Security Assistance Force mission in Afghanistan as well as Iraq. The changing role of the Danish military in international operations meant casualties, in numbers that had not yet been experienced, and necessitated a review of our procedures for handling fatalities in the military. METHODS: The study is a retrospective review of autopsy reports, Military Police reports and medical reports, and the purpose is to examine all Danish fatalities in international operations in 2002-2018 to identify potential areas of improving treatment and protection and to review the contribution of the autopsies. The mechanism of injury, the fatal injuries and causes of death and the time of death within the chain of evacuation were identified. Casualties dying at any time from site of injury until definitive care were included. RESULTS: A total of 53 soldiers died from injuries during international operations in the years 2002-2018. The majority of these (43) died from combat injuries and 10 from accidents. Four of the victims with combat injuries were not autopsied. The majority (36) of the combat deaths were caused by blast/explosions (improvised explosive devices, rocket propelled grenades, fragments), while 7 were caused by bullets. 39 combat victims died instantly on the site or at the arrival to the field hospital, 4 were treated in field hospital and 2 of these were transported back to Denmark. CONCLUSIONS: Most combat fatalities result from fragmentation and blast injury. Forensic autopsies provide valuable information regarding injuries, weaponry, the efficiency of protective equipment and the quality of medical intervention in military fatalities and are recommended in all military fatalities in order to prevent avoidable casualties in the future.

Biopsy-derived oral keratinocytes - A model to potentially test for oral mucosa radiation sensitivity.

Purpose: To establish stable in vitro growth of keratinocytes from very small biopsy specimens and successfully apply new test systems to determine their radiosensitivity. Materials and Methods: Oral mucosa biopsies (diameter: 1.7 mm) from 15 subjects were immobilized with custom-made cups onto culture plates. Outgrowing cells were tested for cytokeratin 5/14 and Ki67, expanded, radiated at different doses, and seeded onto circumscribed areas before being allowed to spread centrifugally. In this newly developed spreading assay, cell-covered areas were measured by image analysis. For statistical analysis, a linear mixed regression model was used; additionally, results were correlated to the radiation dose applied. Colony forming efficiency (CFE) was used to validate the results. DNA damage repair was analysed by gammaH2AX and 53BP1 foci quantification using immunofluorescence microscopy 24 h and 96 h after irradiation. Results: Stable keratinocyte growth continued for up to 7 weeks in 14 biopsies. Cells spread reliably from an initial 16.6 mm2 up to a median of 119.2 mm2 (range: 54.4-290). Radiated cells spread to only 100.7 mm2 (2 Gy; range: 55.3-266.7); 73.2 mm2 (4 Gy; 15-240.4); 47 mm2 (6 Gy; 2-111.9), and 22.7 mm2 (8 Gy; 0-80). Similarly, CFE decreased from 0.223 (0 Gy) to 0.0028 (8 Gy). Using an individual donor as a random factor, cell spread correlated with CFE, where radiation dose was the main driver (decrease by 0.50, adjusted for area). Upon irradiation with 6 Gy, radiation-induced DNA damage was increased after 24 h in all samples, and even after 96 h in 5 out of 7 samples, as detected by a higher number of gammaH2AX/53BP1 foci in irradiated cells (mean 3.7 for 24 h; mean 0.6 for 96 h). Conclusion: In vitro propagation of keratinocytes derived from a small biopsy is feasible. Radiation impairs cellular migration and proliferation, and the newly described spreading assay allows ranking for cellular radioresistance. The keratinocyte model also supports classical functional assays such as clonogenic survival and DNA double strand repair. The clinical relevance awaits upcoming investigations.

Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.

AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to ß subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.

Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin.

AIMS: Patient-reported outcomes from clinical trials offer insight into the impact of disease on health-related quality of life, including treatment satisfaction. This patient-reported outcomes evaluation was a substudy of a 26-week randomized, open-label trial comparing the once-daily injectable human GLP-1 analogue liraglutide with once-daily oral sitagliptin, both added to metformin. The patient reported outcomes substudy aimed to evaluate treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at baseline and 26 weeks. METHODS: In the main 26-week randomized, open-label study (n =658), liraglutide, 1.2 or 1.8 mg, injected with a pen, led to greater HbA1c reduction than oral sitagliptin, 100 mg once daily, both added to metformin = 1500 mg daily: mean HbA1c reduction was 1.5, 1.2 and 0.9% (7, 10 and 14 mmol/mol) for liraglutide 1.8 mg, 1.2 mg and sitagliptin, respectively (P < 0.0001 for both liraglutide doses vs. sitagliptin) and liraglutide patients lost more weight (3 vs.1 kg; P < 0.0001). In this patient-reported outcomes substudy (liraglutide 1.8 mg, n = 171; 1.2 mg, n = 164; sitagliptin, n = 170) DTSQ scores were analyzed by ANCOVA with treatment and country as fixed effects and baseline value as covariate. RESULTS: Overall treatment satisfaction, calculated by adding satisfaction scores for `current treatment', `convenience', `flexibility', `understanding', `recommend', and `continue', improved in all groups at 26 weeks; greater improvement with liraglutide (4.35 and 3.51 vs. 2.96; P = 0.03 for liraglutide 1.8 mg vs. sitagliptin) may reflect greater HbA1c reduction and weight loss. Patients perceived themselves to be hyperglycaemic significantly less frequently with liraglutide 1.8 mg (difference = -0.88; P < 0.0001) and 1.2 mg ( -0.49; P = 0.01). Perceived frequency of hypoglycaemia was similar across all groups. CONCLUSIONS: Injectable liraglutide may lead to greater treatment satisfaction than oral sitagliptin, potentially by facilitating greater improvement in glycaemic control, weight loss and/ or perception of greater treatment efficacy.

One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial.

AIM: The aim of this study was to compare the efficacy and safety of once-daily human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes. METHODS: In an open-label, parallel-group trial, metformin-treated participants were randomised to liraglutide 1.2 mg/day (n=225), liraglutide 1.8 mg/day (n=221) or sitagliptin 100 mg/day (n=219) for 26 weeks (main phase). Participants continued the same treatment in a 26-week extension. RESULTS: Liraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA(1c) from baseline (8.4-8.5%) to 52 weeks: -1.29% and -1.51% vs. -0.88% respectively. Estimated mean treatment differences between liraglutide and sitagliptin were as follows: -0.40% (95% confidence interval -0.59 to -0.22) for 1.2 mg and -0.63% (-0.81 to -0.44) for 1.8 mg (both p<0.0001). Weight loss was greater with liraglutide 1.2 mg (-2.78 kg) and 1.8 mg (-3.68 kg) than sitagliptin (-1.16 kg) (both p<0.0001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly more with liraglutide 1.8 mg than with sitagliptin (p=0.03). Proportions of participants reporting adverse events were generally comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for liraglutide 1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly nausea, initially occurred more frequently with liraglutide, but declined after several weeks. CONCLUSION: Liraglutide provides greater sustained glycaemic control and body weight reduction over 52 weeks. Treatment satisfaction was significantly greater with 1.8 mg liraglutide, similar to 26-week results. The safety profiles of liraglutide and sitagliptin are consistent with previous reports.

Electrical Impedance Plethysmography Versus Tonometry To Measure the Pulse Wave Velocity in Peripheral Arteries in Young Healthy Volunteers: a Pilot Study.

The leading cause of health loss and deaths worldwide are cardiovascular diseases. A predictor of cardiovascular diseases and events is the arterial stiffness. The pulse wave velocity (PWV) can be used to estimate arterial stiffness non-invasively. The tonometer is considered as the gold standard for measuring PWV. This approach requires manual probe fixation above the artery and depends on the skills of the operator. Electrical impedance plethysmography (IPG) is an interesting alternative using skin surface sensing electrodes, that is miniaturizable, cost-effective and allows measurement of deeper arteries. The aim of this pilot study was to explore if IPG can be a suitable technique to measure pulse wave velocity in legs as an alternative for the tonometer technique. The PWV was estimated by differences in the ECG-gated pulse arrival times (PAT) at the a. femoralis, a. popliteal, a. tibialis dorsalis and a. dorsalis pedis in nine healthy young adults using IPG and the SphygmoCor tonometer as a reference. The estimated PWV results from bioimpedance and the tonometer were fairly in agreement, and the beat-to-beat variability in PAT was similar. This pilot study indicates that the use of IPG may be a good alternative for estimating PWV in the legs.