bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction therapy and mTOR inhibition: minimizing calcineurin inhibitor exposure in de novo renal transplant patients
Authors: Nashan Björn 
Published: August 2013

AbstractUse of induction therapy with mTOR inhibitor maintenance immunosuppression to facilitate reduced calcineurin inhibitor (CNI) exposure in de novo kidney transplant patients has been explored in a series of randomized trials. These studies have typically employed interleukin‐2 receptor antagonist (IL‐2RA) induction, in low or standard immunological risk recipients. Although no study has directly compared mTOR inhibition plus reduced CNI exposure with or without induction, inclusion of IL‐2RA induction appears to permit a substantial reduction in CNI exposure without the need for high mTOR inhibitor dosing. IL‐2RA induction with an mTOR inhibitor and steroids has consistently shown similar efficacy to standard‐exposure CNI with mycophenolic acid and steroids and may improve renal function among patients who remain on the mTOR inhibitor‐based regimen. With modern mTOR inhibitor dosing, wound healing complications are of less concern and may be no more frequent than in mycophenolic acid‐based regimens. The incidence of cytomegalovirus infection appears lower in patients receiving de novo mTOR inhibition. The available evidence demonstrates that IL‐2RA induction with an mTOR inhibitor can successfully reduce CNI exposure by at least half without a penalty in terms of rejection in low‐ or moderate‐risk de novo transplant recipients and may offer renal and antiviral benefits.
Indications for intestinal transplantation: recognizing the scope and limits of total parenteral nutrition
Authors: Gotthardt Daniel N. , Gauss Annika , Zech Ulrike , Mehrabi Arianeb , Weiss Karl Heinz , Sauer Peter , Stremmel Wolfgang , Büchler Markus W. , Schemmer Peter 
Published: August 2013

AbstractTotal parenteral nutrition (TPN) is currently the treatment of choice for patients with intestinal failure. Intestinal failure in adults is mostly due to short bowel syndrome, which is most often caused by ischemia and Crohn's disease. However, TPN fails in a substantial number of cases. For patients with TPN failure, intestinal transplantation (ITx) may be offered as a treatment. TPN failure is considered to be present either if nutrition itself is not possible or if complications of TPN occur. These complications can, for example, originate from recurrent line infections or thrombosis. As TPN is usually a lifelong therapy and is associated with substantial impairment of the quality of life, the tolerance of each patient to this procedure is another important consideration in the decision making about whether to perform transplantation. The survival rates of intestinal transplant recipients have now reached the same level as that of recipients of other solid organ transplants. A five‐yr survival of up to 80% has been reported in specialized centers, whereas registry data show rates of <80%. Although in about one‐third of patients, isolated ITx is sufficient, patients with concurrent liver disease (mostly due to TPN) benefit from combined intestinal and liver transplantation. In some cases, multivisceral transplantation is necessary. Here, we review the current indications for ITx with a special focus on TPN.
Intestinal transplantation: review of operative techniques
Authors: Nickkholgh Arash , Contin Pietro , Abu‐Elmagd Kareem , Golriz Mohammad , Gotthardt Daniel , Morath Christian , Schemmer Peter , Mehrabi Arianeb 
Published: August 2013

AbstractThe improvement of outcomes in intestinal transplantation (ITx) over the last two decades has been made possible through standardization in surgical techniques, improvements in immunosuppressive and induction protocols, and post‐operative patient care. From a surgical technical point of view, all different types of small bowel containing transplants can be categorized into three main prototypes, including isolated small bowel, liver–small bowel, and multivisceral transplantations. In this review, we describe these three main prototypes and discuss the most important technical modifications of each type, as well as donor and recipient procedures, and highlight the more recent operative technical topics of discussion in the literature.
Modified body mass index and time interval between diagnosis and operation affect survival after liver transplantation for hereditary amyloidosis: a single‐center analysis
Authors: Franz Clemens , Hoffmann Katrin , Hinz Ulf , Singer Reinhard , Hund Ernst , Gotthardt Daniel N. , Ganten Tom , Kristen Arnt Volko , Hegenbart Ute , Schönland Stefan , Hinderhofer Katrin , Büchler Markus W. , Schemmer Peter 
Published: August 2013

AbstractIntroductionFamilial amyloid polyneuropathy (FAP) is the most common subtype of hereditary amyloidosis. The amyloid protein transthyretin deposits as rigid amyloid fibers in the extracellular matrix of various tissues including peripheral nerves, heart, and gastrointestinal tract. As the mutated amyloid protein is mainly produced in the liver, one form of treatment to halt the progression of disease is liver transplantation (LT). This study was performed to identify risk factors for decreased overall survival.MethodsClinical data of 21 transplant patients who underwent LT for FAP between 1996 and 2011 were analyzed retrospectively.ResultsThe majority of patients had cardiac symptoms (76%), gastrointestinal symptoms (71%), or peripheral polyneuropathy (71%). A conventional operating technique was performed on 11 patients using end‐to‐end caval anastomoses, while the modified piggyback technique by Belghiti was performed on 10 patients. Overall survival analysis revealed a one‐yr survival rate of 74.3% and three‐ and five‐yr survival rates of 60.0% and 52.5%, respectively. Pre‐operative modified body mass index (mBMI) <700 kg g/L m² and time interval between diagnosis and operation before LT resulted in significantly lower overall survival (p = 0.0137; p = 0.033).ConclusionThe pre‐operative nutritional status and time interval between diagnosis and operation before LT influence overall survival after LT for hereditary amyloidosis.
Fathom out: biogeographical subdivision across the Western Australian continental margin – a multispecies modelling approach
Authors: Woolley Skipton N. C. , McCallum Anna W. , Wilson Robin , O'Hara Timothy D. , Dunstan Piers K. 
Published: August 2013

AbstractAimBiogeographical regions are often used as a basis for management strategies, yet a challenge for biodiversity management across broad scales is establishing biogeographical regions that are robust across taxonomic groups.MethodsFinite mixture models were developed to predict multiple species assemblages termed archetypes. Modelled species archetypes were developed using Decapoda, Ophiuroidea and Polychaeta species, which were grouped based on their similar responses to oceanographic and geographical gradients.LocationOuter‐shelf and slope (50–1200 m) of the continental margin of Western Australia (~11° S–36° S).ResultsFour faunal regions were defined based on cross‐taxa surrogates grouped as archetypes. These faunal regions were defined by oxygen, salinity, carbon and temperature gradients across latitude and bathymetry. Two broad latitudinal bands and two bathyal regions were described. Adjacent faunal groups were not defined by abrupt geographical breaks but rather transitions.Main conclusionsThese results suggest that faunal distributions were less finely resolved than existing marine bioregions on the Western Australian continental margin and that environmental gradients are correlated with distributions of benthic marine invertebrates. Identifying biogeographical regions based on these methods has the potential to inform management across a broad range of environments.
Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add‐on to metformin in type 2 diabetes with mild hyperglycaemia
Authors: Rosenstock J. , Seman L. J. , Jelaska A. , Hantel S. , Pinnetti S. , Hach T. , Woerle H. J. 
Published: August 2013

AimsTo evaluate the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin added to metformin for 12 weeks in patients with type 2 diabetes.MethodsThis dose‐ranging, double‐blind, placebo‐controlled trial randomized 495 participants with type 2 diabetes inadequately controlled on metformin [haemoglobin A1c (HbA1c) >7 to ≤10%] to receive 1, 5, 10, 25, or 50 mg empagliflozin once daily (QD), or placebo, or open‐label sitagliptin (100 mg QD), added to metformin for 12 weeks. The primary endpoint was change in HbA1c from baseline to week 12 (empagliflozin groups versus placebo).ResultsReductions in HbA1c of −0.09 to −0.56% were observed with empagliflozin after 12 weeks, versus an increase of 0.15% with placebo (baseline: 7.8–8.1%). Compared with placebo, empagliflozin doses from 5 to 50 mg resulted in reductions in fasting plasma glucose (−2 to −28 mg/dl vs. 5 mg/dl with placebo; p < 0.0001) and body weight (−2.3 to −2.9 kg vs. −1.2 kg; p < 0.01). Frequency of adverse events was generally similar with empagliflozin (29.6–48.6%), placebo (36.6%) and sitagliptin (35.2%). Hypoglycaemia rates were very low and balanced among groups. Most frequent adverse events with empagliflozin were urinary tract infections (4.0% vs. 2.8% with placebo) and pollakiuria (2.5% vs. 1.4% with placebo). Genital infections were reported only with empagliflozin (4.0%).ConclusionsOnce daily empagliflozin as add‐on therapy to metformin was well tolerated except for increased genital infections and resulted in reductions in HbA1c, fasting plasma glucose and body weight in patients with type 2 diabetes inadequately controlled on metformin monotherapy.
Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years
Authors: Wilding J. P. H. , Woo V. , Rohwedder K. , Sugg J. , Parikh S. ,   for the Dapagliflozin 006 Study Group
Published: August 2013

AbstractAimsDapagliflozin, a selective inhibitor of sodium‐glucose cotransporter 2 (SGLT2), has been shown to improve glycaemic control, stabilize insulin dosing and mitigate insulin‐associated weight gain over 48 weeks in patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled despite high doses of insulin. Here the efficacy and safety of dapagliflozin therapy after a total of 104 weeks are evaluated in this population.MethodsThis was a 24‐week, randomized, placebo‐controlled, double‐blinded, multicentre trial followed by two site‐ and patient‐blinded extension periods of 24 and 56 weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on insulin ≥30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of dapagliflozin for 104 weeks. At 48 weeks, patients on dapagliflozin 5 mg were switched to 10 mg. Outcomes over 104 weeks included change from baseline in HbA1c, insulin dose and body weight; analyses used observed cases and included data after insulin up‐titration. Adverse events (AEs) were evaluated throughout 104 weeks.ResultsFive hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104 weeks were −0.4% in the placebo group and −0.6 to −0.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and weight increased by 1.8 kg at 104 weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.9–1.4 kg. AEs, including hypoglycaemia, were balanced across groups. Proportions of patients with events suggestive of genital infection and of urinary tract infection (UTI) were higher with dapagliflozin versus placebo (genital infection 7.4–14.3% vs. 3.0%; UTI 8.4–13.8% vs. 5.6%) but most occurred in the first 24 weeks and most were single episodes that responded to routine management.ConclusionsDapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic episodes over 104 weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy.
Empagliflozin improves glycaemic and weight control as add‐on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24‐week, randomized, placebo‐controlled trial
Authors: Kovacs C. S. , Seshiah V. , Swallow R. , Jones R. , Rattunde H. , Woerle H. J. , Broedl U. C. ,   on behalf of the EMPA‐REG PIO™ trial investigators
Published: August 2013

AimsThis study investigated the efficacy and tolerability of empagliflozin as add‐on to pioglitazone ± metformin in patients with type 2 diabetes (T2DM).MethodsPatients with HbA1c ≥7 and ≤10% were randomized and treated with once daily empagliflozin 10 mg (n = 165), empagliflozin 25 mg (n = 168) or placebo (n = 165) as add‐on to pioglitazone ± metformin for 24 weeks. Endpoints included changes from baseline in HbA1c (primary endpoint), fasting plasma glucose (FPG) and body weight at week 24.ResultsAdjusted mean ± standard error changes in HbA1c were −0.6 ± 0.07% and −0.7 ± 0.07% with empagliflozin 10 mg and 25 mg, respectively, vs. −0.1 ± 0.07% with placebo (both p < 0.001). More patients with HbA1c ≥7% at baseline achieved HbA1c <7% with empagliflozin 10 mg (23.8%) and 25 mg (30.0%) vs. placebo (7.7%) (both p < 0.001). FPG decreased with empagliflozin (−0.94 mmol/l for 10 mg and −1.22 mmol/l for 25 mg) and increased with placebo (+0.36 mmol/l; both p < 0.001). Adjusted mean ± standard error changes in weight were −1.62 ± 0.21 kg and −1.47 ± 0.21 kg with empagliflozin 10 mg and 25 mg, respectively, vs. +0.34 ± 0.21 kg with placebo (both p < 0.001). Similar proportions of patients reported adverse events with empagliflozin (67.3–71.4%) and placebo (72.7%). Confirmed hypoglycaemia was reported by 1.2–2.4% of patients on empagliflozin and 1.8% on placebo.ConclusionEmpagliflozin 10 mg and 25 mg once daily for 24 weeks as add‐on to pioglitazone ± metformin reduced HbA1c, FPG and weight and were well tolerated in patients with T2DM.
Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin
Authors: Bolinder J. , Ljunggren Ö. , Johansson L. , Wilding J. , Langkilde A. M. , Sjöström C. D. , Sugg J. , Parikh S. 
Published: August 2013

AimsDapagliflozin, a highly selective inhibitor of sodium‐glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long‐term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment.MethodsThis randomized, double‐blind, placebo‐controlled study (NCT00855166) enrolled patients with T2DM [mean: age 60.7 years; HbA1c 7.2%; body mass index (BMI) 31.9 kg/m2; body weight 91.5 kg] inadequately controlled on metformin. Patients (N = 182) were randomly assigned 1 : 1 to receive dapagliflozin 10 mg/day or placebo added to open‐label metformin for a 24‐week double‐blind treatment period followed by a 78‐week site‐ and patient‐blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by dual‐energy X‐ray absorptiometry (DXA), serum markers of bone turnover, bone mineral density (BMD) as measured by DXA, and adverse events were evaluated.ResultsA total of 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin‐treated patients showed reductions in HbA1c by −0.3%, weight by −4.54 kg, waist circumference by −5.0 cm and fat mass by −2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of urinary tract infection (UTI) and genital infection was similar in both treatment groups.ConclusionsOver 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin.
Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone—a factorial study
Authors: Henry R. R. , Staels B. , Fonseca V. A. , Chou M. Z. , Teng R. , Golm G. T. , Langdon R. B. , Kaufman K. D. , Steinberg H. , Goldstein B. J. 
Published: August 2013

AimTo evaluate the efficacy and safety of initial combination therapy of sitagliptin 100 mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes.MethodsPatients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100 mg sitagliptin alone; 15, 30 or 45 mg pioglitazone alone, or 100 mg sitagliptin plus 15, 30 or 45 mg pioglitazone for 54 weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol‐specified analyses compared combination therapies with monotherapies at respective dose‐strengths and combination of sitagliptin plus pioglitazone 30 mg with pioglitazone 45 mg monotherapy. Post‐hoc analyses compared sitagliptin plus pioglitazone 15 mg with pioglitazone monotherapy at the two higher doses.ResultsInitial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4–0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low‐dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3–0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8–11.1%) in all treatment groups over the 54 weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7–5.3% among pioglitazone‐treated groups. Significant weight gain was observed in all combination‐treated groups compared with the sitagliptin monotherapy group.ConclusionsInitial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated.
Issues related to development of antiepileptogenic therapies
Authors: Pitkänen Asla , Nehlig Astrid , Brooks‐Kayal Amy R. , Dudek F. Edward , Friedman Daniel , Galanopoulou Aristea S. , Jensen Frances E. , Kaminski Rafal M. , Kapur Jaideep , Klitgaard Henrik , Löscher Wolfgang , Mody Istvan , Schmidt Dieter 
Published: August 2013

SummarySeveral preclinical proof‐of‐concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on “Issues related to development of antiepileptogenic therapies” of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof‐of‐concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing.
The Role of Experts in the Elaboration of the Cape Town Convention: Between Authority and Legitimacy
Authors: Devaux Caroline 
Published: August 2013

AbstractGlobalisation and the development of fast transport and communications have multiplied transnational situations that States, at times, appear ill equipped to handle. Private actors, taking advantage of these new opportunities to claim their authority, are now key actors in the production of transnational law. Since their place in the production process does not have legal grounds, this paper intends to ‘transnationalise’ the legitimacy discourse by comparing its fundamental criteria to the claim to authority of a particular group of private actors—the aviation experts—during the elaboration of the Cape Town Convention. This article challenges this expertise‐based legitimation process which, despite being grounded on the ability of private actors to develop effective solutions, reveals a limited output and input legitimacy. Finally, the article suggests that the EU is well placed to carry out a legitimacy test to block the reception of undemocratic claims to authority made by influential private actors.
The effects of synthetic estrogen exposure on premating and postmating episodes of selection in sex‐role‐reversed Gulf pipefish
Authors: Rose Emily , Paczolt Kimberly A. , Jones Adam G. 
Published: August 2013

AbstractEnvironmental estrogens have been shown to affect populations of aquatic organisms in devastating ways, including feminization of males, alterations in mating behaviors, and disruption of sexual selection. Studies have shown 17α‐ethinylestradiol (EE2) exposure to induce female‐like secondary sexual traits in male Gulf pipefish, changing how females perceive affected males. We aimed to understand the effects of EE2 exposure on the sex‐role‐reversed mating system and the strength of selection in Gulf pipefish. We used artificial Gulf pipefish breeding aggregations and microsatellite‐based parentage analysis to determine maternity. We then calculated the opportunity for selection and selection differentials on body size for both sexes during three consecutive episodes of selection. Exposure to EE2 did not affect the strength of selection, likely due to the unusual sex‐role‐reversed mating system found in this species. With respect to multiply mated females, EE2‐exposed females produced more eggs with higher embryo survivorship than nonexposed females. Thus, short‐term exposure to low concentrations (2.0 ng/L) of EE2 in Gulf pipefish enhanced female reproductive success. However, higher EE2 concentrations (5.0 ng/L) caused complete reproductive failure in Gulf pipefish males. These results call for more work on the long‐term effects of EE2 exposure in Gulf pipefish in artificial and natural populations.