bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study)
Authors: Friedman A. B. , Brown S. J. , Bampton P. , Barclay M. L. , Chung A. , Macrae F. A. , McKenzie J. , Reynolds J. , Gibson P. R. , Hanauer S. B. , Sparrow M. P. 
Published: February 2018

SummaryBackgroundThiopurine hypermethylation towards 6‐methylmercaptopurine (6MMP) instead of 6‐thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation.AimsTo prospectively determine efficacy of allopurinol‐thiopurine combination and to compare 2 doses of allopurinol.DesignIn a multicentre, double‐blind trial, patients with clinically active or steroid‐dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260‐500 pmol/8x108RBCs. The primary endpoint was steroid‐free clinical remission at 24 weeks.ResultsOf 73 patients, 39 (53% [95% CI 42‐65]) achieved steroid‐free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85‐541] vs 821[110‐5892] ug/g, P = 0.03).ConclusionsLow‐dose allopurinol‐thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.
Landscape‐scale vegetation homogenization in Central European sub‐montane forests over the past 50 years
Authors: Prach Jindřich , Kopecký Martin 
Published: February 2018

AbstractQuestionsHow did plant species richness and spatial heterogeneity of the vegetation change across sub‐montane forests over the past 50 years? Did the vegetation changes reflect eutrophication, acidification and management changes, which the area underwent during the second half of the 20th century?LocationOrdinary managed forests sampled across 2500 km2 of a typical Central European sub‐montane landscape in the southern part of the Czech Republic.MethodsWe resampled 156 quasi‐permanent plots sampled in the 1950s–1970s and covering the whole range of forest vegetation in the region. We compared understorey plant species richness and community composition between the surveys and tested for temporal changes in the spatial heterogeneity (β‐diversity) of vegetation.ResultsSpecies richness and dissimilarity in species composition among plots decreased significantly between the surveys. The vegetation of the plots also changed significantly, but there were no clear directional changes across all plots. The vegetation homogenization was driven by local extinctions of specialist species, especially competitively weak species adapted to nutrient‐poor conditions. Few generalist species expanded between the surveys.ConclusionsWe found evidence of taxonomic homogenization of forest understoreys across a large sub‐montane region. This vegetation homogenization was probably driven by complex landscape changes that took place in the last century. Varied traditional management regimes were replaced with largely uniform management, and the once spatially diverse landscape mosaic has become simpler. The resulting transition to species‐poor and less variable vegetation was probably further accelerated by environmental eutrophication. Our results thus complement previous forest herb layer resurveys, which focused mostly on lowland forests and small nature reserves, and suggest that landscape‐scale taxonomic homogenization is occurring across Central European forests.
Computer vision detects subtle histological effects of dutasteride on benign prostate
Authors: Sethi Amit , Sha Lingdao , Kumar Neeraj , Macias Virgilia , Deaton Ryan J. , Gann Peter H. 
Published: February 2018

ObjectiveTo determine whether a computer vision‐based approach applied to haematoxylin and eosin (H&E) prostate biopsy images can distinguish dutasteride‐treated tissue from placebo, and identify features associated with degree of responsiveness to 5α‐reductase inhibitor (5ARI) therapy.Subjects and MethodsOur study population comprised 100 treatment‐adherent men without prostate cancer assigned to dutasteride or placebo in the REDUCE trial, who had slides available from mandatory year‐4 biopsies. Half of the men also provided slides from a year‐2 biopsy. We obtained 20× whole‐slide images and used specialized software to generate a library of 1 300 epithelial and stromal features from objects comprising superpixels and several types of nuclei, including spatial relations among objects between and within each hierarchical level. We used penalized logistic regression and fivefold cross‐validation to find optimal combinations of histological features in the year‐4 biopsies. Feature data from the year‐2 biopsies were fitted to a final model for independent validation. Two pathologists, blinded to treatment, scored each image for focal atrophy and histological features previously linked to 5AR1 treatment.ResultsConsensus classification by pathologists obtained a discrimination accuracy equivalent to chance. A 21‐feature computer vision model gave a cross‐validation area under the curve of 0.97 (95% confidence interval [CI] 0.95–0.99) in the year‐4 biopsies and 0.79 (95% CI: 0.65–0.92) in the set‐aside year‐2 biopsies. Histology scores were not correlated with change in prostate‐specific antigen level, serum dihydrotestosterone level or gland volume. Key features associated with dutasteride treatment included greater shape and colour uniformity in stroma, irregular clustering of epithelial nuclei, and greater variation in lumen shape.ConclusionThe present findings show that a computer vision approach can detect subtle histological effects attributable to dutasteride, resulting in a continuous measure of responsiveness to the drug that could eventually be used to predict individual patient response in the context of BPH treatment or cancer chemoprevention.
Polycystic ovary syndrome and adverse pregnancy outcomes: Current state of knowledge, challenges and potential implications for practice
Authors: Bahri Khomami Mahnaz , Boyle Jacqueline A. , Tay Chau T. , Vanky Eszter , Teede Helena J. , Joham Anju E. , Moran Lisa J. 
Published: February 2018

SummaryAlthough there is a growing body of literature reporting that pregnancies in women with polycystic ovary syndrome (PCOS) are associated with greater complications than those without PCOS, methodological differences across studies make these results difficult to consolidate. This narrative review outlines potential mechanisms involved in adverse pregnancy outcomes in PCOS and the nature of the complications. It covers limitations of current evidence and future research directions. Future research should include prospective studies with phenotypic stratification of PCOS and matching or consideration of specific PCOS manifestations and risk factors specific to each pregnancy complication. This review also emphasizes the importance of following a healthy lifestyle for women with PCOS and of individualized care according to overall risk factors for pregnancy complications.
Bone mineral density and body composition in children with congenital adrenal hyperplasia
Authors: Halper Alyssa , Sanchez Belen , Hodges James S. , Kelly Aaron S. , Dengel Donald , Nathan Brandon M. , Petryk Anna , Sarafoglou Kyriakie 
Published: February 2018

SummaryObjectiveChildren with congenital adrenal hyperplasia (CAH) are exposed to fluctuating cortisol and androgen levels. The effects these hormonal states have on bone mineral density (BMD) and body composition are not well studied. The study’s objective was to compare BMD and body composition, including visceral adipose tissue (VAT) and Android:Gynoid (A:G) ratio, in children with CAH vs healthy age‐matched, sex‐matched and BMI‐matched controls.DesignTotal body BMD (TBMD) Z‐scores were adjusted for height‐for‐age Z‐scores (TBMDHAZ). Hydrocortisone dose (mg/m2/d) was averaged over the past year. Bone age Z‐scores were used as a surrogate for long‐term androgen exposure in cases. Statistical analyses comparing cases and controls accounted for matched groups using mixed linear models.PatientsForty‐two cases with CAH (average age 12.3 years [SE 3]; 17 males) and 101 controls underwent a dual‐energy X‐ray absorptiometry scan.ResultsChildren with CAH had lower TBMD (0.81 vs 1.27, P = .003) and TBMDHAZ Z‐scores (−0.51 vs −0.01, P = .001) than controls. In CAH cases, TBMD and TBMDHAZ Z‐scores were positively correlated with bone age Z‐scores (r = .63, P < .0001; r = .51, P = .001, respectively) but were not associated with HC dose. VAT and the A:G ratio did not differ significantly between children with CAH and controls and neither was associated with HC dose.VAT was not associated with bone age Z‐score.ConclusionLower BMD was observed in CAH cases compared with controls although no differences in body composition were identified. Among CAH cases, increased chronic androgen exposure, as measured by bone age Z‐scores, was associated with higher BMD but was not associated with VAT.
Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism
Authors: Umakoshi Hironobu , Ogasawara Tatsuki , Takeda Yoshiyu , Kurihara Isao , Itoh Hiroshi , Katabami Takuyuki , Ichijo Takamasa , Wada Norio , Shibayama Yui , Yoshimoto Takanobu , Ogawa Yoshihiro , Kawashima Junji , Sone Masakatsu , Inagaki Nobuya , Takahashi Katsutoshi , Watanabe Minemori , Matsuda Yuichi , Kobayashi Hiroki , Shibata Hirotaka , Kamemura Kohei , Otsuki Michio , Fujii Yuichi , Yamamto Koichi , Ogo Atsushi , Yanase Toshihiko , Okamura Shintaro , Miyauchi Shozo , Suzuki Tomoko , Tsuiki Mika , Naruse Mitsuhide 
Published: February 2018

SummaryContextThe current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature.ObjectiveWe sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone.Design and patientsWe retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35‐40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS.Main outcome measureAccuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years.ResultsConcordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35‐40 years and 69% (198/289) in those aged ≥40 years (trend for P < .01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35‐40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35‐40 years.ConclusionPrimary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.
Copeptin role in polyuria‐polydipsia syndrome differential diagnosis and reference range in paediatric age
Authors: Tuli Gerdi , Tessaris Daniele , Einaudi Silvia , Matarazzo Patrizia , De Sanctis Luisa 
Published: February 2018

SummaryObjectivePlasma arginine‐vasopressin (AVP) analysis can help in the differential diagnosis of the polyuria‐polydipsia syndrome (PPS), even if such investigation is hampered by technical difficulties, conversely to its surrogate copeptin. This study aims to enlarge the existing data on normal copeptin levels in childhood, to evaluate the correlation between copeptin, serum sodium and plasma and urine osmolality, and to assess the utility of the copeptin analysis in the diagnostic work‐up of PPS in the paediatric age.Patients and methodsPlasma copeptin levels were evaluated in 53 children without AVP disorders (control population), in 12 hypopituitaric children and in 15 patients with PPS after water deprivation test (WDT).ResultsMean basal copeptin levels were 5.2 ± 1.56 (range 2.4‐8.6 pmol/L) in the control population, 2.61 ± 0.49 pmol/L in the hypopituitaric children with complete diabetes insipidus (CDI) (P = .04) and 6.21 ± 1.17 pmol/L in the hypopituitaric patients without DI (P = .02). After WDT, among 15 naïve polyuric/polydipsic children, copeptin values greater than 20 pmol/L allowed to identify nephrogenic diabetes insipidus (NDI), concentrations below 2.2 pmol/L complete central DI (CCDI) and between 5 and 20 pmol/L primary polydipsia (PP). Copeptin cut‐off level of 3.5 pmol/L distinguished CDI from PP, with a sensitivity and specificity of 75% and 83.3%, respectively.ConclusionCopeptin evaluation holds promises as a diagnostic tool in paediatric PPS; its interpretation might be useful to promptly distinguish NDI, even avoiding the WDT need.
European Surveillance System on Contact Allergies (ESSCA): polysensitization, 2009–2014
Authors: Dittmar Daan , Uter Wolfgang , Bauer Andrea , Fortina Ana B. , Bircher Andreas J. , Czarnecka‐Operacz Magdalena , Dugonik Aleksandra , Elsner Peter , Gallo Rosella , Ghaffar Sharizan A. , Giménez‐Arnau Anna , Johnston Graham A. , Kręcisz Beata , Filon Francesca L. , Rustemeyer Thomas , Sadowska‐Przytocka Anna , Sánchez‐Pérez Javier , Schnuch Axel , Simon Dagmar , Spiewak Radoslaw , Spring Philipp , Corradin Maria T. , Valiukevičienė Skaidra , Vok Marko , Weisshaar Elke , Wilkinson Mark , Schuttelaar Marie L. ,   for the ESSCA Network
Published: February 2018

BackgroundPolysensitization, defined as being allergic to three or more haptens from the European baseline series, is considered to reflect increased susceptibility to developing a contact allergy, and is likely to be associated with an impaired quality of life.ObjectivesTo evaluate the prevalences of polysensitization across Europe and to analyse factors associated with polysensitization.MethodsPatch test data collected by the European Surveillance System on Contact Allergies (ESSCA;
www.essca‐dc.org) in consecutively patch tested patients from January 2009 to December 2014, comprising 11 countries and 57 departments, were retrospectively analysed.ResultsA total of 86 416 patients were available for analysis, showing a standardized prevalence of polysensitization of 7.02%, ranging from 12.7% (Austria) to 4.6% (Italy). Allergen pairs with the strongest association are reported for the total population, for South Europe, and for North/Central Europe. Overall, polysensitized patients showed a higher percentage of extreme (+++) positive patch test reactions than oligosensitized patients. Female sex, occupational dermatitis and age > 40 years were risk factors for polysensitization.ConclusionsThe varying prevalences of polysensitization across Europe most likely reflect differences in patient characteristics and referral patterns between departments. Known risk factors for polysensitization are confirmed in a European dermatitis population.
Impact of the kidney allocation system on young pediatric recipients
Authors: Parker William Fiske , Ross Lainie Friedman , Richard Thistlethwaite J. , Gallo Amy E. 
Published: February 2018

AbstractThe kidney allocation system (KAS) altered pediatric candidate prioritization. We determined KAS's impact on pediatric kidney recipients by examining delayed graft function (DGF) rates from 2010 to 2016. A propensity score‐matched pediatric recipients pre‐ and post‐KAS. A semiparametric decomposition analysis estimated the contributions of KAS‐related changes in donor characteristics and dialysis time on DGF rate. The unadjusted odds of DGF were 69% higher post‐KAS for young (<10 years at listing) recipients (N = 1153, P = .02) but were not significantly increased for older pediatric (10‐17 years at listing) recipients (N = 2624, P = .48). Post‐KAS, young recipients received significantly fewer pediatric (<18 years) donor kidneys (21% vs 32%, P < .01) and had longer median pretransplant dialysis time (603 vs 435 days, P < .01). After propensity score matching, post‐KAS status increased the odds of DGF in young recipients 71% (OR 1.71, 95% CI 1.01‐2.46). In decomposition analysis, 24% of the higher DGF rate post‐KAS was attributable to donor characteristics and 19% to increased recipient dialysis time. In a confirmatory survival analysis, DGF was associated with a 2.2 times higher risk of graft failure (aHR2.28, 95% CI 1.46‐3.54). In conclusion, KAS may lead to worse graft survival outcomes in children. Allocation changes should be considered.
Ambulatory blood pressure monitoring in living kidney donors: What changes in 10 years?
Authors: Yalin Serkan Feyyaz , Trabulus Sinan , Seyahi Nurhan , Cengiz Mahir , Cicik Mustafa Erdogan , Altiparmak Mehmet Riza 
Published: February 2018

AbstractIn renal transplantation, living donations have more significant benefits compared to cadaveric donations. However, a probable increase in blood pressure following donation should also be kept in mind. In this study, we investigated the long‐term changes in blood pressure in living kidney donors using ambulatory blood pressure monitoring and we explored the e‐GFR and albuminuria/proteinuria measurements at 3 time points. Twenty‐eight living kidney donors and 39 healthy individuals were evaluated and compared at the baseline and later at the 10th year. At the 10th year, creatinine levels were higher and eGFR levels were lower in the donors, whereas the systolic and diastolic measurements of the donors and controls and the prevalence of nondipping in the donors and controls were similar. Our study may be underpowered due to its small population size. However, our results at the 10th year follow‐up indicated that the risk of hypertension might not seem to have increased in the well‐selected donors. In addition, the majority of our donors had preserved their GFR values. Therefore, we can suggest that living kidney donation appears to be safe in well‐selected patients over a 10‐year time frame.
Human Behavior in Project Portfolio Selection: Insights from an Experimental Study
Authors: Schiffels Sebastian , Fliedner Thomas , Kolisch Rainer 
Published: February 2018

ABSTRACTChoosing the right subset from a set of candidate projects is a key driver of success and failure in new product development (NPD). In many cases, managers make these decisions based on intuition or simple rules. We investigate how human decision makers act in the context of project portfolio selection conducting experimental studies based on the knapsack problem. We address the question about which decision rules people apply to select a portfolio and how cognitive limitations influence their selection process. Grounded in portfolio selection practice, we investigate subjects' adherence to four heuristics. Decision making is partially explained by adherence to one simple decision rule, but decision makers' cognitive capacity limits the application of this heuristic. Subjects' cognitive deficits can be avoided by offering basic decision support, thereby increasing their heuristic adherence and their performance.
Epigenetic marks of in utero exposure to gestational diabetes and childhood adiposity outcomes: the EPOCH study
Authors: Yang I. V. , Zhang W. , Davidson E. J. , Fingerlin T. E. , Kechris K. , Dabelea D. 
Published: February 2018

AbstractAimsTo identify gestational diabetes mellitus exposure‐associated DNA methylation changes and assess whether such changes are also associated with adiposity‐related outcomes.MethodsWe performed an epigenome‐wide association analysis, using Illumina 450k methylation arrays, on whole blood collected, on average, at 10.5 years of age from 81 gestational diabetes‐exposed and 81 unexposed offspring enrolled in the EPOCH (Exploring Perinatal Outcomes in Children) study, and on the cord blood of 31 gestational diabetes‐exposed and 64 unexposed offspring enrolled in the Colorado Healthy Start cohort. Validation was performed by pyrosequencing.ResultsWe identified 98 differentially methylated positions associated with gestational diabetes exposure at a false discovery rate of <10% in peripheral blood, with 51 loci remaining significant (plus additional 40 loci) after adjustment for cell proportions. We also identified 2195 differentially methylation regions at a false discovery rate of <5% after adjustment for cell proportions. We prioritized loci for pyrosequencing validation and association analysis with adiposity‐related outcomes based on strengths of association and effect size, network and pathway analysis, analysis of cord blood, and previous publications. Methylation in six out of nine (67%) gestational diabetes‐associated genes was validated and we also showed that methylation of SH3PXD2A was significantly (P<0.05) associated with multiple adiposity‐related outcomes.ConclusionsOur findings suggest that epigenetic marks may provide an important link between in utero exposure to gestational diabetes and obesity in childhood, and add to the growing body of evidence that DNA methylation is affected by gestational diabetes exposure.
Pharmacokinetics of metformin in patients with gastrointestinal intolerance
Authors: McCreight Laura J. , Stage Tore B. , Connelly Paul , Lonergan Mike , Nielsen Flemming , Prehn Cornelia , Adamski Jerzy , Brøsen Kim , Pearson Ewan R. 
Published: February 2018

AimsTo assess potential causes of metformin intolerance, including altered metformin uptake from the intestine, increased anaerobic glucose utilization and subsequent lactate production, altered serotonin uptake, and altered bile acid pool.MethodsFor this pharmacokinetic study, we recruited 10 severely intolerant and 10 tolerant individuals, matched for age, sex and body mass index. A single 500‐mg dose of metformin was administered, with blood sampling at 12 time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin and bile acid concentrations, and compared across the phenotypes.ResultsThe intolerant individuals were severely intolerant to 500 mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median (interquartile range [IQR]) peak concentration 2.1 (1.7‐2.3) mg/L and 2.0 (1.8‐2.2) mg/L, respectively (P= .76); time to peak concentration 2.5 hours; median (IQR) area under the curve (AUC)0–2416.9 (13.9‐18.6) and 13.9 (12.9‐16.8) mg/L*h, respectively (P= .72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CI 2.0‐2.8 and 1.8‐3.0 mmol/L, respectively), and similar incremental AUC0–24in each cohort: tolerant cohort 6.98 (95% CI 3.03‐10.93) and intolerant cohort 4.47 (95% CI –3.12‐12.06) mmol/L*h (P= .55). Neither serotonin nor bile acid concentrations were significantly different.ConclusionsDespite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be attributable to local factors within the lumen or enterocyte.