bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of diverse ploidy in the arctic‐alpine Arenaria ciliata species complex (Caryophyllaceae) using shoot meristem staining and flow cytometry analysis of archived frozen tissue
Authors: Abukrees Fathi , Kozlowski Gregor , Meade Conor
Published: February 2018

Ploidy levels were analyzed in 21 European populations of the Arenaria ciliata complex using baseline chromosome counts derived from Feulgen staining of HCl‐treated shoot meristems and calibrated flow‐cytometry analysis of fresh and archival frozen tissue. Calibration with two to three control samples of different ploidy facilitated rapid identification of ploidy states in unknown samples. Observed ploidy levels varied from 2N = 40–200, with the majority of populations showing 2N = 40–80. High‐altitude populations collectively showed the full range of ploidy states, but at low elevations only lower ploidy levels were observed. Populations with the highest observed ploidy contained the greatest observed phylogenetic diversity in the western and eastern Alps. Multiple polyploidization events are inferred in the continental European metapopulation, with lower, more stable ploidy characteristic of the west and north. The method deployed provides an effective approach to ploidy analysis for archival desiccated/frozen tissue samples from biogeographic collections.
Viable but non‐culturable and persistence describe the same bacterial stress state
Authors: Kim Jun‐Seob , Chowdhury Nityananda , Yamasaki Ryota , Wood Thomas K.
Published: February 2018

Bacteria are often thought of as having two dormant phenotypes: the viable but non‐culturable (VBNC) state and the persister state. Here we investigate the relatedness of the two stress‐induced phenotypes at the single‐cell level and examine cell morphology and quantify cell resuscitation. Using the classic starvation conditions to create VBNC cells, we found that the majority of the remaining Escherichia coli population are spherical, have empty cytosol and fail to resuscitate; however, some of the spherical cells resuscitate immediately (most probably those with dense cytosol). Critically, all the culturable cells in this starved population became persister cells within 14 days of starvation. We found that the persister cells initially are rod‐like, have clear but limited membrane damage, can resuscitate immediately and gradually become spherical by aging. After 24 h, only rod‐shaped persister cells survive, and all the spherical cells lyse. Both cell populations formed under the VBNC‐inducing conditions and the persister conditions are metabolically inactive. Therefore, the bacterial population consists of dead cells and persister cells in the VBNC‐inducing conditions; that is, the non‐lysed particles that do not resuscitate are dead, and the dormant cells that resuscitate are persister cells. Hence, ‘VBNC’ and ‘persister’ describe the same dormant phenotype.
Recasting Urban Governance through Leeds City Lab: Developing Alternatives to Neoliberal Urban Austerity in Co‐production Laboratories
Authors: Chatterton Paul , Owen Alice , Cutter Jo , Dymski Gary , Unsworth Rachael
Published: February 2018

This article reports on a research project, Leeds City Lab, that brought together partner organizations to explore the meanings and practices of co‐production in the context of urban change. Our intention is to offer a response to the crisis in urban governance by combining the growing academic and practitioner debates on co‐production and urban laboratories in order to explore radically different institutional personae that can respond to deficits in contemporary urban governance, especially relating to participation and disenfranchisement, and ultimately unlock improved ways of designing, managing and living in cities. Our analysis has identified four key ways in which co‐production labs can recast urban governance to more progressive ends: by moving beyond traditional organizational identities and working practices, embracing grey spaces of new civic interfaces, foregrounding emotions and power and committing to durable solutions. Ultimately, what we point towards is that urban governance can be more effectively enacted in co‐production labs that bring together universities and the public, private and civil society sectors on a basis of equality, trust and openness. These spaces have the potential to unlock a city's knowledge, resources and assets, to unpack complex challenges and to build capacity to deliver improved city‐wide solutions.
Reproductive outcome of patients undergoing in vitro fertilisation treatment and diagnosed with bacterial vaginosis or abnormal vaginal microbiota: a systematic PRISMA review and meta‐analysis
Authors: Haahr T , Zacho J , Bräuner M , Shathmigha K , Skov Jensen J , Humaidan P
Published: February 2018

Background

Despite recent efforts, the risks associated with bacterial vaginosis (BV) or abnormal vaginal microbiota in IVF patients are not well‐established.

Objectives

We aimed to evaluate the risks associated with BV in IVF patients using meta‐analysis.

Search strategy

Following preliminary searches to find relevant keywords and MeSH terms, a systematic search was performed in PubMed (MEDLINE) in September 2017.

Selection criteria

The population was infertile women attending IVF treatment. The exposure was BV or abnormal vaginal microbiota. Outcomes included live birth rate, early spontaneous abortion rate and clinical pregnancy rate.

Data collection and analysis

Data were collected for each study and for each outcome using a summary of findings table. If appropriate, data were quantitatively assessed using meta‐analysis, sensitivity analysis, funnel plots and GRADE evidence assessment were performed for the above‐mentioned outcomes.

Main results

A total of 12 studies were eligible, comprising a total of 2980 patients. The prevalence of BV was 16% (95% CI 15–18%) in the general study population and tubal factor infertility was highly prevalent in patients diagnosed with BV compared with normal vaginal microbiota patients (P = 0.001). Despite a significant association with early spontaneous abortion [relative risk (RR) 1.68, 95% CI 1.24–2.27], BV did not significantly impact the live birth rate (RR 1.47, 95% CI 0.96–1.57) or the clinical pregnancy rate (RR 0.93, 95% CI 0.75–1.15).

Conclusions

BV is associated with tubal factor infertility and early spontaneous abortion. However, the quality of evidence was very low and the equivocal results justify the need for further research.

Tweetable abstract

Abnormal vaginal microbiota is associated with early spontaneous abortion in IVF patients.
Estimating Sex Using Metric Analysis of the Scapula by Postmortem Computed Tomography
Authors: Ali Zabiullah , Cox Christopher , Stock Michala K. , Zandee vanRilland Eddy E. , Rubio Ana , Fowler David R.
Published: February 2018

Postmortem computed tomography (CT) has been extensively used in the last decade for identification purposes and in various anthropologic studies. PostmortemCTmeasurements of scapulae, analyzed using logistic discriminant function developed in this study, showed 94.5% accuracy in estimating sex. Data analyzed using the Dabbs and Moore‐Jansen (2010) discriminant function and the discriminant function generated in this study provided nearly identical results with disagreement in only one case. Height and weight were not statically significant in sex prediction. The results of this study show that data obtained from volume rendered postmortemCTimages can be considered reliable and treated as a practical option to standard anthropological methods, especially in mass fatalities as a rapid triage tool for sex determination.
Regulation of specialised metabolites in Actinobacteria – expanding the paradigms
Authors: Hoskisson Paul A. , Fernández‐Martínez Lorena T.
Published: February 2018

The increase in availability of actinobacterial whole genome sequences has revealed huge numbers of specialised metabolite biosynthetic gene clusters, encoding a range of bioactive molecules such as antibiotics, antifungals, immunosuppressives and anticancer agents. Yet the majority of these clusters are not expressed under standard laboratory conditions in rich media. Emerging data from studies of specialised metabolite biosynthesis suggest that the diversity of regulatory mechanisms is greater than previously thought and these act at multiple levels, through a range of signals such as nutrient limitation, intercellular signalling and competition with other organisms. Understanding the regulation and environmental cues that lead to the production of these compounds allows us to identify the role that these compounds play in their natural habitat as well as provide tools to exploit this untapped source of specialised metabolites for therapeutic uses. Here, we provide an overview of novel regulatory mechanisms that act in physiological, global and cluster‐specific regulatory manners on biosynthetic pathways in Actinobacteria and consider these alongside their ecological and evolutionary implications.
Removal of early fruit branches triggered regulations in senescence, boll attributes and yield of Bt cotton genotypes
Authors: Saleem M.F. , Shahid M. , Shakoor A. , Wahid M.A. , Anjum S.A. , Awais M.
Published: February 2018

Premature senescence, unopened and rotted bolls are the primary constrictions hampering the accomplishment of yield potential in Bt cotton. An experiment was conducted with the objectives to delay senescence, enhance boll opening and reduce the boll rotting. The experiment was conducted at two randomly selected sites of University of Agriculture Faisalabad, Pakistan, during 2015 and repeated in 2016. Each experiment was laid out in randomised complete block design with two by two factorial arrangement structure and replicated five times. Treatments were comprised of R0 = no fruit removal; R1 = removal of early fruit branches (REFB) and two genotypes, viz. V1 = FH‐142 and V2 = MNH‐886. Genotypes were selected on the basis of abiotic stress tolerance (FH‐142) and susceptibility (MNH‐886). Nodes above cracked bolls, monopodial branches, opened bolls per plant and seed cotton yield were enhanced by 23, 12, 13 and 17%, respectively, under the influence of REFB over no fruit branch removal, while the REFB‐mediated decrease in boll rotting was 27%. Moreover, the response of MNH‐886 was more remarkable than FH‐142 for all studied variables. Conclusively, REFB increased the number of nodes above a cracked boll, monopodial branches, opened bolls per plant and seed cotton yield while decreased rotted bolls per plant in both genotypes.
The effects of prescribing varenicline on two‐year health outcomes: an observational cohort study using electronic medical records
Authors: Davies Neil M. , Taylor Gemma M. J. , Taylor Amy E. , Jones Timothy , Martin Richard M. , Munafò Marcus R. , Windmeijer Frank , Thomas Kyla H.
Published: February 2018

Aims

To investigate whether smokers prescribed varenicline had lower risks of serious ill‐health during the 4 years following treatment compared with those prescribed nicotine replacement therapy (NRT).

Design

Observational cohort study of electronic medical records.

Setting

A total of 370 UK general practices sampled from the Clinical Practice Research Datalink.

Participants

A total of 126 718 patients aged 18 and over who were issued smoking cessation prescriptions between 1 September 2006 and 31 March 2014.

Measurements

Our primary outcome was all‐cause mortality within 2 years of first prescription as indicated by linked Office of National Statistics data. Our secondary outcomes were cause‐specific mortality, all‐cause, cause‐specific hospitalization, primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease (COPD), body mass index and attendance rate to primary care within 2 years of first prescription. Risk differences and 95% confidence intervals were estimated by multivariable adjusted regression and propensity score matched regression. We used instrumental variable analysis to overcome residual confounding.

Findings

People prescribed varenicline were healthier at baseline than those prescribed NRT in almost all characteristics, highlighting the potential for residual confounding. Our instrumental variable analysis results found that people prescribed varenicline had a similar risk of mortality at 2 years [risk difference per 100 patients treated = 0.67, 95% confidence interval (CI) = ‐0.11 to 1.46)] to those prescribed NRT, and there were similar rates of all‐cause hospitalization, incident primary‐care diagnoses of myocardial infarction and COPD. People prescribed varenicline subsequently attended primary care less frequently.

Conclusions

Smokers prescribed varenicline in primary care in the United Kingdom do not appear to be less likely to die, be hospitalized or experience a myocardial infarction or chronic obstructive pulmonary disease during the following 2 years compared with smokers prescribed nicotine replacement therapy, but they gain more weight and attend primary care less frequently.
Nutritional influences on brain development
Authors: Georgieff Michael K. , Ramel Sara E. , Cusick Sarah E.
Published: February 2018

There is increasing evidence from preclinical and human studies that nutrition in the late foetal and early neonatal period has a significant impact on neurodevelopment across the lifespan. Certain nutrients have particularly large effects in this time period, and their deficits cause greater long‐term risk. The mechanisms by which nutrients influence early brain growth and the sensitive periods for when certain nutrients should be provided are being elucidated. Assessments of nutritional status that index brain growth and predict long‐term development are important to assess the efficacy of early life nutritional therapies. Conclusion: Optimizing nutrition during foetal and early postnatal life is a golden opportunity to impact neurodevelopment and brain function across the lifespan.
Systematic review: probiotics in the management of lower gastrointestinal symptoms – an updated evidence‐based international consensus
Authors: Hungin A. P. S. , Mitchell C. R. , Whorwell P. , Mulligan C. , Cole O. , Agréus L. , Fracasso P. , Lionis C. , Mendive J. , Philippart de Foy J.‐M. , Seifert B. , Wensaas K.‐A. , Winchester C. , de Wit N. ,   the European Society for Primary Care Gastroenterology
Published: February 2018

Background

In 2013, a systematic review and Delphi consensus reported that specific probiotics can benefit adult patients with irritable bowel syndrome (IBS) and other gastrointestinal (GI) problems.

Aim

To update the consensus with new evidence.

Methods

A systematic review identified randomised, placebo‐controlled trials published between January 2012 and June 2017. Evidence was graded, previously developed statements were reassessed by an 8‐expert panel, and agreement was reached via Delphi consensus.

Results

A total of 70 studies were included (IBS, 34; diarrhoea associated with antibiotics, 13; diarrhoea associated with Helicobacter pylori eradication therapy, 7; other conditions, 16). Of 15 studies that examined global IBS symptoms as a primary endpoint, 8 reported significant benefits of probiotics vs placebo. Consensus statements with 100% agreement and “high” evidence level indicated that specific probiotics help reduce overall symptom burden and abdominal pain in some patients with IBS and duration/intensity of diarrhoea in patients prescribed antibiotics or H. pylori eradication therapy, and have favourable safety. Statements with 70%‐100% agreement and “moderate” evidence indicated that, in some patients with IBS, specific probiotics help reduce bloating/distension and improve bowel movement frequency/consistency.

Conclusions

This updated review indicates that specific probiotics are beneficial in certain lower GI problems, although many of the new publications did not report benefits of probiotics, possibly due to inclusion of new, less efficacious preparations. Specific probiotics can relieve lower GI symptoms in IBS, prevent diarrhoea associated with antibiotics and H. pylori eradication therapy, and show favourable safety. This study will help clinicians recommend/prescribe probiotics for specific symptoms.
Microvesicles in hepatic and peripheral vein can predict nonresponse to corticosteroid therapy in severe alcoholic hepatitis
Authors: Sukriti S. , Maras J. S. , Bihari C. , Das S. , Vyas A. K. , Sharma S. , Hussain S. , Shasthry S. , Choudhary A. , Premkumar M. , Kumar D. , Kumar G. , Mukhopadhyay C. , Kumar A. , Trehanpati N. , Rautou P. E. , Moreau R. , Sarin S. K.
Published: February 2018

Background

Severe alcoholic hepatitis patients have high mortality and limited response to corticosteroids. Microvesicles reflect cellular stress and disease conditions.

Aims

To investigate whether microvesicles are associated with severity, response to steroid therapy and inflammation in severe alcoholic hepatitis.

Methods

Microvesicles originating from different cells were studied pre‐therapy in 101 patients; (71 responder to corticosteroid therapy and 30 nonresponders) and 20 healthy controls. Microvesicles and cells were determined in peripheral and hepatic vein samples using flow cytometry and correlated with outcomes. Inflammatory signalling pathways and functional alterations of immune cells after stimulation with microvesicles were also investigated.

Results

Microvesicles mean levels were higher in nonresponders for T cells (CD3+ CD4+; 10.1 MV/μL vs 5.4; P = 0.06), macrophages (CD68+ CD11b+; 136.5 vs 121.9 MV/μL; P = 0.01), haematopoietic stem‐cells (CD45+ CD34+; 116.8 vs 13.4 MV/μL; P = 0.0001) and hepatocytes (ASGPR+; 470 vs 361 MV/μL; P = 0.01); the latter two predicting steroid nonresponse in 94% patients at baseline in peripheral plasma. Microvesicle levels correlated with histological and liver disease severity indices. Whereas, in non‐responders hepatic vein CD34+ cells were lower (P = 0.02), the CD34+ microvesicles there from were higher (P = 0.04), thus suggesting impaired regeneration. Also, microvesicles of 0.2‐0.4 μm size were higher in nonresponders (P < 0.03) at baseline. Microvesicles from patients trigger more (P = 0.04) ROS generation, TNF‐α production (P = 0.04) and up‐regulate pro‐inflammatory cytokine related genes in neutrophils in vitro.

Conclusions

Pre‐therapy peripheral plasma levels of CD34+ and ASGPR+ microvesicles are reliable non‐invasive markers of steroid nonresponse and mortality in patients with severe alcoholic hepatitis.
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

Background

Thiopurine hypermethylation towards 6‐methylmercaptopurine (6MMP) instead of 6‐thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation.

Aims

To prospectively determine efficacy of allopurinol‐thiopurine combination and to compare 2 doses of allopurinol.

Design

In 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.

Results

Of 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).

Conclusions

Low‐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

Questions

How 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?

Location

Ordinary managed forests sampled across 2500 km2 of a typical Central European sub‐montane landscape in the southern part of the Czech Republic.

Methods

We 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.

Results

Species 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.

Conclusions

We 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

Objective

To 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 Methods

Our 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.

Results

Consensus 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.

Conclusion

The 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

Although 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

Objective

Children 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.

Design

Total 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.

Patients

Forty‐two cases with CAH (average age 12.3 years [SE 3]; 17 males) and 101 controls underwent a dual‐energy X‐ray absorptiometry scan.

Results

Children 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.

Conclusion

Lower 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

Context

The 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.

Objective

We 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 patients

We 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 measure

Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years.

Results

Concordance 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.

Conclusion

Primary 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

Objective

Plasma 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 methods

Plasma 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).

Results

Mean 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.

Conclusion

Copeptin 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

Background

Polysensitization, 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.

Objectives

To evaluate the prevalences of polysensitization across Europe and to analyse factors associated with polysensitization.

Methods

Patch 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.

Results

A 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.

Conclusions

The 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

The 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

In 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

Choosing 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

Aims

To identify gestational diabetes mellitus exposure‐associated DNA methylation changes and assess whether such changes are also associated with adiposity‐related outcomes.

Methods

We 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.

Results

We 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.

Conclusions

Our 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.
Epigenetic effects of metformin: From molecular mechanisms to clinical implications
Authors: Bridgeman Stephanie Claire , Ellison Gaewyn Colleen , Melton Phillip Edward , Newsholme Philip , Mamotte Cyril Desire Sylvain
Published: February 2018

There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP‐activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.
Five‐year long‐term clinical outcome after bariatric metabolic surgery: A multi‐ethnic Asian population in Singapore
Authors: Toh Bin C. , Chan Weng H. , Eng Alvin K. H. , Lim Eugene K. W. , Lim Chin H. , Tham Kwang W. , Fook‐Chong Stephanie , Tan Jeremy T. H.
Published: February 2018

Bariatric surgery is an effective treatment for morbid obesity and its metabolic related comorbidities; type 2 diabetes, hypertension and hyperlipidaemia.1 However, the literature is scarce regarding the long‐term outcome after bariatric surgery, especially among multi‐ethnic Asian populations. Considering the growing number of bariatric metabolic surgeries in Asia, we have attempted to provide a regional perspective on 5‐year long‐term clinical outcomes post bariatric surgery in Singapore. Between 2010 and 2016, all bariatric operative cases were included, and these comprised: laparoscopic sleeve gastrectomy (LSG), 393; laparoscopic Roux‐En‐Y gastric bypass (RYGB), 125; laparoscopic mini‐gastric bypass (MGB), 43. The primary outcome measure was the percentage of excess weight loss (% EWL) at 6 months, 1, 2, 3, 4 and 5 years, with % remission of type 2 diabetes mellitus (T2DM) at 1 year following LSG (49.7%, 61.2%, 56.1%, 47.8%, 40.8% and 47.3%; 82.2%), RYGB (60.2%, 62.1%, 57.6%, 50.1%, 48.7% and 47.7%; 86.9%) and MGB (58%, 68.1%, 62.7%, 66.2%, 64.0%, 65.2%; 71.9%). In conclusion, MGB and RYGB showed the greatest % EWL at 5 years and are recommended for moderate T2DM. LSG is an effective bariatric operation with a high % EWL up to 2 years, and a high remission rate of mild T2DM. The remission rate of T2DM was equally high in all 3 surgical groups, independent of ethnic differences.
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

Aims

To 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.

Methods

For 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.

Results

The 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.

Conclusions

Despite 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.