bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcineurin broadly regulates the initiation of skeletal muscle-specific gene expression by binding target promoters and facilitating the interaction of the SWI/SNF chromatin remodeling enzyme
Authors: Witwicka Hanna , Nogami Jumpei , Syed Sabriya A. , Maehara Kazumitsu , Padilla-Benavides Teresita , Ohkawa Yasuyuki , Imbalzano Anthony N.
Published: May 2019

Calcineurin (Cn) is a calcium-activated serine/threonine protein phosphatase that is broadly implicated in diverse cellular processes, including the regulation of gene expression. During skeletal muscle differentiation, Cn activates the NFAT transcription factor but also promotes differentiation by counteracting the negative influences of protein kinase C beta (PKCβ) via dephosphorylation and activation of BRG1, an enzymatic subunit of the mammalian SWI/SNF ATP-dependent chromatin remodeling enzyme. Here we identified four major temporal patterns of Cn-dependent gene expression in differentiating myoblasts and determined that Cn is broadly required for the activation of the myogenic gene expression program. Mechanistically, Cn promotes gene expression through direct binding to myogenic promoter sequences and facilitating the binding of BRG1, other SWI/SNF subunit proteins, and MyoD, a critical lineage determinant for skeletal muscle differentiation. We conclude that the Cn phosphatase directly impacts the expression of myogenic genes by promoting ATP-dependent chromatin remodeling and formation of transcription-competent promoters.
Preparation and in vitro release of fluorouracil polylactide glycolide-polyethylene glycol monomethyl ether nanoparticles
Authors: Shumroni Anil , Gupta David
Published: May 2019

This report demonstrates a novel strategy to prepare fluorouracil polylactide glycolide-polyethylene glycol monomethyl ether (PLGA-mPEG) nanoparticles and study their in vitro release characteristics. Fluorouracil PLGA-mPEG nanoparticles were prepared by nanoprecipitation method. The encapsulation efficiency was determined by high performance liquid chromatography. Based on the single factor experiment, the prescription and preparation process were optimized by orthogonal experiments. The in vitro release characteristics of nanoparticles were studied by dynamic membrane dialysis. Results The prepared nanoparticles were relatively uniform spheroidal particles with an average particle size of about 124. 3 nm, a Zeta potential of - 20. 6 mV, and an average encapsulation efficiency of (44.72 ± 0.38%). In vitro drug release experiments showed that the particle burst release was less than 30% at 2 h, and the drug was slowly released within 48 h after burst release.
Targeting study of HepG2 hepatoma cells in vitro by drug-loaded pectin-based nanoparticles
Authors: Shumroni Anil , Gupta David
Published: May 2019

The biodegradable and biodegradable natural polysaccharide has always been used as a drug delivery system, and has the following advantages: It can prolong the biological half life of the drug and reduce the side effects of the drug. This experiment aimed to prepare a 5-fluorouracil (5-FU) nanoparticle (P-5-FU) drug-loading system based on pectin, and explored a large number of pectin-based nano drug-loading systems. The galactose residue is a natural target that targets human hepatoma cell HepG2. MTT assay was used to determine the proliferation inhibition effect of drug-loaded pectin-based nanoparticles on HepG2 and A549 cells. MTT assay showed that P-5-FU inhibited the proliferation of HepG2 cells in a dose-dependent manner, and the effect was stronger than 5-FU. P-5-FU also inhibited the proliferation of A549 cells in a dose-dependent manner, but there was no significant difference compared with 5-FU. High performance liquid chromatography (HPLC) on two kinds of cells loaded with drug-loaded nanoparticles the uptake and targeting were measured. The results of cell uptake showed that the uptake of P-5-FU by HepG2 cells was significantly higher than that of 5-FU, but there was no significant difference in the uptake of P-5-FU and 5-FU by A549 cells. There was no significant difference in the uptake of P-5-FU and 5-FU between the two cells after the galactose-saturated ASGPR binding site. The results indicate that pectin-based nano drug-loaded particles can specifically target highly expressed cells.
Using the beta distribution to analyse plant cover data
Authors: Damgaard Christian F. , Irvine Kathryn M.
Published: May 2019

Most plant species are spatially aggregated. Local demographic and ecological processes (e.g. vegetative growth and limited seed dispersal) result in a clustered spatial pattern within an environmentally homogenous area. Spatial aggregation should be considered when modelling plant abundance data.

Commonly, plant abundance is quantified by measuring cover within multiple areal plots or along multiple lines randomly placed within a study area. A common practice for analysing plant cover is to use statistical methods that rely on the normal distribution for quantifying uncertainty. This is problematic because plant cover data tend to be left‐skewed (J‐shaped), right skewed (L‐shaped) or U‐shaped and, therefore, commonly violate classic statistical assumptions, such as normality.

We outline statistical analyses that explicitly account for spatial aggregation by assuming that plant cover is beta‐distributed. The beta distribution is a flexible choice because within the open unit interval it can take on a wide range of shapes (L, J, U, or a bell‐shaped). We discuss and introduce extensions to the beta distribution that address common analysis issues encountered in plant cover datasets, such as (a) the treatment of zero and one cover values, (b) hierarchical data structures and (c) observations errors. For heuristic purposes, we focus on single species analyses, but we demonstrate how the outlined methods can be generalized to more species.

The assumption that plant cover is beta‐distributed allows us to estimate the degree of spatial aggregation, and the ecological significance of this new knowledge is discussed. We provide a summary of available software for analyses (emphasizing standard R packages) and include worked examples and a simulation study comparing analysis options as supplemental information.

Synthesis. Previously, the state of the statistical software made it practically difficult for empirical plant ecologists to analyze their cover data correctly, but new theory and R‐packages have been developed, and this difficulty no longer exists. We recommend that empirical plant ecologists embrace the new statistical possibilities for exploring the exciting ecological features in spatial variation of plant cover.
Is civic nationalism necessarily inclusive? Conceptions of nationhood and anti‐Muslim attitudes in Europe
Authors: SIMONSEN KRISTINA BAKKÆR , BONIKOWSKI BART
Published: May 2019

Despite the centrality of national identity in the exclusionary discourse of the European radical right, scholars have not investigated how popular definitions of nationhood are connected to dispositions toward Muslims. Moreover, survey‐based studies tend to conflate anti‐Muslim attitudes with general anti‐immigrant sentiments. This article contributes to research on nationalism and out‐group attitudes by demonstrating that varieties of national self‐understanding are predictive of anti‐Muslim attitudes, above and beyond dispositions toward immigrants. Using latent class analysis and regression models of survey data from 41 European countries, it demonstrates that conceptions of nationhood are heterogeneous within countries and that their relationship with anti‐Muslim attitudes is contextually variable. Consistent with expectations, in most countries, anti‐Muslim attitudes are positively associated with ascriptive – and negatively associated with elective (including civic) – conceptions of nationhood. Northwestern Europe, however, is an exception to this pattern: in this region, civic nationalism is linked to greater antipathy toward Muslims. It is suggested that in this region, elective criteria of belonging have become fused with exclusionary notions of national culture that portray Muslims as incompatible with European liberal values, effectively legitimating anti‐Muslim sentiments in mainstream political culture. This may heighten the appeal of anti‐Muslim sentiments not only on the radical right, but also among mainstream segments of the Northwestern European public, with important implications for social exclusion and political behaviour.
Hedge Fund Regulation and Fund Governance: Evidence on the Effects of Mandatory Disclosure Rules
Authors: HONIGSBERG COLLEEN
Published: May 2019

This paper uses three alternating changes in hedge fund regulation to study whether regulation reduces hedge funds’ misreporting, and, if so, why regulation is effective. Relative to public companies, hedge fund regulation is relatively light. Much of the regime is a “comply‐or‐explain” framework that allows funds to forego compliance with governance rules, providing that they disclose their lack of compliance. The results show that regulation reduces misreporting at hedge funds. Further analysis suggests that the disclosure requirements led funds to make changes in their internal governance, such as hiring or switching the fund's auditor, and that these changes induced funds to report their financial performance more accurately.
Anti‐Diabetic Effects of Gynura Bicolor Aqueous Extract in Mice
Authors: Pai Pei‐ying , Mong Mei‐chin , Yang Ya‐cheng , Liu Yin‐tso , Wang Zhi‐hong , Yin Mei‐chin
Published: May 2019

The effects of Gynura bicolor aqueous extract (GAE) upon glycemic control, coagulation disorder, lipid accumulation, and glycative, oxidative, and inflammatory stresses in diabetic mice were investigated. Mice were treated with streptozotocin to induce type 1 diabetes. Diabetic mice were divided into four groups, consumed GAE at 0%, 0.25%, 0.5%, or 1%. Normal group consumed standard mouse basal diet. After 8‐week treatments, mice were sacrificed after overnight fasting. Results showed that GAE supplement at 0.5% and 1% decreased plasma glucose level and increased plasma insulin level. Diabetes lowered plasma level of protein C and anti‐thrombin III; and raised plasminogen activator inhibitor‐1 activity and fibrinogen level in plasma. GAE supplement at 0.5% and 1% reversed these alterations. Histological data, assayed by Oil Red O stain, indicated that GAE supplement decreased lipid accumulation in liver. GAE supplement at 0.5% and 1% reduced aldose reductase activity in heart and kidney; and lowered the levels of carboxymethyllysine and pentosidine in plasma and two organs. Diabetes decreased glutathione content, and increased reactive oxygen species, interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐α production in heart and kidney. GAE supplement at three test doses reversed these changes. Diabetes upregulated the mRNA expression of p38 and nuclear factor kappa (NF‐κ)B in heart and kidney. GAE supplement suppressed the mRNA expression of both p38 and NF‐κB. These novel findings suggest that Gynura bicolor is a potent functional food for diabetic prevention or alleviation.
Safeguarding Wetlands and Their Connections within Wetlandscapes to Improve Conservation Outcomes for Threatened Amphibian Species
Authors: Zaffaroni Marta , Zamberletti Patrizia , Creed Irena F. , Accatino Francesco , De Michele Carlo , DeVries Ben
Published: May 2019

Wetlands should not be considered as independent objects but as dynamically connected objects, collectively known as wetlandscapes. We developed a framework that analyzes the influences of wetland suitability and connectivity on amphibian distributions. We defined two indices: a Wetland Suitability Index describing wetland quality and a Movement Permeability Index characterizing wetland connectivity for amphibian population dynamics. These indices were calculated from raster datasets and time‐varying inundation estimates. The indices were used to define a wetlandscape and an amphibian model was used to simulate population dynamics within the wetlandscape. The framework was applied to the Nose Creek watershed, a highly modified wetlandscape in Alberta, Canada. Two amphibian species were selected with different habitat preferences: the Northern Leopard Frog that prefers wet habitats and has high mobility over land, and the Great Plains Toad that prefers terrestrial habitats and has low mobility over land. We found each amphibian species had a “preferred” wetlandscape, reflecting their life cycle traits and migration strategies which in turn were dependent on the hydrological and ecological connections within the wetlandscape. This study highlights the importance of investigating both individual wetlands and the wetlandscape and considering both wetland habitat quality and connectivity as non‐substitutable properties that act jointly, but differently, on population dynamics.
RAD‐sequencing for estimating genomic relatedness matrix‐based heritability in the wild: A case study in roe deer
Authors: Gervais Laura , Perrier Charles , Bernard Maria , Merlet Joël , Pemberton Josephine M. , Pujol Benoit , Quéméré Erwan
Published: May 2019

Estimating the evolutionary potential of quantitative traits and reliably predicting responses to selection in wild populations are important challenges in evolutionary biology. The genomic revolution has opened up opportunities for measuring relatedness among individuals with precision, enabling pedigree‐free estimation of trait heritabilities in wild populations. However, until now, most quantitative genetic studies based on a genomic relatedness matrix (GRM) have focused on long‐term monitored populations for which traditional pedigrees were also available, and have often had access to knowledge of genome sequence and variability. Here, we investigated the potential of RAD‐sequencing for estimating heritability in a free‐ranging roe deer (Capreolous capreolus) population for which no prior genomic resources were available. We propose a step‐by‐step analytical framework to optimize the quality and quantity of the genomic data and explore the impact of the single nucleotide polymorphism (SNP) calling and filtering processes on the GRM structure and GRM‐based heritability estimates. As expected, our results show that sequence coverage strongly affects the number of recovered loci, the genotyping error rate and the amount of missing data. Ultimately, this had little effect on heritability estimates and their standard errors, provided that the GRM was built from a minimum number of loci (above 7,000). Genomic relatedness matrix‐based heritability estimates thus appear robust to a moderate level of genotyping errors in the SNP data set. We also showed that quality filters, such as the removal of low‐frequency variants, affect the relatedness structure of the GRM, generating lower h2 estimates. Our work illustrates the huge potential of RAD‐sequencing for estimating GRM‐based heritability in virtually any natural population.
Probe‐based confocal laser endomicroscopy for rapid on‐site evaluation of transbronchial biopsy specimens
Authors: Takemura Masao , Kurimoto Noriaki , Hoshikawa Masahiro , Maeno Toshitaka , Hisada Takeshi , Kurabayashi Masahiko , Inoue Takeo , Miyazawa Teruomi , Mineshita Masamichi
Published: May 2019

Background

Probe‐based confocal laser endomicroscopy (pCLE) is a novel, noninvasive technology that provides real‐time lung imaging during bronchoscopy. pCLE shows the elastic fiber network without the use of a fluorescent dye. Elastic fibers produce argon laser‐induced autofluorescence at a wavelength of 488 nm, but tumor cells do not produce autofluorescence at this wavelength. As a result, the tumor cells cannot be observed directly. Therefore, we stained transbronchial biopsy (TBB) specimens with acriflavine to evaluate the benign and malignant structures using pCLE of ex vivo samples and to determine whether rapid histopathological diagnosis of TBB specimens could be made via pCLE.

Methods

After bronchoscopy, 36 TBB specimens were stained with acriflavine and observed using pCLE. Benign and malignant lesions were classified by cell density and nuclear magnitude disparity.

Results

We defined the confocal laser endomicroscopic atypia classification from the findings of the cells. The sensitivity for malignancy was 91.3%, and the specificity was 76.9%. Both inter‐observer (κ = 0.48) and intra‐observer (κ = 0.57) agreement confirmed moderate agreement.

Conclusion

pCLE with acriflavine staining was useful to differentiate malignant from benign TBB specimens, and might be useful as a substitute for rapid on‐site evaluation of histopathological diagnosis.
Use of a filter cartridge combined with intra‐cartridge bead‐beating improves detection of microbial DNA from water samples
Authors: Ushio Masayuki
Published: May 2019

Microbial communities play an important role in driving the dynamics of aquatic ecosystems. As difficulties in DNA sequencing faced by microbial ecologists are continuously being reduced, sample collection methods and DNA extraction protocols are becoming more critical to the outcome of any sequencing study.

In the present study, I added a manual, intra‐cartridge, bead‐beating step in the protocol using a DNeasy® Blood & Tissue kit for DNA extraction from a filter cartridge without breaking the cartridge unit (“Beads” method) and compared its performance with those of two other protocols (“NoBeads” method, which was similar to the Beads method but without the bead‐beating step and “PowerSoil” method, which followed the manual of the DNeasy® PowerSoil kit after breaking apart the filter cartridge). Water samples were collected from lake, river, pond and coastal ecosystems in Japan and DNA was extracted using the three protocols. Then, the V4 region of prokaryotic 16S rRNA genes was amplified. In the library preparation process, internal standard DNAs were included to estimate the number of DNA copies. The DNA library was sequenced using Illumina MiSeq and sequences were analysed using the amplicon sequence variant (ASV) approach.

I found that, (a) the total prokaryotic DNA yields were highest with the Beads method, (b) the number of ASVs (a proxy for species richness) was also highest with the Beads method, (c) overall community compositions were significantly different among the three methods and (d) the number of method‐specific ASVs was highest with the Beads method. These results were generally robust across samples from all aquatic ecosystems examined.

In conclusion, the inclusion of a bead‐beating step performed inside the filter cartridge increased the DNA yield as well as the number of prokaryotic ASVs detected compared with the other two methods. Performing the bead‐beating step inside the filter cartridge causes no dramatic increase in either handling time or processing cost and it can reduce the potential contamination risk from the ambient air and/or other samples. Therefore, this method has the potential to become one of the major choices when one aims to extract aquatic microbial DNAs.
Exogenous progesterone for smoking cessation in men and women: a pilot double‐blind, placebo‐controlled randomized clinical trial
Authors: Tosun Nicole L. , Fieberg Ann M. , Eberly Lynn E. , Harrison Katherine A. , Tipp Angela R. , Allen Alicia M. , Allen Sharon S.
Published: May 2019

Background and Aims

In some clinical studies men and women have been found to differ in their ability to quit smoking, perhaps as a result of progesterone. The primary aim of this study was to provide a preliminary test of whether progesterone (PRO), compared with placebo (PBO), was more effective for smoking cessation in men and women.

Design

Pilot double‐blind, placebo‐controlled randomized clinical trial.

Setting

Minneapolis/St Paul metro area, Minnesota, USA.

Participants

A total of 216 participants were randomized, including 113 men (18–60 years; PRO = 56, PBO = 57) and 103 women (18–50 years, pre‐menopausal with self‐reported regular menstrual cycles; PRO = 51, PBO = 52).

Intervention

Participants were randomized (1 : 1 within sex group) to either PRO (200 mg twice daily) or PBO. Participants were assigned a quit date approximately 7 days after starting medication (luteal phase for women) and were followed for 12 weeks to assess relapse.

Measurements

The primary outcome was self‐reported 7‐day point prevalence abstinence (PPA) at week 4. Secondary outcomes included 7‐day PPA at weeks 8 and 12, prolonged abstinence, continuous abstinence, urine cotinine < 50 ng/ml, expired carbon monoxide ≤ 5 parts per million (p.p.m.) and days to relapse.

Findings

There was a significant difference in 7‐day PPA at week 4 among women [PRO: 18 (35.3%) versus PBO: 9 (17.3%), odds ratio (OR) = 2.61, 95% confidence interval (CI) = 1.04, 6.54, P = 0.041], but not among men [PRO: 13 (23.2%) versus PBO: 12 (21.1%), 1.13 (0.47, 2.76), P = 0.782]. There was some evidence that PRO delayed relapse in women (days to relapse; PRO: 20.5 ± 29.6 versus PBO: 14.3 ± 26.8, P = 0.03) but not in men (PRO: 13.4 ± 25.9 versus PBO: 13.3 ± 23.8, P = 0.69).

Conclusions

Oral micronized progesterone may aid smoking cessation in women.
Systematic review with meta‐analysis: ultra‐thin gastroscopy compared to conventional gastroscopy for the diagnosis of oesophageal varices in people with cirrhosis
Authors: Wickremeratne Tehara , Turner Stephanie , O'Beirne James
Published: May 2019

Background

Haemorrhage from ruptured oesophageal varices is a common cause of death in people with cirrhosis. Guidelines recommend screening for varices at time of cirrhosis diagnosis and throughout the course of the disease. Conventional gastroscopy is the criterion standard for variceal screening; however, is invasive, costly, and carries risks related to use of sedation. Ultra‐thin gastroscopy (using endoscopes with a shaft diameter ≤6 mm) has been proposed as an alternative method of variceal screening that mitigates these risks.

Aim

To determine the diagnostic accuracy of ultra‐thin gastroscopy compared to conventional gastroscopy for the diagnosis of varices in people with cirrhosis.

Methods

MEDLINE, EMBASE and Cochrane library databases were searched for studies that evaluated the accuracy of ultra‐thin gastroscopy compared to conventional gastroscopy in the diagnosis of oesophageal varices.

Results

Ten studies, 7 in known cirrhosis, with 752 participants were included in this systematic review. The overall prevalence of oesophageal varices was 42%. On bivariate modelling, pooled estimates of sensitivity and specificity were 98% (95% CI 93%‐99%) and 96% (95% CI 91%‐99%) respectively. The positive and negative likelihood ratios were 28 (95% CI 10.7‐73.2) and 0.02 (95% CI 0.01‐0.72) respectively. Kappa coefficient for inter‐observer agreement for any varices ranged from 0.45 to 0.90. No serious adverse events related to ultra‐thin gastroscopy were reported.

Conclusions

Ultra‐thin gastroscopy is accurate in the diagnosis of oesophageal varices, safe and well tolerated. It is a valid alternative to conventional gastroscopy for the screening and surveillance of varices in people with cirrhosis.
Predicting biochemical recurrence and prostate cancer‐specific mortality after radical prostatectomy: comparison of six prediction models in a cohort of patients with screening‐ and clinically detected prostate cancer
Authors: Remmers Sebastiaan , Verbeek Jan F. M. , Nieboer Daan , van der Kwast Theo , Roobol Monique J.
Published: May 2019

Objectives

To perform a comparison and external validation of three models predicting biochemical recurrence (BCR) and three models predicting prostate cancer (PCa)‐specific mortality (PCSM) in a screening setting, i.e. patients with screening‐detected PCa (S‐PCa) and in those with clinically detected PCa (C‐PCa).

Subjects and Methods

We retrospectively evaluated 795 men with S‐PCa, from the European Randomized Study of Screening for Prostate Cancer, Rotterdam, and 1123 men with C‐PCa initially treated with RP. The discriminative ability of the models was assessed according to the area under the curve (AUC) of the receiver‐operating characteristic, and calibration was assessed graphically using calibration plots.

Results

The median (interquartile range [IQR]) follow‐up for the S‐PCa group was 10.4 (6.8–14.3) years and for the C‐PCa group it was 8.8 (4.8–12.9) years. A total of 123 men with S‐PCa (15%) and 389 men with C‐PCa (35%) experienced BCR. Of the men with S‐PCa and BCR, 24 (20%) died from PCa and 29 (23%) died from other causes. Of the men with C‐PCa and BCR, 68 (17%) died from PCa and 105 (27%) died from other causes. The discrimination of the models predicting BCR or PCSM was higher for men with S‐PCa (AUC: BCR 0.77–0.84, PCSM 0.60–0.77) than for the men with C‐PCa (AUC: BCR 0.75–0.79, PCSM 0.51–0.68) as a result of the similar patient characteristics of the men with S‐PCa in the present study and those of the cohorts used to develop these models. The risk of BCR was typically overestimated, while the risk of PCSM was typically underestimated.

Conclusion

Prediction models for BCR showed good discrimination and reasonable calibration for both men with S‐PCa and men with C‐PCa, and even better discrimination for men with S‐PCa. For PCSM, the evaluated models are not applicable in both settings of this Dutch cohort as a result of substantial miscalibration. This warrants caution when using these models to communicate future risks in other clinical settings.
Differences in trends in the use of robot‐assisted and open radical cystectomy and changes over time in peri‐operative outcomes among selected centres in North America and Europe: an international multicentre collaboration
Authors: Zamboni Stefania , Soria Francesco , Mathieu Romain , Xylinas Evanguelos , Abufaraj Mohammad , D`Andrea David , Tan Wei Shen , Kelly John D. , Simone Giuseppe , Gallucci Michele , Meraney Anoop , Krishna Suprita , Konety Badrinath R. , Antonelli Alessandro , Simeone Claudio , Baumeister Philipp , Mattei Agostino , Briganti Alberto , Gallina Andrea , Montorsi Francesco , Rink Michael , Aziz Atiqullah , Karakiewicz Pierre I. , Rouprêt Morgan , Koupparis Anthony , Scherr Douglas S. , Ploussard Guillaume , Sooriakumaran Prasanna , Shariat Shahrokh F. , Moschini Marco ,   the European Association of Urology ‐ Young Academic Urologists (EAU‐YAU), Urothelial carcinoma working group
Published: May 2019

Objectives

To compare trends in the use of robot‐assisted radical cystectomy (RARC) and changes over time in peri‐operative outcomes in selected North American and European centres.

Materials and Methods

We conducted a retrospective evaluation of 2401 patients treated with open radical cystectomy (ORC) or RARC for bladder cancer at 12 centres in North America and Europe between 2006 and 2018. We used the Kruskal–Wallis and chi‐squared test to evaluate differences between continuous and categorical variables.

Results

Overall, 49.5% of patients underwent RARC and 51.5% ORC. RARC became the most commonly performed procedure in contemporary patients, with an increase from 29% in 2006–2008 to 54% in 2015–2018 (P < 0.001). In the North American centres the use of RARC was higher than that of ORC from 2006, and remained stable over time, whereas in the European centres its use increased exponentially from 2% to 50%. In both groups patients who underwent RARC had less advanced T stages (P < 0.001), lower American Society of Anesthesiologists scores (P < 0.05), lower blood loss (P = 0.001) and shorter length of hospital stay (P < 0.05). No differences were found in early complications. Early readmission and re‐operation rates were worse for patients treated with RARC in the European centres; however, when contemporary patients only were considered, the statistical significance was lost.

Conclusion

The present study shows that the use of RARC has constantly increased since its introduction, overtaking ORC in the most contemporary series. While RARC was more frequently performed than ORC since its introduction in the North American centres and its use remained substantially stable over time, its use increased exponentially in the European centres. The different trends in use of RARC/ORC and changes over time in peri‐operative outcomes between the North American and European centres can be attributed to the earlier introduction and spread of RARC in the former compared with the latter.
Lymph node count impacts survival following post‐chemotherapy retroperitoneal lymphadenectomy for non‐seminomatous testicular cancer: a population‐based analysis
Authors: Bhanvadia Raj R. , Rodriguez Joseph , Bagrodia Aditya , Eggener Scott E.
Published: May 2019

Objective

To evaluate the prognostic significance of lymph node count (LNC) at post‐chemotherapy retroperitoneal lymphadenectomy (PC‐RPLND) in metastatic non‐seminomatous germ cell tumour (NSGCT) using the Surveillance, Epidemiology, and End Results (SEER) database and National Cancer Database (NCDB).

Patients and methods

SEER (2000–2013, n = 572) and NCDB (2004–2013, n = 731) identified patients undergoing PC‐RPLND for Stage II and III NSGCT. Correlation between linear or categorial variables and LNC was conducted using Spearman's rank correlation or Kruskal–Wallis test by ranks. Patients were stratified by ≤20, 21–40, and >40 LNs for Kaplan–Meier analysis. Cox proportional hazards models evaluated the association of LNC at PC‐RPLND with overall mortality (OM) in the NCDB and cancer‐specific mortality (CSM) in the SEER database. The relationship between LNC and OM or CSM was also modelled as a non‐linear function to determine a threshold for survival benefit.

Results

Amongst all patients, the median (interquartile range) LNC was 17 (3–26) LNs in the NCDB, and 18 (6–31) LNs in the SEER database. More recent diagnosis year, higher hospital volume, higher median income, private insurance status, and positive LNC were associated with greater total LNC in one or both databases (P < 0.05). On Kaplan–Meier analysis, >40 LNs was associated with 5‐year cancer‐specific survival (CSS) of 99% and overall survival (OS) of 96%, whereas ≤20 LNs had a 5‐year CSS of 91% and OS of 78% (CSS, P = 0.04; OS, P < 0.01). Risk‐adjusted Cox model showed increasing LNC (per node) was inversely associated with OM (hazard ratio [HR] 0.96, 95% confidence interval [CI], 0.94–0.98; P < 0.01) and CSM (HR 0.96, 95% CI, 0.94–0.99; P = 0.01). Non‐linear modelling showed the greatest benefit in OM at between 10 and 20 LNs, but continued survival benefit for OM and CSM beyond 20 LNs.

Conclusions

Greater LNC during PC‐RPLND appears to be associated with improved CSS and OS in NSGCT. Our data support the role of thorough RPLND for post‐chemotherapy metastatic NSGCT.
Hubert's multi‐rater kappa revisited
Authors: Martín Andrés Antonio , Álvarez Hernández María
Published: May 2019

There is a frequent need to measure the degree of agreement among R observers who independently classify n subjects within K nominal or ordinal categories. The most popular methods are usually kappa‐type measurements. When R = 2, Cohen's kappa coefficient (weighted or not) is well known. When defined in the ordinal case while assuming quadratic weights, Cohen's kappa has the advantage of coinciding with the intraclass and concordance correlation coefficients. When R > 2, there are more discrepancies because the definition of the kappa coefficient depends on how the phrase ‘an agreement has occurred’ is interpreted. In this paper, Hubert's interpretation, that ‘an agreement occurs if and only if all raters agree on the categorization of an object’, is used, which leads to Hubert's (nominal) and Schuster and Smith's (ordinal) kappa coefficients. Formulae for the large‐sample variances for the estimators of all these coefficients are given, allowing the latter to illustrate the different ways of carrying out inference and, with the use of simulation, to select the optimal procedure. In addition, it is shown that Schuster and Smith's kappa coefficient coincides with the intraclass and concordance correlation coefficients if the first coefficient is also defined assuming quadratic weights.
Residual endogenous corticosteroid production in patients with adrenal insufficiency
Authors: Vulto Annet , Bergthorsdottir Ragnhildur , van Faassen Martijn , Kema Ido P. , Johannsson Gudmundur , van Beek André P.
Published: May 2019

Objective

This study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency.

Design

Twenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies.

Patients and measurements

Patients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC‐MS/MS

Results

Compared to controls, progressively lower concentrations of the glucocorticoid precursors 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone conce

ntrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11‐deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24‐hour free cortisol excretion in urine.

Conclusions

Adrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.
Brain structure mediates the association between socioeconomic status and attention‐deficit/hyperactivity disorder
Authors: Machlin Laura , McLaughlin Katie A. , Sheridan Margaret A.
Published: May 2019

Low socioeconomic status (SES) is associated with greater risk for symptoms of attention‐deficit/hyperactivity disorder (ADHD). One mechanism through which SES may confer risk for ADHD is by influencing brain structure. Alterations to cortical thickness, surface area and subcortical volume have been associated with low SES and with the presence of ADHD across multiple studies. The current study examined whether cortical thickness, surface area or subcortical volume mediate the associations between SES and ADHD in youth 3–21 years old (N = 874) from the Pediatric Imaging, Neurocognition and Genetics Study. Freesurfer was used to estimate cortical thickness, surface area and subcortical volume from structural magnetic resonance imaging. Parents reported on demographics, family SES, ADHD diagnoses and the presence of child attention problems. Statistical mediation was assessed using a bootstrap resampling procedure. Controlling for parental ADHD, child age, gender, birth weight and scanner, children in low SES families were more likely to be in the ADHD group. Consistent with previous reports in this sample, low SES was associated with reduced surface area across the frontal lobe and reduced subcortical volume in the amygdala, cerebellum, hippocampus and basal ganglia. Of these regions, a significant indirect effect of SES on ADHD status through subcortical volume was observed for the left cerebellum (95% confidence interval: 0.004, 0.022), the right cerebellum (95% confidence interval: 0.006, 0.025), and the right caudate (95% confidence interval: 0.002, 0.022). Environmentally mediated changes in the cerebellum and the caudate may be neurodevelopmental mechanisms explaining elevated risk of ADHD in children in low SES families.
Human rights protection and foreign direct investment: The case of post‐socialist countries
Authors: Lewczuk Anna
Published: May 2019

The main aim of the paper is to evaluate the impact of respect for human rights in post‐socialist countries on the volume of foreign direct investment (FDI). The methodology used in the study consists of the two econometric model specifications–GMM spatial panel Durbin error model and panel gravity ordinary least squares model. The main results indicate a positive and significant relationship between respect for human rights and foreign investment. The outcomes of the spatial model suggest the presence of competition and reinforcement effects of particular kinds of human rights on FDI as well as significance of the ‘human rights distance’.
Factors predicting early mortality after new diagnosis of myelodysplastic syndrome: A population‐based study
Authors: Jacobsen Annie M. , Poynter Jenny N. , Richardson Michaela R. , Nguyen Phuong L. , Hirsch Betsy , Cioc Adina , Roesler Michelle A. , Warlick Erica D.
Published: May 2019

Objective

Little prospective data regarding factors determining patient outcomes in myelodysplastic syndromes (MDS) are available. To establish features of early mortality in MDS, we compare characteristics of patients dying within 1 year of diagnosis with those surviving longer.

Methods

We prospectively enrolled adults with a new MDS diagnosis in a population‐based case‐control study. Logistic regression was used to calculate odds ratios and 95% confidence intervals for potential predictors of early mortality. Subgroup analyses were conducted within the following groups: high‐/very‐high‐risk IPSS‐R; very‐low‐/low‐/intermediate‐risk IPSS‐R; treated patients; and supportive care only patients.

Results

We observed early mortality in those with abnormal cytogenetics (OR: 3.36, 95% CI: 1.52‐7.46), three or greater cytogenetic abnormalities (OR: 3.48, 95% CI: 1.51‐7.99), treatment at a community medical center (versus academic) (OR: 2.55, 95% CI: 1.18‐5.47), and with 2‐3 concurrent medical comorbidities (OR: 2.14, 95% CI: 1.08‐4.22). Similarly, in subgroup analyses, abnormal cytogenetics remained the main predictor of early mortality.

Conclusion

Complex cytogenetics and prognostic risk category have been associated with early mortality without intervention. Our data confirm these associations in a large, prospectively followed cohort and highlight the significance of cytogenetic abnormalities and complexity regardless of IPSS‐R risk categorization or treatment.
Subregional differences in groundfish distributional responses to anomalous ocean bottom temperatures in the northeast Pacific
Authors: Li Lingbo , Hollowed Anne B. , Cokelet Edward D. , Barbeaux Steven J. , Bond Nicholas A. , Keller Aimee A. , King Jacquelynne R. , McClure Michelle M. , Palsson Wayne A. , Stabeno Phyllis J. , Yang Qiong
Published: May 2019

Although climate‐induced shifts in fish distribution have been widely reported at the population level, studies that account for ontogenetic shifts and subregional differences when assessing responses are rare.In this study, groundfish distributional changes in depth, latitude, and longitude were assessed at different size classes by species within nine subregions. We examined large, quality‐controlled datasets of depth‐stratified‐random bottom trawl surveys conducted during summer in three large regions—the Gulf of Alaska and the west coasts of Canada and the United States—over the period 1996–2015, a time period punctuated by a marine “heat wave.” Temporal biases in bottom temperature were minimized by subdividing each region into three subregions, each with short‐duration surveys. Near‐bottom temperatures, weighted by stratum area, were unsynchronized across subregions and exhibited varying subregional interannual variability. The weighted mean bottom depths in the subregions also vary largely among subregions. The centroids (centers of gravity) of groundfish distribution were weighted with catch per unit effort and stratum area for 10 commercially important groundfish species by size class and subregion. Our multivariate analyses showed that there were significant differences in aggregate fish movement responses to warm temperatures across subregions but not among species or sizes. Groundfish demonstrated poleward responses to warming temperatures only in a few subregions and moved shallower or deeper to seek colder waters. The temperature responses of groundfish depended on where they were. Under global warming, groundfish may form geographically distinct thermal ecoregions along the northeast Pacific shelf. Shallow‐depth species exhibited greatly different distributional responses to temperature changes across subregions while deep‐depth species of different subregions tend to have relatively similar temperature responses. Future climate studies would benefit by considering fish distributions on small subregional scales.
High‐Precision Measurement of 187Os/188Os Isotope Ratios of Nanogram to Picogram Amounts of Os in Geological Samples by N‐TIMS using Faraday Cups Equipped with 1013 Ω Amplifiers
Authors: Wang Guiqin , Vollstaedt Hauke , Xu Jifeng , Liu Wengui
Published: May 2019

N(187Os)/N(188Os) ratios of six geological reference materials were measured using static Faraday cups (FCs) with 1013 Ω amplifiers by N‐TIMS. Our results show that the repeatability precision was 2–3‰ (2 RSD, n = 3), when taking ~ 1 g of BHVO‐2 with 76 pg g−1 of Os mass fraction and ~ 2 g of BCR‐2 with 21 pg g−1 of Os mass fraction for each sample, whether measured by FCs or by secondary electron multiplier. The repeatability precision measured by FCs was 1–0.2‰ (2 RSD, n = 3) when taking ~ 1 g of BIR‐2 with 350 pg g−1 of Os mass fraction, ~ 1 g of WGB‐1 with 493 pg g−1 of Os mass fraction or ~ 0.5 g of WPR‐1 with 13.3 ng g−1 of Os mass fraction for each sample, which is much better than those measured by secondary electron multiplier. Instead, when taking ~ 2 g of AGV‐2 with 4 pg g−1 Os mass fraction, the repeatability precision measured by secondary electron multiplier is 3–4‰ (RSD, n = 3), which is better than those measured by FCs. Of the six reference materials analysed, WPR‐1 and BIR‐1a are the most homogeneous with regard to Os isotopic composition (2 RSD of 0.08% and 0.23%, respectively) when test portion masses are 0.5–1 g.
Loss of SMAD4 protein expression in gastrointestinal and extra‐gastrointestinal carcinomas
Authors: Ritterhouse Lauren L , Wu Elizabeth Yiru , Kim Woo Gyeong , Dillon Deborah A , Hirsch Michelle S , Sholl Lynette M , Agoston Agoston T , Setia Namrata , Lauwers Gregory Y , Park Do Youn , Srivastava Amitabh , Doyle Leona A
Published: May 2019

Aims

SMAD4 (DPC4) is a tumour suppressor gene that is dysregulated in various tumour types, particularly pancreaticobiliary and gastrointestinal carcinomas. Corresponding loss of protein expression has been reported in approximately 50% of pancreatic and 25% of colonic adenocarcinomas. In the evaluation of carcinoma of unknown primary site, immunohistochemical loss of SMAD4 expression is often used to suggest pancreaticobiliary origin, but there are limited data on the spectrum of SMAD4 expression in carcinomas of other sites. This study evaluates the frequency of SMAD4 loss in a large cohort of carcinomas from diverse anatomical sites.

Methods and results

Immunohistochemistry for SMAD4 was performed on tissue microarrays or whole tissue sections of 1210 carcinomas from various organs: gastrointestinal tract, liver, pancreas/biliary tract, lung, breast, thyroid, kidney, ovary and uterus. Expression was considered lost when there was complete absence of staining in tumour cell nuclei, in the presence of intact staining in non‐neoplastic cells. SMAD4 loss was seen in 58% of pancreatic adenocarcinomas, 27% of appendiceal adenocarcinomas, 19% of colorectal adenocarcinomas, 16% of cholangiocarcinomas, 10% of lung adenocarcinomas and <5% of oesophageal, breast, gastric and mucinous ovarian adenocarcinomas. All papillary thyroid, hepatocellular, non‐mucinous ovarian, endometrial and renal cell carcinomas showed intact SMAD4 nuclear expression.

Conclusion

In addition to pancreaticobiliary, appendiceal and colonic tumours, SMAD4 loss is also seen in a small subset of other carcinomas, specifically breast, lung, oesophageal and gastric adenocarcinomas, all of which are typically CK7‐positive, similar to pancreaticobiliary carcinoma. Awareness of SMAD4 loss in these other carcinoma types is helpful in the evaluation of carcinomas of unknown or uncertain primary site.
Detection of 5‐HMF in apple juice with artificial sensing systems
Authors: Li Zhao , Yuan Yahong , Yue Tianli , Meng Jianghong
Published: May 2019

5‐HMF (5‐hydroxymethyl‐furfural) is a product of thermal treatment and is increasingly considered a food contaminant. Here, different concentrations of 5‐HMF were measured in apple juice to evaluate the performance of the electronic nose (EN) and electronic tongue (ET) as rapid detection techniques for 5‐HMF when coupled with chemometric analysis. Principal component analysis (PCA) and linear discriminant analysis (LDA) evaluated the discrimination capacity of EN and ET for 5‐HMF. Loading analysis examined the discrimination contribution of the EN sensors. Partial least square (PLS) regression analysis established a quantitative prediction model for different concentrations of 5‐HMF based on EN and ET data set. The optimal models had a coefficient of determination (R2) of 0.926 and a root‐mean‐square error of prediction (RMSEP) of 0.4168 in EN; there were R2 of 0.914 and RMSEP of 0.5836 in ET. These results demonstrate that EN and ET coupled with chemometric analysis are two promising approaches for the rapid and online detection of 5‐HMF in apple juice.
Haematological adverse effects associated with linezolid in patients with drug-resistant tuberculosis: an exploratory study
Authors: Letswee Gotlhe , Kamau Hellen , Gaida Razia , Truter Ilse
Published: May 2019

Objectives

Identify the incidence of haematological adverse effects associated with linezolid.

Methods

Medical records of 27 hospitalised patients in South Africa with drug-resistant tuberculosis (DR-TB) and prescribed linezolid therapy were retrospectively reviewed.

Key findings

Approximately a quarter (n = 7) of patients experienced haematological adverse effects. These included anaemia (14.8%; n = 4), low haemoglobin (7.4%; n = 2) and macrocytosis (3.7%; n = 1). All patients who exhibited haematological adverse effects were living with HIV.

Conclusion

The haematological effects of linezolid manifested in patients who were suffering from co-morbid HIV. Haematological monitoring should be done monthly in order to detect adverse effects timeously and intervene as appropriate.