bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the thermodynamic viability of the formation of benzyl alcohol and toluene from benzoates in milk and fruit yoghurts
Authors: Bocharova Oksana
Published: July 2019

Recent data in respect of the reduction of benzoates to benzyl alcohol and toluene in orange juice show that a risk of toxic substances formation in fruit yoghurt containing benzoates should be re‐evaluated. In this article, the thermodynamic viability of the reduction of benzoates to benzyl alcohol and toluene in milk and yoghurt has been substantiated. Tafel region of redox reactions in milk on the platinum electrode was −0.2 to −0.4 V against  the silver chloride electrode. It has been demonstrated that spontaneous redox processes in fruit yoghurt include the conversion of oxidised forms of fruit polyphenols to reduced forms.
Lactobacilli‐containing vaginal probiotics to cure or prevent bacterial or fungal vaginal dysbiosis: a systematic review and recommendations for future trial designs
Authors: van de Wijgert JHHM , Verwijs MC
Published: July 2019

Background

Vaginal probiotics claiming to cure and/or prevent bacterial and/or fungal vaginal dysbiosis are available on the market but, until recently, did not have to be approved as drugs for human use.

Objectives

We evaluated the impact of vaginal probiotics on bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) cure and/or recurrence, as well as vaginal microbiota (VMB) composition and vaginal detection of probiotic strains.

Search strategy

We performed a systematic literature search in MEDLINE and Embase up to 15 January 2019.

Selection criteria

There were no restrictions in probiotic strains/formulations, study populations, and designs. BV had to be diagnosed by Nugent or Ison‐Hay Gram stain scoring, VVC by culture, wet mount or PCR, and VMB composition/detection by molecular techniques.

Data collection and analysis

The authors independently extracted data.

Main results

All 22 vaginal probiotics evaluated in the 34 eligible studies contained Lactobacillus strains, and some contained additional active ingredients. The probiotics hold promise for BV cure and prevention, but much less so for VVC cure and prevention. No major safety concerns were reported in any of the studies. Vaginal detection of probiotic strains never lasted long beyond the dosing period, suggesting that they did not colonise the vagina. However, findings are not definitive because heterogeneity was high and the quality of most studies suboptimal.

Conclusions

Availability of vaginal probiotics for vaginal health indications will likely decline in 2020 because of regulatory changes. We urge the field to invest in clinical evidence‐based product development and to conduct future trials more rigorously.

Tweetable abstract

Lactobacilli‐containing vaginal probiotics hold promise for bacterial vaginosis cure and prevention, but not for vulvovaginal candidiasis.
Sustained clinical remission of rheumatoid arthritis and its predictive factors in an unselected adult Chinese population from 2009 to 2018
Authors: Xie Wenhui , Li Ji , Zhang Xiaohui , Sun Xiaoying , Zhang Zhuoli
Published: July 2019

Aim

To investigate the prevalence and predictors of sustained remission (SR) in an unselected Chinese rheumatoid arthritis (RA) population.

Patients and methods

Medical records of RA patients from 2009 to 2016 were retrospectively reviewed. Clinical remission was defined according to Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28‐ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and Boolean criteria. Remission persisting for at least 6 months was regarded as SR (6‐month SR). Kaplan‐Meier method and Cox regression analyses were performed to plot cumulative possibility of achieving 6‐month SR and to identify predictors.

Results

Seven hundred and seventy‐nine patients contributing 7958 clinic visits were included. During the follow‐up period, nearly half of patients achieved 6‐month SR according to DAS28‐ESR (51.6%), CDAI (45.6%), SDAI (44.0%), as well as Boolean definitions (42.4%). Median time periods to 6‐month SR were respectively 20.5, 28.7, 30.6, and 32.9 months based on the above criteria. Specifically, 29.4% to 41.2% of patients achieved 6‐month SR at least once in the first year of follow‐up, depending on instruments. Multivariate Cox regression indicated that increasing age, longer disease duration, higher baseline disease activity were independently correlated with reduced possibility of 6‐month SR assessed by nearly all definitions. Conversely, male, early RA, disease‐modifying antirheumatic drug‐naïve and lower disease activity scores in remission measured by corresponding criteria positively contributed to SR. Importantly, treat‐to‐target (T2T) adherence therapy and shorter time to remission were identified as stable determinants of SR across all definitions.

Conclusions

Achieving 6‐month SR was not uncommon in daily practice. Male, early RA, treatment‐naïve, T2T application, shorter time to remission, and lower disease activity scores in remission increased the occurrence of SR, while increasing age, longer disease duration, and higher baseline disease activity reduced the chance of remission sustainability.
Extracorporeal membrane oxygenation (ECMO) assisted mediastinal tumor resection and superior vena cava replacement are safe and feasible
Authors: Zhang Shixin , Tan Deli , Wu Wei , He Bo , Jing Tao , Tang Meng , Wu Tao , Liu Hongxiang , Zhang Ming , Zhou Ni , Tang Lingfeng , Chen Qiao , Tang Jinghua , Xia Mei , Huang Aihong , Liao Yi , Qiu Yang , Wang Haidong
Published: July 2019

Background

How to maximally improve the drainage of intracranial and upper body venous and to reduce neurological complications during thoracic tumor‐causedsuperior vena cava replacement are still clinical problems to be solved.

Methods

We have innovatively used the bilateral jugular vein‐left femoral vein ECMO shunting to perform mediastinal tumor resection and superior vena cava replacement in a 50‐year‐old woman.

Results

During the operation, this technique maintained the patient's hemodynamic stability, improved the cerebral oxygen saturation and reduced the cerebral ischemia, hypoxia as well as the neurological complications.

Conclusion

It is indicated for patients with superior vena cava replacement who are unable to perform venous bypass (such as innominate vein to right atrial bypass) or venous shunting (such as differential pressure drainage from internal jugular vein to femoral vein).
The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand
Authors: Pantazis Caroline B. , James Morgan H. , Bentzley Brandon S. , Aston‐Jones Gary
Published: July 2019

Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as after a 2‐week period of abstinence, to relate the number of LH orexin cells to economic demand for cocaine. We also knocked down LH orexin expression with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. We found that animals with greater baseline motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a 2‐week abstinence from cocaine, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence, indicating that orexin expression is a persistent marker for demand. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual motivation for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.
Landscape characteristics of non‐native pine plantations and invasions in Southern Chile
Authors: Curtis Caroline A. , Pasquarella Valerie J. , Bradley Bethany A.
Published: July 2019

The spread of non‐native conifers into areas naturally dominated by other vegetation types is a growing problem in South America. This process results in a landscape transformation as the conifers suppress native vegetation leading to reduced biodiversity, lower water availability and altered nutrient dynamics. Previous research highlights the broad spatial extents of land cover change in parts of Chile. However, in Southern Chile, the extent of plantations and the landscape characteristics associated with plantations and ongoing pine invasions are poorly understood. Here, we characterised non‐native pine land cover within one Landsat scene (World Reference System 2 Path 232/Row 92; ~34 000 km2) in Southern Chile. We created training data based on historical high‐resolution imagery, derived land cover predictors from time series of Landsat observations and used a Random Forest classifier to map the distribution of non‐native pines. The overall classification accuracy was 88%, and the accuracy of the non‐native pine class exceeded 90%. Although 71% of non‐native pine patches were within 500 m of other non‐native pine patches, isolated non‐native pine patches were found to occur up to 55 km from the nearest neighbour. These distant plantations could exacerbate invasion risk by creating propagule sources for novel invasion fronts. In relation to landscape characteristics, non‐native pines were found to be more likely to occur in low slope and mid‐elevation areas. Because most of the study area is native forest, most non‐native pine patches border native forest. However, non‐native pine patches were almost three times more likely than random patches to border grass/agriculture. This suggests that grasslands and disturbed sites, which have low resistance to non‐native pine invasion, are disproportionately exposed to pine propagules. Our results indicate that non‐native pine plantations are extensive across Southern Chile, and well poised to cause future invasion.
A genome‐wide association study for gestation length in swine
Authors: See G. M. , Trenhaile‐Grannemann M. D. , Spangler M. L. , Ciobanu D. C. , Mote B. E.
Published: July 2019

Selection for increased litter size in swine has potentially resulted in a correlated increase in preweaning mortality. Additional selection criteria should be considered when selecting for increased litter size to account for associated decreases in piglet quality, specifically piglet survival, initial weight and growth. Traits such as gestation length (GL), which have been associated with piglet performance, could be utilized to improve piglet development and survivability. The objective of this study was to conduct a genome‐wide association study to identify genomic regions associated with GL in differing parities in swine (n = 831) from the University of Nebraska–Lincoln reproductive longevity project. Gestation length was calculated as the number of days between last insemination administered and farrowing. Sows were genotyped with the Illumina SNP60 BeadArray, and the data were analyzed using Bayesian mixture models for GL at parity 1, 2, 3 and 4 (GL1, GL2, GL3 and GL4 respectively). Means (SD) for GL1–GL4 were 113 (1.4), 114 (1.2), 114 (1.3) and 115 (1.2) respectively. Posterior mean heritability estimates (PSD) for GL1, GL2, GL3 and GL4 were 0.33 (0.06), 0.34 (0.07), 0.32 (0.08) and 0.20 (0.08) respectively. Rank correlations between genomic estimated breeding values between GL1 and GL2, GL3 and GL4 respectively were moderate: 0.67, 0.65 and 0.60. The top SNP (ASGA0017859, SSC4, 7.8 Mb), located in the top common genomic region associated with GL1, GL2 and GL3, was associated with a difference of 1.1 days in GL1 between homozygote genotypes (P < 0.0001). The results of this study suggest that GL is a largely polygenic trait with relatively minor contributions from multiple genomic regions.
Pulse oximetry screening in a midwifery‐led maternity setting with high antenatal detection of congenital heart disease
Authors: Cloete Elza , Gentles Thomas L. , Webster Dianne R. , Davidkova Sarka , Dixon Lesley A. , Alsweiler Jane M. , Bloomfield Frank H. ,   for the Pulse Oximetry Screening Steering Committee
Published: July 2019

Aim

To assess local and individual factors that should be considered in the design of a pulse oximetry screening strategy in New Zealand's midwifery‐led maternity setting.

Methods

An intervention study was conducted over 2 years. Three hospitals and four primary maternity units participated in the study. Post‐ductal saturation levels were measured on well infants with a gestation of ≥35 weeks. Infant activity and age (hours) at the time of the test were recorded.

Results

Screening was performed on 16 644 of 27 172 (61%) eligible infants. The age at which the screening algorithm was initiated varied significantly among centres. The probability of achieving a pass result (saturations ≥95%) in the context of no underlying pathology ranged from .94 for an unsettled infant screened <4 hours of age to .99 (P < .001) when the test was performed after 24 hours on a settled infant. Forty‐eight (0.3%) infants failed to reach saturation targets: 37 had significant pathology of which three had cardiac disease.

Conclusion

Screening practices were influenced by the setting in which it was undertaken. Infant activity and age at the time of testing can influence saturation levels. Screening is associated with the identification of significant non‐cardiac pathology.
Human myometrial artery function and endothelial cell calcium signalling are reduced by obesity: Can this contribute to poor labour outcomes?
Authors: Prendergast Clodagh , Wray Susan
Published: July 2019

Aims

Determining how obesity affects function in human myometrial arteries, to help understand why childbirth has poor outcomes in obese women.

Methods

Myometrial arteries were studied from 84 biopsies. Contraction (vasopressin and U‐46619) and relaxation (carbachol, bradykinin, SNAP) was assessed using wire myography. eNOS activity was assessed using L‐NAME. Cholesterol was reduced using methyl‐β‐cyclodextrin to determine whether it altered responses. Differences in endothelial cell intracellular Ca2+ signalling were assessed using confocal microscopy.

Results

The effects of BMI on relaxation were agonist specific and very marked; all vessels, irrespective of BMI, relaxed to bradykinin but 0% of vessels (0/13) from obese women relaxed to carbachol, compared to 59% (10/17) from normal weight women. Cholesterol‐lowering drugs did not restore carbachol responses (n = 6). All vessels, irrespective of BMI, relaxed when NO was directly released by SNAP (n = 19). Inhibition of eNOS with L‐NAME had a significant effect in normal but not overweight/obese vessels. Compared to bradykinin, a lower proportion of endothelial cells responded to carbachol and the amplitude of the calcium response was significantly less, in all vessels. Furthermore, a significantly lower proportion of endothelial cells responded to carbachol in the overweight/obese group compared to control. In contrast to relaxation, the effect of contractile agonists was unchanged with increasing BMI.

Conclusions

The ability of human myometrial arteries to relax is significantly impaired with obesity, and our data suggest this is due to a deficit in endothelial calcium signalling. This inability to recover following compression during contractions, might contribute to poor labours in obese women.
No increased risk of nephrotoxicity associated with 5‐aminosalicylic acid in IBD: a population‐based cohort and nested case‐control study
Authors: Jairath Vipul , Hokkanen Suvi R. K. , Guizzetti Leonardo , Boxall Naomi , Campbell‐Hill Sarah , Patel Haridarshan
Published: July 2019

Background

There is conflicting evidence about nephrotoxicity risk associated with 5‐aminosalicylates for treatment of IBD.

Aims

To determine population‐based temporal trends for 5‐aminosalicylates and estimated risk of nephrotoxicity associated with 5‐aminosalicylate use for ulcerative colitis (UC) and Crohn's disease (CD).

Methods

Retrospective cohort and nested case‐control study, using the Health Improvement Network primary care database linked to hospital discharge coding for patients in England, 1996‐2017. Nephrotoxicity risk analysis was a first recorded renal impairment diagnosis adjusted for key variables and was assessed between 2008 and 2017.

Results

A total of 35 601 patients with prevalent UC or CD were included. The proportion of patients prescribed 5‐aminosalicylates fell from 83% in 1996‐1999 to 71% in 2012‐2015 for UC patients and 64% to 45% for CD patients. Thirty per cent of patients had prolonged 5‐aminosalicylate use. Between 2008 and 2017, the incident rate of nephrotoxicity was similar and stable for UC (12.6/1000 person‐years) and CD (10.9/1000 person‐years) patients. Multivariate analysis showed no evidence for association between current prescription of 5‐aminosalicylate and nephrotoxicity in UC or CD patients, comparing ≤ 30 days prescription prior to index vs 31‐≤180 days. However, active disease, disease duration, concomitant cardiovascular disease or diabetes and nephrotoxic drug use were independently associated with development of nephrotoxicity in UC and CD.

Conclusions

Despite the paucity of evidence for their benefit, 5‐aminosalicylates were prescribed to approximately half of CD patients (30% prolonged therapy). Nephrotoxicity was rare in this patient cohort, and was not associated with 5‐aminosalicylate use, but rather with disease status, comorbidity and use of nephrotoxic drugs.
Ten‐year survivors in AL amyloidosis: characteristics and treatment pattern
Authors: Muchtar Eli , Gertz Morie A. , Lacy Martha Q. , Go Ronald S. , Buadi Francis K. , Dingli David , Grogan Martha , AbouEzzeddine Omar F. , Hayman Suzanne R. , Kapoor Prashant , Leung Nelson , Fonder Amie , Hobbs Miriam , Hwa Yi Lisa , Gonsalves Wilson , Warsame Rahma , Kourelis Taxiarchis V. , Russell Stephen , Lust John A. , Lin Yi , Zeldenrust Steven , Kyle Robert A. , Rajkumar S. Vincent , Kumar Shaji K. , Dispenzieri Angela
Published: July 2019

Improvement in survival in Light chain (AL) amyloidosis has been seen over recent decades, enabling more patients to achieve long‐term survival. Patients with AL amyloidosis who survived ≥10 years from time of diagnosis (n = 186) were the subject of this study. Ten‐year survivors represented 22% of the total population. These patients were characterized by favourable patient, organ and plasma cell features. Of note, trisomies were less common among 10‐year survivors compared to those who did not survive to 10 years. All‐time best haematological response was complete response in 67%, very good partial response in 30%, partial response in 2% and no response in 1%, with 11% having received a consolidative strategy for inadequate response to first line therapy. The overall organ response rate to first‐line therapy was 76%, which increased to 86% when considering subsequent line(s) of therapy. Forty‐seven percent of the 10‐year survivors did not require a second‐line therapy. The median treatment‐free survival (TFS) among the 10‐year survivors was 10·5 years (interquartile range 7·4‐12·2). On multivariate analysis independent predictors for TFS were the achievement of complete haematological response and lack of cardiac involvement. Long‐term survivors are increasingly seen in AL amyloidosis and present distinct patient, organ and clonal disease features.
The medium can influence the message: Print‐based versus digital reading influences how people process different types of written information
Authors: Haddock Geoffrey , Foad Colin , Saul Victoria , Brown Will , Thompson Rose
Published: July 2019

While electronic reading devices are extremely popular, research is equivocal regarding their benefits for outcomes such as reader comprehension. Integrating literatures on reading medium comparisons and matching effects in persuasion, this research tested whether comprehension is maximized when the content of the material (e.g., whether it is traditional vs. modern) matches the medium (e.g., reading from a traditional book vs. digital e‐reader). In Study 1, participants read a traditional‐ or modern‐themed short story from either a book or an e‐reader. Story comprehension was greater when participants read from the printed medium compared to the e‐reader, an effect that was marginally moderated by story content, consistent with a matching effect. In Study 2, participants read a persuasive message that emphasized either a traditional versus modern solution to improving health in either a magazine format or on aniPad. Message comprehension was marginally greater among participants who read their message in a printed format. Participants’ interest in weight loss showed evidence of a matching effect – participants were more interested in losing weight when a modern solution to obesity article was presented on aniPad compared to a printed format. The results are applied to the study of reading and attitude change.
Between plate and salt tectonics—New stratigraphic constraints on the architecture and timing of the Dead Sea basin during the Late Quaternary
Authors: Coianiz Lisa , Schattner Uri , Lang Guy , Ben‐Avraham Zvi , Lazar Michael
Published: July 2019

The Dead Sea is an extensional basin developing along a transform fault plate boundary. It is also a terminal salt basin. Without knowledge of precise stratigraphy, it is difficult to differentiate between the role of plate and salt tectonics on sedimentary accumulation and deformation patterns. While the environmental conditions responsible for sediment supply are reasonably constrained by previous studies on the lake margins, the current study focuses on deciphering the detailed stratigraphy across the entire northern Dead Sea basin as well as syn and post‐depositional processes. The sedimentary architecture of the late Quaternary lacustrine succession was examined by integrating 851 km of seismic reflection data from three surveys with gamma ray and velocity logs and the stratigraphic division from an ICDP borehole cored in 2010. This allowed seismic interpretation to be anchored in time across the entire basin. Key surfaces were mapped based on borehole lithology and a newly constructed synthetic seismogram. Average interval velocities were used to calculate isopach maps and spatial and temporal sedimentation rates. Results show that the Amora Formation was deposited in a pre‐existing graben bounded by two N‐S trending longitudinal faults. Both faults remained active during deposition of the late Pleistocene Samra and Lisan Formations—the eastern fault continued to bound the basin while the western fault remained blind. On‐going plate motion introduced a third longitudinal fault, increasing accommodation space westwards from the onset of deposition of the Samra Formation. During accumulation of these two formations, sedimentation rates were uniform over the lake and similar. High lake levels caused an increase in hydrostatic pressure. This led to salt withdrawal, which flowed to the south and southwest causing increased uplift of the Lisan and En Gedi diapirs and the formation of localized salt rim synclines. This induced local seismicity and slumping, resulting in an increased thickness of the Lisan succession within the lake relative to its margins. Sedimentation rates of the Holocene Ze'elim Fm were 4–5 times higher than before. The analysis presented here resolves central questions of spatial extent and timing of lithology, deposition rates and their variability across the basin, timing of faulting at and below the lake floor, and timing and extent of salt and plate tectonic phases and their effect on syn and post‐depositional processes. Plate tectonics dictated the structure of the basin, while salt tectonics and sediment accumulation were primarily responsible for its fill architecture during the timeframe examined here.
The Public Library as Resistive Space in the Neoliberal City
Authors: Aptekar Sofya
Published: July 2019

With reduced hours, decaying infrastructure, and precariously positioned staff, local public libraries provide much needed services in cities devastated by inequality and slashed safety nets. In this article, I draw on ethnographic research of a small public library in a diverse, mostly working class neighborhood in Queens, New York. I show that in addition to providing an alternative to the capitalist market by distributing resources according to people's needs, the library serves as a moral underground space, where middle–class people bend rules to help struggling city residents. Although the library occasionally replicates hegemonic ideologies about immigrant assimilation, it provides a striking example of cross–class and interclass solidarities and resistance to the neoliberal social order. I conclude by discussing the potential of public libraries as everyday spaces of subversion and emancipation, as well as research sites for urban scholars.
Reflectance confocal microscopy may enhance the accuracy of histopathologic diagnosis: A case series
Authors: Shahriari Neda , Grant‐Kels Jane M. , Rabinovitz Harold , Oliviero Margaret , Scope Alon
Published: July 2019

Although histopathology is the time‐honored gold standard diagnostic measure in dermatology, several factors may detract from an accurate microscopic diagnosis. Limiting factors include: human error, suboptimal biopsy‐site selection or biopsy technique, and inherent restrictions of vertical tissue sectioning that lead to incomplete microscopic evaluation of the lesion. Reflectance confocal microscopy (RCM) is a non‐invasive imaging tool that allows for the cellular‐level examination of the lesion, at a horizontal plane, which may complement the subsequent vertical histopathological tissue examination. Herein, we report a case series whereby prebiopsy RCM examination enhanced the accuracy of histopathological diagnosis or allowed for a critical appraisal of initial histopathological misdiagnosis.
Cerebrospinal fluid cytology with abnormal cells: Diagnostic considerations
Authors: Dudrey Ellen , Qiao Jesse , Ezhapilli Sajeev , Gilani Syed M.
Published: July 2019

This is a picture quiz of a finding in cerebrospinal fluid cytology
A 96‐week, multinational, randomized, double‐blind, parallel‐group, clinical trial evaluating the safety and effectiveness of bexagliflozin as a monotherapy for adults with type 2 diabetes
Authors: Halvorsen Yuan‐Di C. , Walford Geoffrey A. , Massaro Joseph , Aftring Robert P. , Freeman Mason W.
Published: July 2019

Aim

To explore the safety and effectiveness of extended exposure to bexagliflozin as a monotherapy for type 2 diabetes.

Methods

Adults with diabetes (n = 288) from the USA, Colombia and Mexico were randomized 1:1 to receive bexagliflozin (20 mg) or placebo for 96 weeks. The primary endpoint was the placebo‐adjusted change in HbA1c at 24 weeks. Dosing was continued an additional 72 weeks to assess safety and the durability of the treatment effect. Secondary endpoints measured changes from baseline in body mass and systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 24, and the change, over study duration, in HbA1c.

Results

The placebo‐adjusted change in HbA1c from baseline to week 24 was −0.79% (−8.6 mmol/mol) [95%CI −0.53, −1.06 (−5.8, −11.6), P < .0001]. The unadjusted change from baseline through week 96 was −0.55% (−6.0 mmol/mol) ± 1.184% (12.9) (SD) for the bexagliflozin arm compared with 0.53% (5.8 mmol/mol) ± 1.215% (13.3) for the placebo arm (P < .0001). Significant decreases in body mass, SBP and DBP could be attributed to bexagliflozin exposure. The incidence of serious adverse events was lower in the bexagliflozin‐treated group (2.8%) than in the placebo group (8.5%). Urinary tract infections occurred less frequently in the active arm (14.5%) than in the placebo arm (20.6%).

Conclusions

Bexagliflozin at 20 mg/d was well tolerated and provided a durable, clinically meaningful improvement in glycaemic control over 96 weeks to participants in this phase 2 trial. A substantial reduction in weight and blood pressure was produced by bexagliflozin, with no increase in significant adverse event rates.
B‐cell frequencies and immunoregulatory phenotypes in myeloproliferative neoplasms: Influence of ruxolitinib, interferon‐α2, or combination treatment
Authors: Sørensen Anders Lindholm , Bjørn Mads Emil , Riley Caroline H. , Holmstrøm Morten , Andersen Mads Hald , Svane Inge Marie , Mikkelsen Stine Ulrik , Skov Vibe , Kjær Lasse , Hasselbalch Hans C. , Nielsen Claus H.
Published: July 2019

Objective

Given a proposed role for PD‐L1+ and IL‐10‐producing B‐cell subsets in promoting certain cancers, we sought to characterize the frequency and phenotype of B cells in patients with chronic myeloproliferative neoplasms (MPNs) and the influence of ruxolitinib and interferon‐α2 therapy.

Methods

We analyzed B‐cell frequencies and phenotype in patients with MPNs (n = 107), before and during treatment with ruxolitinib (n = 29), interferon‐α2 (n = 21), or the two drugs in combination (COMBI; n = 42) and healthy donors (HDs; n = 52) using flow cytometry.

Results

Myelofibrosis patients had lower lymphocyte counts and proportions of B cells than patients with essential thrombocythemia or polycythemia vera and HDs. The B‐cell count correlated inversely with JAK2‐V617F allele burden and spleen size and increased after ruxolitinib or COMBI treatment. The proportions of PD‐L1+ B cells and PD‐1+ B cells were significantly higher in patients with myelofibrosis or polycythemia vera than in HDs and decreased during ruxolitinib and COMBI treatment. The proportions of TNF‐α+ and IL‐6+ B cells were elevated in myelofibrosis patients. The proportion of IL‐6+ B cells decreased, and the proportion of IL‐10+ B cells increased during ruxolitinib treatment.

Conclusion

B‐cell frequency and phenotype were altered in MPN patients. Ruxolitinib therapy had marked effects on both frequency and phenotype.
Fluoxetine‐induced plasticity in the visual cortex outlasts the duration of the naturally occurring critical period
Authors: Steinzeig Anna , Cannarozzo Cecilia , Castrén Eero
Published: July 2019

Heightened neuronal plasticity expressed during early postnatal life has been thought to permanently decline once critical periods have ended. For example, monocular deprivation is able to shift ocular dominance in the mouse visual cortex during the first months of life, but this effect is lost later in life. However, various treatments, such as the antidepressant fluoxetine, can reactivate a critical period‐like plasticity in the adult brain. When monocular deprivation is supplemented with chronic fluoxetine administration, a major shift in ocular dominance is produced after the critical period has ended. In the current study, we characterized the temporal patterns of fluoxetine‐induced plasticity in the adult mouse visual cortex, using in vivo optical imaging. We found that artificially induced plasticity in ocular dominance extended beyond the duration of the naturally occurring critical period and continued as long as fluoxetine was administered. However, this fluoxetine‐induced plasticity period ended as soon as the drug was not given. These features of antidepressant‐induced plasticity may be useful when designing treatment strategies involving long‐term antidepressant treatment in humans.
Cognitive interference as a possible therapeutic strategy to prevent expression of benzodiazepine withdrawal
Authors: Artur de la Villarmois Emilce , Pérez Mariela Fernanda
Published: July 2019

Benzodiazepines are usually prescribed for anxiety and sleep disorders in long‐term schedules that may cause drug dependence. Discontinuation after prolonged administration may lead to withdrawal expression, being anxiety the most predominant sign. The context‐dependent associative learning process that underlies diazepam dependence can be interfered by pre‐exposure to the drug administration context, an effect known as latent inhibition. Considering this background, the primary aim of the present investigation is to develop a therapeutic strategy to prevent diazepam withdrawal in male Wistar rats by interfering with this learning process. Nitric oxide is a crucial player in learning and memory, hippocampal synaptic transmission and in diazepam withdrawal. Then, a secondary goal is to determine how latent inhibition could alter functional plasticity and neuronal nitric oxide synthase enzyme (NOS‐1) expression within the hippocampus, by using multi‐unitary cell recordings and Western blot, respectively. Our results indicate that chronic diazepam treated animals under latent inhibition did not show anxiety, or changes in hippocampal synaptic transmission, but a significant reduction in NOS‐1 expression was observed. Accordingly, pharmacological NOS‐1 inhibition resembles behavioral and electrophysiological changes induced by latent inhibition. Contrary, diazepam treated animals under Control protocol expressed anxiety and evidenced an increased hippocampal‐plasticity, without alterations in NOS‐1 expression. In conclusion, manipulation of the contextual cues presented during diazepam administration may be considered as an effective non‐pharmacological tool to prevent the withdrawal syndrome. This behavioral strategy may influence hippocampal synaptic transmission, probably by alterations in nitric oxide signaling pathways in this structure.
Rainfall variability maintains grass‐forb species coexistence
Authors: Hallett Lauren M. , Shoemaker Lauren G. , White Caitlin T. , Suding Katharine N.
Published: July 2019

Environmental variability can structure species coexistence by enhancing niche partitioning. Modern coexistence theory highlights two fluctuation‐dependent temporal coexistence mechanisms —the storage effect and relative nonlinearity – but empirical tests are rare. Here, we experimentally test if environmental fluctuations enhance coexistence in a California annual grassland. We manipulate rainfall timing and relative densities of the grass Avena barbata and forb Erodium botrys, parameterise a demographic model, and partition coexistence mechanisms. Rainfall variability was integral to grass–forb coexistence. Variability enhanced growth rates of both species, and early‐season drought was essential for Erodium persistence. While theoretical developments have focused on the storage effect, it was not critical for coexistence. In comparison, relative nonlinearity strongly stabilised coexistence, where Erodium experienced disproportionately high growth under early‐season drought due to competitive release from Avena. Our results underscore the importance of environmental variability and suggest that relative nonlinearity is a critical if underappreciated coexistence mechanism.
Increased electroencephalography connectivity precedes epileptic spasm onset in infants with tuberous sclerosis complex
Authors: Davis Peter E. , Kapur Kush , Filip‐Dhima Rajna , Trowbridge Sara K. , Little Elaina , Wilson Andrew , Leuchter Andrew , Bebin Elizabeth M. , Krueger Darcy , Northrup Hope , Wu Joyce Y. , Sahin Mustafa , Peters Jurriaan M. ,   on behalf of the Tuberous Sclerosis Autism Centers of Excellence Research Network
Published: July 2019

Objective

To identify whether abnormal electroencephalography (EEG) connectivity is present before the onset of epileptic spasms (ES) in infants with tuberous sclerosis complex (TSC).

Methods

Scalp EEG recordings were collected prospectively in infants diagnosed with TSC in the first year of life. This study compared the earliest recorded EEG from infants prior to ES onset (n = 16) and from infants who did not develop ES (n = 28). Five minutes of stage II or quiet sleep was clipped and filtered into canonical EEG frequency bands. Mutual information values between each pair of EEG channels were compared directly and used as a weighted graph to calculate graph measures of global efficiency, characteristic path length, average clustering coefficient, and modularity.

Results

At the group level, infants who later developed ES had increased EEG connectivity in sleep. They had higher mutual information values between most EEG channels in all frequency bands adjusted for age. Infants who later developed ES had higher global efficiency and average clustering coefficients, shorter characteristic path lengths, and lower modularity across most frequency bands adjusted for age. This suggests that infants who went on to develop ES had increased local and long‐range EEG connectivity with less segregation of graph regions into distinct modules.

Significance

This study suggests that increased neural connectivity precedes clinical ES onset in a cohort of infants with TSC. Overconnectivity may reflect progressive pathologic network synchronization culminating in generalized ES. Further research is needed before scalp EEG connectivity measures can be used as a potential biomarker of ES risk and treatment response in pre‐symptomatic infants with TSC.
Structural basis for the recognition of MucA by MucB and AlgU in Pseudomonas aeruginosa
Authors: Li Shanshan , Lou Xiaorui , Xu Yueyang , Teng Xiaozhen , Liu Ruihua , Zhang Qionglin , Wu Weihui , Wang Yingying , Bartlam Mark
Published: July 2019

Alginate production in Pseudomonas aeruginosa is regulated by the alternate σ factor AlgU, which in turn is regulated by the MucABCD system. The anti‐σ factor MucA binds AlgU in the cytoplasm and prevents AlgU from binding to the RNA polymerase for transcription. MucB binds MucA in the periplasm and inhibits proteolysis of MucA and subsequent release of AlgU. In this work, we report crystal structures of MucA in complex with AlgU and MucB. A structure of MucB alone reveals the structural changes required for MucA recognition. A unique disulfide bond is identified in MucB, and mutation of this disulfide bond results in a shift from monomer to MucB dimers or tetramers. As MucB tetramers have previously been shown to be unable to bind MucA, this suggests a redox‐sensitive stress response mechanism in MucB. The AlgU–MucA structure reveals a conserved σ factor/anti‐σ factor complex, but AlgU lacks a disulfide bond conserved in many other σ factors. Our structures reveal the molecular basis for MucA recognition by MucB in the periplasm and AlgU in the cytoplasm, thus providing an important step in understanding the mechanisms that regulate a key signal transduction pathway involved in P. aeruginosa pathogenesis.

Database

The atomic coordinates and structure factors for MucAcyto–AlgU, MucB, and MucAperi–MucB have been deposited in the Protein Data Bank (PDB) with the accession code 6IN7, 6IN8, and 6IN9, respectively.
Urbanization‐driven homogenization is more pronounced and happens at wider spatial scales in nocturnal and mobile flying insects
Authors: Merckx Thomas , Van Dyck Hans
Published: July 2019

Aim

We test whether urbanization drives biotic homogenization. We hypothesize that declines in abundance and species diversity of aerial insects are exacerbated by the urbanization‐driven loss of species with low habitat generalism, mobility and warm‐adaptedness. We predict this homogenization to be more pronounced for nocturnal taxa, and at wider scales for mobile taxa.

Location

Belgium.

Time period

Summers 2014–2015.

Major taxa studied

Lepidoptera.

Methods

We compare communities along urbanization gradients using a shared, replicated and nested sampling design, in which butterflies were counted within 81 grassland and macro‐moths light‐trapped in 12 woodland sites. We quantify taxonomic and functional community composition, the latter via community‐weighted means and variation of species‐specific traits related to specialization, mobility and thermophily. Using linear regression models, variables are analysed in relation to site‐specific urbanization values quantified at seven scales (50–3,200 m radii). At best‐fitting scales, we test for taxonomic homogenization.

Results

With increasing urbanization, abundance, species richness and Shannon diversity severely declined, with butterfly and macro‐moth declines due to local‐ versus landscape‐scale urbanization (200 vs. 800–3,200 m radii, respectively). While taxonomic homogenization was absent for butterflies, urban macro‐moth communities displayed higher nestedness than non‐urban communities. Overall, communities showed mean shifts towards generalist, mobile and thermophilous species, displaying trait convergence too. These functional trait models consistently fit best with urbanization quantified at local scales (100–200 m radii) for butterfly communities, and at local to wider landscape scales (200–800 m radii) for macro‐moth communities.

Main conclusions

Urban communities display functional homogenization that follows urbanization at scales linked to taxon‐specific mobility. Light pollution may explain why homogenization was more pronounced for the nocturnal taxon. We discuss that urbanization is likely to impact flying insect communities across the globe, but also that impacts on their ecosystem functions and services could be mitigated via multi‐scale implementation of urban green infrastructure.
Comparing Methods of Barometric Efficiency Characterization for Specific Storage Estimation
Authors: Turnadge Chris , Crosbie Russell S. , Barron Olga , Rau Gabriel C.
Published: July 2019

Groundwater responses to barometric pressure fluctuations are characterized using the concept of barometric efficiency (BE). For semiconfined and confined aquifers, BE values can be used to provide efficient, low‐cost estimates of specific storage. This study compares, for the first time, eight existing methods of BE estimation. Comparisons were undertaken using data from the Peel region of Western Australia. Fourier analysis and regression deconvolution methods were used to estimate aquifer confinement status. The former approach was found to be robust and provided a quantitative basis for spatial comparisons of the degree of confinement. The latter approach was confounded by the presence of diurnal and/or semidiurnal signals. For wells at which semiconfined or confined responses were identified, frequency and time domain methods were used to estimate BE values. Most BE estimation methods were similarly confounded by diurnal and/or semidiurnal signals, with the exception of the Acworth et al. (2016) method. Specific storage values calculated from BE values were order‐of‐magnitude consistent with the results of four historical pumping tests. The methods implemented in this research provide efficient, low‐cost alternatives to hydraulic testing for estimating aquifer confinement, as well as the BE and specific storage of semiconfined and confined aquifers. The frequency and duration of observations required by these methods are minimal; for example, typically requiring a minimum of four observations per day over a four month period. In some locations they may allow additional insights to be derived from existing groundwater hydrograph data.
Martin Trow’s elite‐mass‐universal triptych: Conceptualising Higher Education development
Authors: Scott Peter
Published: July 2019

Martin Trow was among the most influential scholar in Higher Education studies in the second half of the 20th century. He is best known for his conceptualisation of the development of Higher Education into three stages—elite, mass and universal systems. This article considers, first, his intellectual method and the underpinning theory (or lack of it); secondly, the extent to which his ideas, generated in the exceptional environment of post‐war America were, and are, relevant to different national contexts and in the very different environment of the 21st century; thirdly, the strengths—and weaknesses—of Trow’s conceptualisation of three stages of Higher Education development; and, finally the new lines of research suggested by an overall assessment of his work.
Conventional chondrosarcoma with focal clear cell change: a clinicopathological and molecular analysis
Authors: Lam Suk Wai , van Langevelde Kirsten , Suurmeijer Albert J H , Cleven Arjen H G , Bovée Judith V M G
Published: July 2019

Aims

Clear cell chondrosarcomas are known to occasionally contain areas of low‐grade conventional chondrosarcoma; however, the opposite phenomenon has not yet been described. We identified five cases of conventional chondrosarcoma alongside clear cell chondrosarcoma. Here, we report on their clinicopathological and molecular characteristics, and investigate whether these hybrid lesions should be considered to be a collision tumour, conventional chondrosarcoma with clear cell change, or clear cell chondrosarcoma with extensive areas of conventional chondrosarcoma, as this has clinical implications.

Methods and results

Clinicohistopathological features were characterised, immunohistochemistry was performed for H3 histone family member 3B (H3F3B), histone H3 trimethylated on lysine 27 (H3K27me3), and p53, and genetic alterations of IDH1 (encoding isocitrate dehydrogenase 1), IDH2 (encoding isocitrate dehydrogenase 2), TP53 and H3F3B were evaluated. All five chondrosarcomas consisted predominantly of areas with conventional chondrosarcoma. Different grades were found [grade I (n = 1), grade II (n = 2), and grade III (n = 2)]. Up to 20% of the tumour consisted of classic features of clear cell chondrosarcoma. Gradual merging between both components was observed. Molecular analysis of conventional chondrosarcoma components revealed an IDH1 c.395G>T, p.(Arg132Leu) mutation in two cases, and an IDH1 c.394C>T, p.(Arg132Cys) mutation in one case, with identical IDH mutations in the clear cell chondrosarcoma counterpart (100%). Two cases were IDH wild‐type. In all cases, none of the components harboured H3F3B mutations. High‐grade tumours had an aggressive course, as three patients died of the disease.

Conclusion

On the basis of clinicopathological characterisation and genetic alterations, it is suggested that these lesions should be considered to be conventional chondrosarcoma, with clear cell change. Pathologists should be aware of their existence to avoid confusion with clear cell chondrosarcoma, dedifferentiated chondrosarcoma, or chondroblastic osteosarcoma.
Interface evaluation on the brazed system of AlN‐Ticusil‐Graphite
Authors: Chou Tsung‐Te , Tuan Wei‐Hsing , Lin Kun‐Lin
Published: July 2019

The graphite‐Ticusil‐AlN system was joined under vacuum or flowing atmospheres, such as 5% H2‐95% N2 and argon atmosphere, to investigate the morphology and forming mechanism of the reaction phases at the interfaces of AlN‐Ticusil‐graphite layers. Scanning electron microscopy, energy‐dispersive spectroscopy, electron probe microanalysis, and transmission electron microscopy were used to examine the composition and structure of the interface products. The AlN‐Ticusil interface could be divided into two layers, the TiN layer and titanium‐copper–rich compound layer. The thickness of the TiN layer was only affected by the joining temperature and could be regarded as mainly dependent on the reaction. The titanium‐copper compound layer was composed of (Ti,Cu,Al)6N column when joined under vacuum and was composed of TiN particles when joined in a flowing atmosphere. The products on the graphite‐Ticusil interface were also examined as TiC, which was strictly bonded with graphite and Ticusil filler.