bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of novel diagnostic and therapeutic exosomes to detect and deplete pro-tumorigenic M2-macrophages
Authors: Rashid Mohammad Harun , Borin Thaiz F. , Ara Roxan , Alptekin Ahmet , Liu Yutao , Arbab Ali S.
Published: November 2019

Given their pro-tumorigenic function and prevalence in most malignant tumors with lower survival, early detection and intervention of CD206-positive M2-macrophages may boost the clinical outcome. To determinein vivodistribution of M2-macrophages, we adopted111In-oxine-based radiolabeling of the targeted exosomes. When injected these radiolabeled targeted exosomes into breast tumor-bearing mice, exosomes accumulated at the periphery of the primary tumor, metastatic foci in the lungs, spleen, and liver.Ex vivoquantification of radioactivity also showed similar distribution. Injected DiI dye-labeled exosomes into the same mice showed adherence of exosomes to the CD206-positive M2-macrophages onex vivofluorescent microscopy imaging. In addition, we utilized these engineered exosomes to carry the Fc portion of IgG2b with the intention of augmenting antibody-dependent cell-mediated cytotoxicity. We have auspiciously demonstrated that M2-macrophage targeting therapeutic exosomes deplete M2-macrophages bothin vitroandin vivo, and reduce tumor burden increasing survival in a metastatic breast cancer model.
Redox signaling modulates Rho activity and tissue contractility in theC. elegansspermatheca
Authors: Kelley Charlotte A. , De Henau Sasha , Bell Liam , Dansen Tobias B. , Cram Erin J.
Published: November 2019

Actomyosin based contractility in smooth muscle and non-muscle cells is regulated by signaling through the small GTPase Rho and by calcium-activated pathways. We use the myoepithelial cells of theCaenorhabditis elegansspermatheca to study the mechanisms of coordinated myosin activationin vivo. Here, we demonstrate that redox signaling regulates RHO-1/Rho activity in this contractile tissue. Exogenous hydrogen peroxide treatment decreases spermathecal contractility by inhibiting RHO-1, which is mediated through a conserved cysteine in its active site (C20). Further, we identify a gradient of oxidation across the spermathecal tissue, which is regulated by the cytosolic superoxide dismutase, SOD-1. SOD-1 functions in the Rho pathway to inhibit RHO-1 through oxidation of C20. Our results suggest that SOD-1 functions to regulate the redox environment and to fine-tune Rho activity across the spermatheca.
A two-lane mechanism for selective biological ammonium transport
Authors: Williamson Gordon , Tamburrino Giulia , Mirandela Gaëtan Dias , Boeckstaens Mélanie , Bage Marcus , Pisliakov Andrei , Ives Callum M. , Terras Eilidh , Bizior Adriana , Hoskisson Paul A. , Marini Anna Maria , Zachariae Ulrich , Javelle Arnaud
Published: November 2019

The transport of charged molecules across biological membranes faces the dual problem of accommodating charges in a highly hydrophobic environment while maintaining selective substrate translocation. A particular controversy has existed around the mechanism of ammonium exchange by the ubiquitous Amt/Mep/Rh transporter family, an essential process in all kingdoms of life. Here, using a combination of electrophysiology, yeast functional complementation and extended molecular dynamics simulations, we reveal a unique two-lane pathway for electrogenic NH4+ transport in two archetypal members of the family. The pathway underpins a mechanism by which charged H+ and neutral NH3 are carried separately across the membrane after NH4+ deprotonation. This mechanism defines a new principle of achieving transport selectivity against competing ions in a biological transport process.
Structure and activation mechanism of the BBSome membrane-protein trafficking complex
Authors: Singh Sandeep , Gui Miao , Koh Fujiet , Yip Matthew C.J. , Brown Alan
Published: November 2019

Bardet-Biedl syndrome (BBS) is an incurable ciliopathy caused by the failure to correctly establish or maintain cilia-dependent signaling pathways. Eight proteins associated with BBS assemble into the BBSome, a master regulator of the ciliary membrane proteome. We report the electron cryomicroscopy (cryo-EM) structures of the native bovine BBSome in inactive and active states at 3.1 and 3.5 Å resolution, respectively. In the active state, the BBSome is bound to an Arf-family GTPase (ARL6/BBS3) that recruits the BBSome to ciliary membranes. ARL6 recognizes a composite binding site formed by BBS1 and BBS7 that is occluded in the inactive state. Activation requires an unexpected swiveling of the β-propeller domain of BBS1, the key subunit implicated in substrate recognition, which widens a central cavity of the BBSome. Structural mapping of disease-causing mutations suggests that pathogenesis predominantly results from disruption of autoinhibition and activation.
An extracellular domain of the EsaA membrane component of the type VIIb secretion system: expression, purification and crystallization
Authors: Mietrach Nicole , Schlosser Andreas , Geibel Sebastian
Published: November 2019

The membrane protein EsaA is a conserved component of the type VIIb secretion system. Limited proteolysis of purified EsaA from Staphylococcus aureus USA300 identified a stable 48 kDa fragment, which was mapped by fingerprint mass spectrometry to an uncharacterized extracellular segment of EsaA. Analysis by circular dichroism spectroscopy showed that this fragment folds into a single stable domain made of mostly α-helices with a melting point of 34.5°C. Size-exclusion chromatography combined with multi-angle light scattering indicated the formation of a dimer of the purified extracellular domain. Octahedral crystals were grown in 0.2 M ammonium citrate tribasic pH 7.0, 16% PEG 3350 using the hanging-drop vapor-diffusion method. Diffraction data were analyzed to 4.0 Å resolution, showing that the crystals belonged to the enantiomorphic tetragonal space groups P41212 or P43212, with unit-cell parameters a = 197.5, b = 197.5, c = 368.3 Å, α = β = γ = 90°.
Crystal structure of the MIF4G domain of the Trypanosoma cruzi translation initiation factor EIF4G5
Authors: Camillo dos Santos Lucca Pietro , de Matos Bruno Moisés , de Maman Ribeiro Brenda Cecilia , Zanchin Nilson Ivo Tonin , Guimarães Beatriz Gomes
Published: November 2019

Kinetoplastida, a class of early-diverging eukaryotes that includes pathogenic Trypanosoma and Leishmania species, display key differences in their translation machinery compared with multicellular eukaryotes. One of these differences involves a larger number of genes encoding eIF4E and eIF4G homologs and the interaction pattern between the translation initiation factors. eIF4G is a scaffold protein which interacts with the mRNA cap-binding factor eIF4E, the poly(A)-binding protein, the RNA helicase eIF4A and the eIF3 complex. It contains the so-called middle domain of eIF4G (MIF4G), a multipurpose adaptor involved in different protein–protein and protein–RNA complexes. Here, the crystal structure of the MIF4G domain of T. cruzi EIF4G5 is described at 2.4 Å resolution, which is the first three-dimensional structure of a trypanosomatid MIF4G domain to be reported. Structural comparison with IF4G homologs from other eukaryotes and other MIF4G-containing proteins reveals differences that may account for the specific interaction mechanisms of MIF4G despite its highly conserved overall fold.
SpaB, an atypically adhesive basal pilin from the lactobacillar SpaCBA pilus: crystallization and X-ray diffraction analysis
Authors: Kumar Megta Abhin , Palva Airi , von Ossowski Ingemar , Krishnan Vengadesan
Published: November 2019

The SpaB pilin is recognized as the basal subunit of the sortase-dependent SpaCBA pilus, which is known to be produced by the Gram-positive Lactobacillus rhamnosus GG, a gut-adapted commensal advocated to have health benefits. Despite seeming to function as an archetypal basal pilin by serving as the terminal subunit in pilus assembly, SpaB also assumes an atypical role as a mucoadhesive protein. To shed light on the structural factors that contribute to this dual functional behaviour, a recombinant form of the L. rhamnosus GG SpaB pilin was produced and purified for crystallization and X-ray diffraction experiments. The crystallization of SpaB remained particularly challenging until the implementation of a three-pronged crystallization approach involving C-terminal tail truncation, surface lysine methylation and magnesium additives. Ultimately, hexagonal crystals of SpaB were produced and were able to diffract to a resolution of 2.4 Å. This crystal form belonged to space group P6522 or P6122, with unit-cell parameters a = b = 51.53, c = 408.22 Å, α = β = 90.0, γ = 120.0°. Obtaining an interpretable electron-density map via single-wavelength anomalous diffraction (SAD) using iodide-derivative data sets did not succeed owing to the weak anomalous signal. As an alternative, attempts to provide phases by molecular replacement using the iodide-SAD data from SpaB and a collection of distant homology models (<28% sequence identity) are in progress.
Managing customer relationships in emerging markets
Authors: Gaur Sanjaya Singh , Kingshott Russel P.J. , Sharma Piyush
Published: November 2019

Purpose

The purpose of this paper is to study the impact of relationship comfort and relationship proneness on the ability of service firms to build and maintain customer relationships in emerging markets (EMs).

Design/methodology/approach

A field-survey was conducted with retail-banking customers in India (n=300) using a structured self-administered questionnaire with well-established scales.

Findings

Relationship comfort positively affects key relationship marketing (RM) constructs (e.g. customer satisfaction, trust, commitment and loyalty) and relationship proneness positively moderates (strengthens) the impact of relationship comfort on customer commitment and loyalty.

Research limitations/implications

The findings may not be generalizable to all customer types using bank services as well as other types of services and in other EMs.

Practical implications

Service firms in EMs can build and maintain robust customer relationships by using relationship comfort and relationship proneness to strengthen key RM constructs, such as customer satisfaction, trust, commitment and loyalty.

Originality/value

The paper highlights the importance of maintaining RM as a tool to build valuable customer relationships but also reveals the importance of relationship comfort and relationship proneness in building trust-based customer relationships in the EMs.
The impact of surveillance and procedurally just behavior on civilian affect and responses in hypothetical interactions with police officers
Authors: Roche Sean Patrick
Published: November 2019

Purpose

The purpose of this paper is to investigate the impact of surveillance from civilian smartphones and police body-worn cameras (BWCs), procedurally just tactics, and legal culpability on individuals’ emotional reactions and willingness to comply during police interactions.

Design/methodology/approach

Data are used from two randomized factorial survey vignette experiments conducted with a national sample of Americans (n=962).

Findings

The presence of BWCs reduces reported fear in both vignettes, and also reduces reported anger in one vignette. In contrast, the presence of a smartphone is not significantly related to anger or fear. In both vignettes, non-procedurally just treatment increases reported fear and anger, and decreases intent to comply, with reported anger mediating the relationship between non-procedurally just treatment and compliance.

Originality/value

These findings suggest different forms of surveillance may have distinct effects on citizens’ reported emotional states and behavioral intentions. Further, the results corroborate research on the relationship between procedural justice and affect, and provide evidence procedurally just strategies may decrease crime directly by preemptively dampening non-compliance.
Trade‐offs between age‐related breeding improvement and survival senescence in highly polygynous elephant seals: Dominant males always do better
Authors: Lloyd Kyle J. , Oosthuizen W. Chris , Bester Marthán N. , de Bruyn P. J. Nico
Published: November 2019

Life‐history trade‐off theory predicts that current reproduction can negatively affect survival and future reproduction. Few studies have assessed breeding costs for males of polygynous species compared to females, despite substantial variation in breeding success among individual males (e.g. subordinate cf. dominant breeders). Specifically, differentiating between the cost of attending breeding events, and the additional cost of successfully securing and mating females is lacking.

We investigated whether trade‐offs are present in the highly polygynous male southern elephant sealMirounga leoninausing 34 years of individual‐level data. We compare age‐specific survival, recruitment and future breeding success probabilities of pre‐breeders (males yet to recruit) and breeders (subordinate and dominant social ranks) using multievent models.

Pre‐breeders and breeders of overlapping ages had similar survival probabilities, suggesting that there was no attendance cost for early recruits. In addition, the probability of recruiting as a dominant breeder never exceeded recruitment probability as a subordinate breeder of the same age. Therefore, older pre‐breeders that delayed attendance costs generally did not improve their breeding success (probability of being dominant) at recruitment more than younger recruits. Rather, recruitment age may be a function of individual quality, with lower quality individuals requiring more time to socially mature.

When comparing subordinate and dominant breeders, we found clear evidence for survival senescence, with subordinate breeders having a higher baseline mortality. In contrast, age‐specific future breeding success (probability of being dominant att + 1) increased with age, with dominant breeders maintaining higher subsequent breeding success than subordinate breeders.

The opposite trends in survival and future breeding success for both subordinate and dominant breeders may indicate a lifetime, population‐level trade‐off. However, we found no evidence to suggest that being a dominant breeder consecutively (and having a higher accumulated breeding cost) accelerated the rate of senescence when compared to individuals that were previously subordinate.

Thus, males experienced actuarial senescence regardless of social rank, with dominant (and possibly high quality) breeders showing a reduced trade‐off between survival and future breeding success. We make several novel contributions to understanding polygynous male life histories and southern elephant seal demography.
Augustus Earle's Waterfall in Australia and the Logic of Fantasy
Authors: Broadfoot Keith
Published: November 2019

Augustus Earle's depiction of a colonial waterfall in his major painting, Waterfall in Australia, has been understood as one that challenges convention. Earle represents himself as turning away from the waterfall, seemingly uninterested in the sublime vista behind him. This essay offers a new reading of the painting, proposing that Earle's gesture should be understood as a turn from the sublime as prospect to what Slavoj Žižek, after Jacques Lacan, has theorized as the sublime as object. Not so much highlighting Earle's ability to step outside of the governing ideology of the time, then, with Earle's placement of an Aborigine in front of the waterfall the argument is made that there is the staging of a colonial fantasy, one that presents the Aborigine as all that the colonial lacks. Through the close analysis of this one painting, what this essay ultimately seeks to demonstrate is how colonial art can be seen anew by a re‐engaging with the work of Lacan.
Social Stigma and Support for the Populist Radical Right: An Experimental Study
Authors: Harteveld Eelco , Dahlberg Stefan , Kokkonen Andrej , van der Brug Wouter
Published: November 2019

The ‘taboo’ or ‘stigma’ associated with many populist radical right parties (PRRPs) has been argued to be an important constraint on their electoral success. In comparison to mainstream parties, there seems to be a higher barrier keeping voters from supporting PRRPs. However, this mechanism has not been tested directly. We conducted a randomized survey‐embedded experiment manipulating the social stigma of a fictitious radical right party in Sweden. We compare three conditions. Two of these contain subtle signals about how other respondents feel about this party. In one condition the fictitious party is supported by many voters (the neutralizing condition) and in the other it is evaluated negatively by the overwhelming majority (the stigma condition). Both experimental groups do not differ significant from the control group in support for this fictitious party. However, the difference between the two experimental groups is borderline significant. This suggests that there is a causal effect of social stigma on support for a RRP, even though the evidence is rather tentative.
Boundaryless careers in the gig economy: An oxymoron?
Authors: Kost Dominique , Fieseler Christian , Wong Sut I
Published: November 2019

Advocates of the boundaryless career perspective have relied to a great extent on the assumption that actors take responsibility for their own career development and that they consequently take charge of developing their career competencies. In this provocation piece, we debate the obstructions to and potential ways to promote boundaryless careers in the gig economy, which—despite appearing on the surface to offer suitable conditions for boundaryless careers—suffers from numerous conditions that hinder such careers. Thus, boundaryless careers in the gig economy could be an oxymoron. In particular, we conjecture that intraorganisational and interorganisational career boundaries restrict gig workers' development of relevant career competencies and thus limit their mobility. We then put forward the notion that we have to consider moving away from traditional, employer‐centric human resource management and introduce new forms of network‐based and self‐organised human resource management practices (in the form of collaborative communities of practice) in order to diminish these boundaries.
‘All the productions of that nature’: Ephemera, Mycology and Sexual Classification at the Bulstrode Estate
Authors: Schurch Millie
Published: November 2019

The study of fungi posed challenges to the botanical activities at the scientific and sociable site of Bulstrode between 1763 and 1785. This article examines the mycological practices at Bulstrode as they appeared in letters, sketches and notes by John Lightfoot, Mary Delany, Georg Dionysius Ehret and Margaret Bentinck, duchess of Portland. I argue that the descriptive and analytical difficulties that fungi presented, and the flexibility and inconclusiveness of ephemeral productions, gave the botanists at Bulstrode opportunities to configure their own botanical identities, pursue their scientific ambitions and address the limitations of Linnaeus's sexual system of classification.
The Sexes and the Sciences
Authors: Wagner Darren N. , Wharton Joanna
Published: November 2019

This is an introduction to a special issue on the theme ‘The Sexes and the Sciences’. Here we provide useful context for the ensuing research articles by way of discussing specific terms (‘science’ and ‘sex’), detailing relevant historiographies and presenting select, illuminating case studies. Taken as a whole, this special issue demonstrates that eighteenth‐century scientific understandings of the sexes – male and female – were diverse and debated, and that, while formal scientific institutions and publications were almost exclusively comprised of men, their gendered relationships were various, and numerous women still meaningfully contributed to science as both practitioners and patrons.
Sex and Prisons: Women and Spanish Penitentiary Reform, 1787‐1808
Authors: Serrano Elena
Published: November 2019

Whereas prisons had previously been thought of as transitory places for those awaiting trial, the new prison system aimed at the reformation of convicts. In Spain the first organisation set up to improve prison conditions was the Señoras de las Cárceles. This article shows how the Señoras attempted to erase the sexual aspect of women's prisons and create instead a morally acceptable space in which to educate female prisoners. Their practices reveal how changing ideas about punishment and education, sexuality and gender, entered the Spanish penal system, permeated civil society and facilitated the transition to a different legal regime.
Isolated peripheral pulmonary stenosis in Takayasu arteritis
Authors: Alizadehasl Azin , Saedi Sedigheh , Ganji Hanifeh , Pourafkari Leili
Published: November 2019

Takayasu arteritis is a chronic granulomatous vasculitis generally affecting large vessels including the thoracic aorta and its branches. Intimal proliferation subsequently causes segmental stenosis and occlusion, and frequently aneurysmal dilatation in the affected vessels. Although involvement of pulmonary arteries is not uncommon, isolated branch pulmonary stenosis is rarely encountered. Here, we report a patient presenting with isolated peripheral pulmonary stenosis as the primary manifestation of Takayasu arteritis.
Natural Killer Cells Contribute to Pathogenesis of Severe Alcoholic Hepatitis by Inducing Lysis of Endothelial Progenitor Cells
Authors: Sehgal Rashi , Kaur Savneet , Shasthry Saggere Murli , Agrawal Tanvi , Dwivedi Varsha , Seth Devanshi , Ramakrishna Gayatri , Sarin Shiv Kumar , Trehanpati Nirupma
Published: November 2019

Background

Endothelial progenitor cells (EPCs) help in neovascularization and endothelial repair during injury. Patients with cirrhosis show increased number and function of EPCs in circulation.

Methods

Since natural killer (NK) cells regulate EPCs, we investigated the relationship between the 2 in alcoholic cirrhosis (AC, n = 50) and severe alcoholic hepatitis (SAH, n = 18) patients and compared with nonalcoholic cirrhosis (n = 15) and healthy controls (HC, n = 30). Levels of systemic inflammatory cytokines were measured, and coculture assays were performed between EPCs and NK cells in contact‐dependent and contact‐independent manner. NK cell–mediated killing of EPCs was evaluated, and expression of receptors including fractalkine (FKN) on EPCs and its cognate receptor CX3CR1 on NK cells was studied by RT‐PCR assays.

Results

Patients with SAH had higher regulated on activation, normal T cell expressed and secreted (RANTES) (p = 0.01), vascular endothelial growth factor (VEGF) (p = 0.04), IL‐1β (p = 0.04), and IL‐6 (p = 0.00) growth factors and proinflammatory cytokines as compared to AC and HC. Distinct populations of CD31+ CD34+ EPCs with low and high expression of CD45 were significantly lower in SAH than HC (CD45low, p = 0.03; CD45hi, p = 0.04) and AC (CD45low, p = 0.05; CD45hi, p = 0.02). SAH patients, however, showed increased functional capacity of EPCs including colony formation and LDL uptake. NK cells were reduced in SAH compared with AC (p = 0.002), however with higher granzyme ability (p < 0.001 and p = 0.04, respectively). In SAH, EPC‐NK cell interaction assays showed that NK cells lysed the EPCs in both contact‐dependent and contact‐independent assays. Expression of interaction receptor CX3CR1 was significantly higher on NK cells (p = 0.0005), while its cognate receptor, FKN, was increased on EPCs in SAH patients as compared to HC (p = 0.0055).

Conclusion

We conclude that in SAH, NK cells induce killing of EPCs via CX3CR1/FKN axis that may be one of the key events contributing to disease severity and proinflammatory responses in SAH.
Personalized medicine begins with the phenotype: identifying antipsychotic response phenotypes in a first‐episode psychosis cohort
Authors: Mas S. , Gassó P. , Rodríguez N. , Cabrera B. , Mezquida G. , Lobo A. , González‐Pinto A. , Parellada M. , Corripio I. , Vieta E. , Castro‐Fornieles J. , Bobes J. , Usall J. , Saiz‐Ruiz J. , Contreras F. , Parellada E. , Bernardo M. ,   PEPs group
Published: November 2019

Aims

Here, we present a clustering strategy to identify phenotypes of antipsychotic (AP) response by using longitudinal data from patients presenting first‐episode psychosis (FEP).

Method

One hundred and ninety FEP with complete data were selected from the PEPs project. The efficacy was assessed using total PANSS, and adverse effects using total UKU, during one‐year follow‐up. We used the Klm3D method to cluster longitudinal data.

Results

We identified four clusters: cluster A, drug not toxic and beneficial; cluster B, drug beneficial but toxic; cluster C, drug neither toxic nor beneficial; and cluster D, drug toxic and not beneficial. These groups significantly differ in baseline demographics, clinical, and neuropsychological characteristics (PAS, total PANSS, DUP, insight, pIQ, age of onset, cocaine use and family history of mental illness).

Conclusions

The results presented here allow the identification of phenotypes of AP response that differ in well‐known simple and classic clinical variables opening the door to clinical prediction and application of personalized medicine.
Behavioral couples therapy versus cognitive behavioral therapy for problem gambling: a randomized controlled trial
Authors: Nilsson Anders , Magnusson Kristoffer , Carlbring Per , Andersson Gerhard , Hellner Clara
Published: November 2019

Background and aims

There is evidence that cognitive behavioral therapy (CBT) is effective for treating problem gambling (PG). Some research points to the possible benefits of involving concerned significant others (CSOs) in treatment. This study compared the efficacy of behavioral couples therapy (BCT) and CBT for both the gambler and the CSO.

Design

Two parallel‐group randomized controlled study comparing two different internet‐based treatments for PG. Follow‐up measures were conducted at treatment finish, and at 3‐, 6‐ and 12‐month post‐treatment.

Setting

Stockholm, Sweden.

Participants

A total of 136 problem gamblers and 136 CSOs were included in the study: 68 gamblers and 68 CSOs for each treatment condition. The gamblers were on average 35.6 years old and 18.4% were female. CSOs were on average 45.3 years old and 75.7% were women.

Interventions

A treatment based on BCT was compared with a CBT intervention. Both treatments were internet‐based, with 10 therapist‐guided self‐help modules accompanied by weekly telephone and e‐mail support from a therapist. CSOs were given treatment in the BCT condition, but not in the CBT condition.

Measurements

The primary outcome measures were time‐line follow‐back for gambling (TLFB‐G) and the NORC Diagnostic Screen for Gambling Problems (NODS) for problem gamblers, corresponding to DSM‐IV criteria for pathological gambling. Secondary outcomes measures were the Patient Health Questionnaire‐9 (PHQ‐9), the Generalized Anxiety Disorder seven‐item scale (GAD‐7), the Relation Assessment Scale Generic (RAS‐G), the Alcohol Use Disorders Identification Test (AUDIT), the Inventory of Consequences of Gambling for the Gambler and CSO (ICS) and adherence to treatment for both the problem gambler and the CSO.

Findings

The outcomes of both gambler groups improved, and differences between the groups were not statistically significant: TLFB‐G: multiplicative effect = 1.13, 95% confidence interval (CI) = 0.30;4.31); NODS: multiplicative effect = 0.80, 95%, 95% CI = 0.24;2.36. BCT gamblers began treatment to a higher proportion than CBT gamblers: P = 0.002.

Conclusions

Differences in the efficacy of internet‐based behavioral couples therapy and cognitive behavioral therapy for treatment of problem gambling were not significant, but more gamblers commenced treatment in the behavioral couples therapy group.
Socioeconomic disparities in leisure activities over the life course of the oldest‐old in China
Authors: Cao Jiangling , Qian Dongfu , Yang Fan
Published: November 2019

Objective

To identify the socioeconomic factors leading to disparities in participation in leisure activities over the life course among Chinese oldest‐old people.

Methods

Data are from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a sample of adults aged 80 years or older in the period 1998‐2012, featuring 38 312 individuals (58 945 observations).

Results

The younger birth cohorts were found to have significantly higher levels of participation in leisure activities, with a non‐linear decrease in age observed for oldest‐old men and women. Higher participation levels were significantly related to higher education levels, economic independence and non‐manual occupations before retirement among the Chinese oldest‐old.

Conclusions

Leisure activity participation has increased substantially in recent cohorts of Chinese oldest‐olds. Those with lower socioeconomic status may represent a disadvantaged population in terms of participation in leisure activities over their life course.
Short‐term antibiotic exposure affected the type and resistance of uropathogens similar to long‐term antibiotic prophylaxis in children hospitalised for urinary tract infections
Authors: Fostira Ekaterini , Bitsori Maria , Vergadi Eleni , Maraki Sofia , Galanakis Emmanouil
Published: November 2019

Aim

We investigated the impact of any antibiotic exposure on unusual and resistant pathogens in children with a urinary tract infection (UTI).

Methods

This was a retrospective cohort study of 695 children (54% female) hospitalised with 711 UTI episodes at Heraklion University Hospital, Greece, from January 2007 to December 2017. Three groups were studied: no previous antibiotic exposure, ongoing prophylaxis and short‐term exposure to antibiotics in the last six months.

Results

The median age at hospitalisation was 0.8 years (range 25 days to 15.9 years). Previous short‐term exposure and prophylaxis were important determinants of non‐Escherichia coli (E. coli) (OR 2.05, 95% CI 1.25‐3.36, P = .0017 and OR 3.84, 95% CI 2.32‐6.34, P < .0001, respectively) and extended‐spectrum beta‐lactamase‐positive uropathogens (OR 2.43, 95% CI 1.36‐4.32, P = .0025 and OR 2.63, 95% CI 1.31‐5.33, P = .0070, respectively). Short‐term antibiotics in the last 30 days or intravenous antibiotics were mostly associated with non‐E. coli pathogens (OR 6.71 and OR 2.55, respectively). The most important determinants of E. coli resistance were short‐term antibiotics for ampicillin (OR 2.58) and prophylaxis for cotrimoxazole (OR 2.64).

Conclusion

Recent short‐term exposure to antibiotics and ongoing prophylaxis both had a significant impact on the type and resistance of uropathogens.
Review article: new therapeutic interventions for advanced hepatocellular carcinoma
Authors: Bangaru Saroja , Marrero Jorge A. , Singal Amit G.
Published: November 2019

Background

Advanced hepatocellular carcinoma (HCC) portends a poor prognosis; however recent advances in first‐line and second‐line treatment options should yield significant improvements in survival.

Aim

To summarize the evolving landscape of treatment options for patients with advanced HCC.

Methods

We reviewed published clinical trials conducted in patients with advanced HCC published in PubMed or presented at national conferences.

Results

Sorafenib was approved for treatment of unresectable HCC in 2007 and remained the only therapy with proven survival benefit in advanced HCC for several years. Lenvatinib, another tyrosine‐kinase inhibitor, was recently shown to have non‐inferior survival vs sorafenib and is another first‐line treatment option. The tyrosine‐kinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second‐line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second‐line setting among patients with AFP ≥ 400 ng/dL. Phase II data highlight potential durable objective responses with immune checkpoint inhibitors, prompting conditional FDA approval of nivolumab and pembrolizumab in the second‐line setting; however, recent phase III data have failed to demonstrate improved survival compared to other treatment options. Ongoing trials are evaluating combination immune checkpoint inhibitor and immune checkpoint inhibitors with tyrosine‐kinase inhibitors or VEGF inhibitors in hopes of further increasing objective responses and overall survival in this patient population.

Conclusion

There are several first‐line and second‐line therapeutic options available for patients with advanced HCC. Further studies are needed to determine how best to select between and sequence the growing number of therapeutic options.
The Persistence of a NonResponsive Political Regime in Vietnam
Authors: Nguyen Hai Hong
Published: November 2019

This article attempts to explain the persistence and adaptability of Vietnam’s political system that has been described in the conventional literature as an oppressive and a nonresponsive political regime. The analysis, supported by two case studies, shows that the regime may have survived and buttressed its grip on power because it has relied on both coercion and consent, which allowed the regime to flexibly adapt to real‐life politics; to avoid and minimize conflict between state and society; and to suppress any challenge to its power emerging from the civil society . The article finally observes that the future survival of the regime depends on how the ruling party fixes its inherent “system fault” and sustains public trust.
Accelerated hippocampal biological aging in bipolar disorder
Authors: Fries Gabriel R. , Bauer Isabelle E. , Scaini Giselli , Valvassori Samira S. , Walss‐Bass Consuelo , Soares Jair C. , Quevedo Joao
Published: November 2019

Objectives

Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain, in particular in association with other biological clocks. To investigate this, we interrogated genome‐wide DNAm in postmortem hippocampus from 32 BD‐I patients and 32 non‐psychiatric controls group‐matched for age and sex from the NIMH Human Brain Collection Core.

Methods

DNAm age and epigenetic aging acceleration were estimated using the Horvath method. Telomere length (TL) and mitochondrial DNA (mtDNA) copy number were quantified by real‐time PCR. Between‐group differences were assessed by linear regression and univariate general linear models with age, sex, race, postmortem interval, tissue pH, smoking, and body mass index included as co‐variates.

Results

Groups did not differ for epigenetic aging acceleration when considering the entire sample. However, after splitting the sample by the median age, an epigenetic aging acceleration was detected in patients compared to controls among older subjects (P = .042). While TL did not differ between groups, a reduction in mtDNA copy number was observed in patients compared to controls (P = .047). In addition, significant correlations were observed between epigenetic aging acceleration and TL (r = −.337, P = .006), as well as between TL and mtDNA copy number (r = .274, P = .028).

Conclusions

Hippocampal aging may underlie neurocognitive dysfunctions observed in BD patients. Moreover, our results suggest a complex cross‐talk between biological clocks in hippocampus that may underlie clinical manifestations of premature aging in BD.
Preterm births in Iceland 1997‐2016: Preterm birth rates by gestational age groups and type of preterm birth
Authors: Grétarsdóttir Áslaug Salka , Aspelund Thor , Steingrímsdóttir Þóra , Bjarnadóttir Ragnheiður Ingibjörg , Einarsdóttir Kristjana
Published: November 2019

Background

The frequency of preterm births has been increasing globally, mainly due to a rise in iatrogenic late preterm births. The aim of this study was to assess the prevalence of preterm births in Iceland during 1997‐2016 by type of preterm birth.

Methods

This study included all live births in Iceland during 1997‐2016 identified from the Icelandic Medical Birth Registry. Risk of preterm birth by time period was assessed with Poisson regression models adjusted for demographic variables and indications for iatrogenic births.

Results

The study population included 87 076 infants, of which 4986 (5.7%) were preterm. The preterm birth rate increased from 5.3% to 6.1% (adjusted rate ratio [ARR] = 1.16, confidence interval [CI] = 1.07‐1.26) between 1997‐2001 and 2012‐2016 overall. The increase was only evident in multiples (ARR 1.41, 95% CI 1.21‐1.65), not singletons (1.07, 0.97‐1.19). The rate of late preterm births (34‐36 weeks) increased significantly (1.24, 1.14‐1.40), and the rate of iatrogenic preterm births more than doubled during this period even after adjustment for identified medical indications (2.40, 2.00‐2.88). The rate of spontaneous preterm births decreased during the study period (0.63, 0.55‐0.73), and the rate of PPROM increased (1.31, 1.09‐1.57). The most common contributing indications for iatrogenic births were fetal distress (26.2%), hypertensive disorders (18.2%), and severe preeclampsia (16.9%).

Conclusions

Preterm birth rates increased in multiples in Iceland between 1997 and 2016, and late and iatrogenic preterm births increased overall. The increase in iatrogenic preterm births remained significant after adjusting for medical indications, suggesting that other factors might be affecting the rise.
Translating a walking intervention for health professional delivery within primary care: A mixed‐methods treatment fidelity assessment
Authors: Williams Stefanie L. , McSharry Jennifer , Taylor Claire , Dale Jeremy , Michie Susan , French David P.
Published: November 2019

Objectives

Existing fidelity studies of physical activity interventions are limited in methodological quality and rigour, particularly those delivered by health care providers in clinical settings. The present study aimed to enhance and assess the fidelity of a walking intervention delivered by health care providers within general practice in line with the NIH Behavior Change Consortium treatment fidelity framework.

Design

Two practice nurses and six health care assistants delivered a theory‐based walking intervention to 63 patients in their own practices. A cross‐sectional mixed‐methods study assessed fidelity related to treatment delivery and treatment receipt, from the perspectives of health care providers and patients.

Methods

All providers received training and demonstrated delivery competence prior to the trial. Delivery of intervention content was coded from audio‐recordings using a standardized checklist. Qualitative interviews with 12 patients were conducted to assess patient perspectives of treatment receipt and analysed using framework analysis.

Results

Overall, 78% of intervention components were delivered as per the protocol (range 36–91%), with greater fidelity for components requiring active engagement from patients (e.g., completion of worksheets). The qualitative data highlighted differences in patients’ comprehension of specific intervention components. Understanding of, and engagement with, motivational components aimed at improving self‐efficacy was poorer than for volitional planning components.

Conclusions

High levels of fidelity of delivery were demonstrated. However, patient‐, provider‐, and component‐level factors impacted on treatment delivery and receipt. We recommend that methods for the enhancement and assessment of treatment fidelity are consistently implemented to enhance the rigour of physical activity intervention research.

Statement of contribution

What is already known on this subject?

Physical activity interventions delivered within primary care by health professionals have so far demonstrated limited impact on behaviour change initiation and maintenance.

Treatment fidelity enhancement and assessment strategies can support the successful translation of behaviour change interventions into real‐life settings.

Few studies have examined treatment fidelity within the context of physical activity interventions, particularly within clinical settings, and existing fidelity studies are limited by methodological quality and rigour.

What does this study add?

High levels of fidelity were found for a physical activity intervention delivered in primary care.

Patient‐, provider‐, and component‐level factors may impact on treatment delivery and receipt.

The implementation of best practice fidelity recommendations can support near‐optimal fidelity.
Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy
Authors: Sugimori Makoto , Sugimori Kazuya , Tsuchiya Hiromi , Suzuki Yoshimasa , Tsuyuki Sho , Kaneta Yoshihiro , Hirotani Akane , Sanga Katsuyuki , Tozuka Yuichiro , Komiyama Satoshi , Sato Takeshi , Tezuka Shun , Goda Yoshihiro , Irie Kuniyasu , Miwa Haruo , Miura Yuuki , Ishii Tomohiro , Kaneko Takashi , Nagahama Masatsugu , Shibata Wataru , Nozaki Akito , Maeda Shin
Published: November 2019

According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct‐DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue‐ and ct‐DNA samples. The 21 patients were subjected to quantitative ct‐DNA monitoring at 4 to 8‐week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation‐negative cases, next‐generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct‐DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%‐31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%‐0.2%]). In the ct‐DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression‐free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P < .001). Therefore, ct‐DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.
Young Children’s Mathematical Learning From Intelligent Characters
Authors: Calvert Sandra L. , Putnam Marisa M. , Aguiar Naomi R. , Ryan Rebecca M. , Wright Charlotte A. , Liu Yi Hui Angella , Barba Evan
Published: November 2019

Children’s math learning (N = 217;Mage = 4.87 years; 63% European American, 96% college‐educated families) from an intelligent character game was examined via social meaningfulness (parasocial relationships [PSRs]) and social contingency (parasocial interactions, e.g., math talk). In three studies (data collected in the DC area: 12/2015–10/2017), children’s parasocial relationships and math talk with the intelligent character predicted quicker, more accurate math responses during virtual game play. Children performed better on a math transfer task with physical objects when exposed to an embodied character (Study 2), and when the character used socially contingent replies, which was mediated by math talk (Study 3). Results suggest that children’s parasocial relationships and parasocial interactions with intelligent characters provide new frontiers for 21st century learning.
Key role of the epithelium in chronic upper airways diseases
Authors: Gohy Sophie , Hupin Cloé , Ladjemi Maha Zohra , Hox Valérie , Pilette Charles
Published: November 2019

The respiratory epithelium of the upper airways is a first‐line defence against inhaled irritants, pathogens and allergens. It ensures a physical barrier provided by apical junctions and mucociliary clearance to avoid excessive activation of the immune system. The epithelium also forms a chemical and immunological barrier, extensively equipped to protect the airways against external aggressions before the adaptive immune system is required. Under normal circumstances, the epithelium is capable of recovering rapidly after damage. This manuscript reviews these main properties of the upper airway epithelium as well as its reported impairments in chronic inflammatory diseases. The knowledge on normal epithelial functions and their dysregulation in upper airway diseases should help to design new epithelial‐targeted treatments.
Abnormal linear growth in paediatric adrenal diseases: Pathogenesis, prevalence and management
Authors: Minnetti Marianna , Caiulo Silvana , Ferrigno Rosario , Baldini‐Ferroli Barbara , Bottaro Giorgia , Gianfrilli Daniele , Sbardella Emilia , De Martino Maria Cristina , Savage Martin O.
Published: November 2019

Abnormal adrenal function can interfere with linear growth, potentially causing either acceleration or impairment of growth in paediatric patients. These abnormalities can be caused by direct effects of adrenal hormones, particularly glucocorticoids and sex steroids, or be mediated by indirect mechanisms such as the disturbance of the growth hormone‐insulin‐like growth factor‐1 axis and aromatization of androgens to oestrogens. The early diagnosis and optimal treatment of adrenal disorders can prevent or minimize growth disturbance and facilitate improved height gain. Mechanisms of growth disturbance in the following abnormal states will be discussed; hypercortisolaemia, hyperandrogenaemia and obesity. Prevalence and features of growth disturbance will be discussed in ACTH‐dependent and ACTH‐independent Cushing's syndrome, adrenocortical tumours, premature adrenarche, congenital adrenal hyperplasia and adrenal insufficiency disorders. Recommendations for management have been included.
Agriculture in the United States, Mexico, Canada Agreement: Agreeing to keep things pretty much the same
Authors: Kerr William A.
Published: November 2019

North American Free Trade Agreement (NAFTA) was referred to by U.S. President Trump as one of the worst trade deals ever made. Given this billing, one might have expected the result of its renegotiation to be a major change to the trading relationship between the United States and Canada. The new United States, Mexico, Canada Agreement (USMCA), however, retains a great deal of its predecessor. This is particularly true for agricultural trade. Canadian market access into the United States remains virtually unchanged. No major domestic regulatory changes were agreed to by Canada. While there were concessions made on market access for U.S. products into Canada's heavily protected sectors where the supply management policy applies, they do not appear to threaten the system. While the value of the compensation has not yet been announced, compensation for losses that will be suffered by farmers producing under supply management is agreed in principle. The USMCA is an agreement to keep things pretty much the same.