bluuebunny/crossref_metadata_2025 huggingface dataset:
The unsafe haven: Eating disorders as attachment relationships
Authors: Forsén Mantilla Emma , Clinton David , Birgegård Andreas
Published: May 2018

Objectives

Some patients with eating disorders (EDs) seem to experience their illness as an entity, a symbolic other to whom they relate, and which may influence both symptom levels and self‐image. Extending previous research, this study investigated whether the patient–ED relationship has attachment qualities.

Design

Structural Analysis of Social Behaviour was used to operationalize the patient–ED relationship, and the Attachment Style Questionnaire was used to measure attachment.

Method

We examined ED patients’ (N = 148) relationship with their ED, attachment behaviour, symptoms, and self‐image. Attachment dimensions of Confidence, Anxious/ambivalence, and Avoidance were found to be significantly correlated with aspects of the patient–ED relationship. Introjection (i.e., whether ED actions were incorporated into patients’ self‐image) was investigated by examining the match between self‐image profiles and the actions of patients’ EDs. A double mediation model was tested in which ED control/emancipation and patients’ Self‐blame mediated the effect of attachment security on ED symptoms.

Results

Attachment insecurity was associated with greater ED control and patient submission. In 28.5% of patients, there was a high degree of correlation between self‐image and ED action profile. Data supported the mediation model.

Conclusions

Attachment processes appear to be associated with the manner in which ED patients relate to their disorder, at least in some cases. Attempts to maintain psychological proximity to the ED as an introjected attachment figure may help to explain treatment resistance and ambivalence about change. This perspective may be useful in treatment.

Practitioner points

Attachment behaviours are associated with the patient–ED relationship, in which attachment insecurity is correlated with greater eating disorder control and patient submission.

Some patients seem to incorporate the actions of the ED in their self‐image, suggesting the presence of introjection.

The patient–ED relationship may help explain patients’ anxiety and ambivalence about change, seen from an attachment perspective.

In treatment, it may be important to explore alternative safe havens and secure bases to the ED, such as interpersonal relationships and activities.
The ethics of crashes with self‐driving cars: A roadmap, I
Authors: Nyholm Sven
Published: May 2018

Self‐driving cars hold out the promise of being much safer than regular cars. Yet they cannot be 100% safe. Accordingly, they need to be programmed for how to deal with crash scenarios. Should cars be programmed to always prioritize their owners, to minimize harm, or to respond to crashes on the basis of some other type of principle? The article first discusses whether everyone should have the same “ethics settings.” Next, the oft‐made analogy with the trolley problem is examined. Then follows an assessment of recent empirical work on lay‐people's attitudes about crash algorithms relevant to the ethical issue of crash optimization. Finally, the article discusses what traditional ethical theories such as utilitarianism, Kantianism, virtue ethics, and contractualism imply about how cars should handle crash scenarios. The aim of the article is to provide an overview of the existing literature on these topics and to assess how far the discussion has gotten so far.
Revisiting the Table 2 fallacy: A motivating example examining preeclampsia and preterm birth
Authors: Bandoli Gretchen , Palmsten Kristin , Chambers Christina D. , Jelliffe‐Pawlowski Laura L. , Baer Rebecca J. , Thompson Caroline A.
Published: May 2018

Background

A “Table Fallacy,” as coined by Westreich and Greenland, reports multiple adjusted effect estimates from a single model. This practice, which remains common in published literature, can be problematic when different types of effect estimates are presented together in a single table. The purpose of this paper is to quantitatively illustrate this potential for misinterpretation with an example estimating the effects of preeclampsia on preterm birth.

Methods

We analysed a retrospective population‐based cohort of 2 963 888 singleton births in California between 2007 and 2012. We performed a modified Poisson regression to calculate the total effect of preeclampsia on the risk of PTB, adjusting for previous preterm birth. pregnancy alcohol abuse, maternal education, and maternal socio‐demographic factors (Model 1). In subsequent models, we report the total effects of previous preterm birth, alcohol abuse, and education on the risk of PTB, comparing and contrasting the controlled direct effects, total effects, and confounded effect estimates, resulting from Model 1.

Results

The effect estimate for previous preterm birth (a controlled direct effect in Model 1) increased 10% when estimated as a total effect. The risk ratio for alcohol abuse, biased due to an uncontrolled confounder in Model 1, was reduced by 23% when adjusted for drug abuse. The risk ratio for maternal education, solely a predictor of the outcome, was essentially unchanged.

Conclusions

Reporting multiple effect estimates from a single model may lead to misinterpretation and lack of reproducibility. This example highlights the need for careful consideration of the types of effects estimated in statistical models.
Effect of Deploying Trained Community Based Reproductive Health Nurses (CORN) on Long‐Acting Reversible Contraception (LARC) Use in Rural Ethiopia: A Cluster Randomized Community Trial
Authors: Zerfu Taddese Alemu , Ayele Henok Taddese , Bogale Tariku Nigatu
Published: May 2018

To investigate the effect of innovative means to distribute LARC on contraceptive use, we implemented a three arm, parallel groups, cluster randomized community trial design. The intervention consisted of placing trained community‐based reproductive health nurses (CORN) within health centers or health posts. The nurses provided counseling to encourage women to use LARC and distributed all contraceptive methods. A total of 282 villages were randomly selected and assigned to a control arm (n = 94) or 1 of 2 treatment arms (n = 94 each). The treatment groups differed by where the new service providers were deployed, health post or health center. We calculated difference‐in‐difference (DID) estimates to assess program impacts on LARC use. After nine months of intervention, the use of LARC methods increased significantly by 72.3 percent, while the use of short acting methods declined by 19.6 percent. The proportion of women using LARC methods increased by 45.9 percent and 45.7 percent in the health post and health center based intervention arms, respectively. Compared to the control group, the DID estimates indicate that the use of LARC methods increased by 11.3 and 12.3 percentage points in the health post and health center based intervention arms. Given the low use of LARC methods in similar settings, deployment of contextually trained nurses at the grassroots level could substantially increase utilization of these methods.
Joint Central Limit Theorem for Eigenvalue Statistics from Several Dependent Large Dimensional Sample Covariance Matrices with Application
Authors: Li Weiming , Li Zeng , Yao Jianfeng
Published: May 2018

Let Xn = (xij) be a k×n data matrix with complex‐valued, independent and standardized entries satisfying a Lindeberg‐type moment condition. We consider simultaneously R sample covariance matrices
, where the Qr's are non‐random real matrices with common dimensions p×k(k≥p). Assuming that both the dimension p and the sample size n grow to infinity, the limiting distributions of the eigenvalues of the matrices {Bnr} are identified, and as the main result of the paper, we establish a joint central limit theorem (CLT) for linear spectral statistics of the R matrices {Bnr}. Next, this new CLT is applied to the problem of testing a high‐dimensional white noise in time series modelling. In experiments, the derived test has a controlled size and is significantly faster than the classical permutation test, although it does have lower power. This application highlights the necessity of such joint CLT in the presence of several dependent sample covariance matrices. In contrast, all the existing works on CLT for linear spectral statistics of large sample covariance matrices deal with a single sample covariance matrix (R = 1).
Bayesian nonparametric inference beyond the Gibbs‐type framework
Authors: Camerlenghi Federico , Lijoi Antonio , Prünster Igor
Published: May 2018

The definition and investigation of general classes of nonparametric priors has recently been an active research line in Bayesian statistics. Among the various proposals, the Gibbs‐type family, which includes the Dirichlet process as a special case, stands out as the most tractable class of nonparametric priors for exchangeable sequences of observations. This is the consequence of a key simplifying assumption on the learning mechanism, which, however, has justification except that of ensuring mathematical tractability. In this paper, we remove such an assumption and investigate a general class of random probability measures going beyond the Gibbs‐type framework. More specifically, we present a nonparametric hierarchical structure based on transformations of completely random measures, which extends the popular hierarchical Dirichlet process. This class of priors preserves a good degree of tractability, given that we are able to determine the fundamental quantities for Bayesian inference. In particular, we derive the induced partition structure and the prediction rules and characterize the posterior distribution. These theoretical results are also crucial to devise both a marginal and a conditional algorithm for posterior inference. An illustration concerning prediction in genomic sequencing is also provided.
Situating the self in global context: Reconceptualizing transnational and cosmopolitan identities
Authors: Watson Lesley
Published: May 2018

Scholars interested in the effects of globalization on internationally mobile individuals have tended to study this by drawing comparisons between national identity and transnationalism (i.e., connectedness and involvement in more than one country simultaneously) and cosmopolitanism (i.e., a sense of belonging to the world as a whole rather than a single nation). Empirical patterns generally suggest the pervasiveness and resilience of national identity even among globally mobile populations, but findings do show that international experience can bring about changes to individual identity. By comparing transnationalism and cosmopolitanism to national identity, the extant literature makes a tacit assumption that these identities are group‐based. The social psychological literature on identity refers to three different types, or bases, of identity: group, role, and person. This paper argues for a reconceptualization of transnationalism and cosmopolitanism as role‐ or person‐based identities, and outlines several avenues for research based on this reconceptualization.
Sequels to tattoo removal by caustic products
Authors: Hutton Carlsen K. , Serup J.
Published: May 2018

Background

Caustic products are used as affordable alternatives to laser removal of tattoos.

Objective

Describe a series of patients with sequels after tattoo removal by caustic products.

Methods

11 patients with complications referred from 2013 to 2017 were studied. Objective findings, sequels, corrective treatments, cost and psychological aspects were obtained. Numeric Rating Scale (NRS, score 10 extremely dissatisfied) was used to describe patient satisfaction with tattoos before and after removal.

Results

Scarring and residual tattoo pigments were detected in all patients. Chronic itching (73%), redness (73%) and swelling (64%) were frequent. Patients were less satisfied with their tattoo after removal attempts; Average NRS prior to removal was 7.5 (range 5‐10), and afterwards 8.9 (range 4.5‐10), t test non‐significant. Removal was performed by medical professionals (82%) and cosmetologists (18%), involving the marketed injection brands Tatt2Away and Rejuvi. Ten patients had corrections eg. laser, plastic surgery or cover‐up tattoos. Private expense for corrections was mean 1.953 EUR, not including consultations provided by the Hospital.

Conclusion

Tattoo removal by caustic products can cause severe and chronic sequels with dissatisfaction despite therapeutic interventions to correct disfiguring changes. Removal by caustic products is freely permitted. Products are obscured and liability and consumer protection is unacceptable; limitation is needed.
Administration of platelets to ruptured abdominal aortic aneurysm patients before open surgery: a prospective, single‐blinded, randomised study
Authors: Lunen T. B. , Johansson P. I. , Jensen L. P. , Homburg K. M. , Roeder O. C. , Lonn L. , Secher N. H. , Helgstrand U. , Carstensen M. , Jensen K. B. , Lange T. , Sillesen H. , Swiatek F. , Nielsen H. B.
Published: May 2018

Background

In patients undergoing open surgery for a ruptured abdominal aortic aneurysm (rAAA), survivors demonstrate a high platelet count, and proactive administration of platelets (and fresh frozen plasma) appears to influence mortality.

Objectives

This trial investigated the effect of platelets administered before transport to surgery.

Methods

In a prospective study design, patients were randomised to receive platelets (intervention; n = 61) or no platelets (control; n = 61) before transport to vascular surgery from 11 local hospitals. The study was terminated when one of the vascular surgical centres implemented endovascular repair for rAAA patients.

Results

Thirty days after surgery, mortality was 36% for patients with intervention vs 31% for controls (P = 0·32). Post‐operative thrombotic events (14 vs 15; P = 0·69), renal failure (11 vs 10; P = 0·15) and pulmonary insufficiency (34 vs 39; P = 0·15) were similar in the two groups of patients. No adverse reactions to platelet administration were observed. In addition, length of stay in the intensive care unit was unaffected by intervention.

Conclusions

For patients planned for open repair of a rAAA, we observed no significant effect of early administration of platelets with regard to post‐operative complications and stay in the ICU or in hospital and also no significant effect on mortality.
Diversity of Staphylococcus pseudintermedius in carriage sites and skin lesions of dogs with superficial bacterial folliculitis: potential implications for diagnostic testing and therapy
Authors: Larsen Rikke Friis , Boysen Lene , Jessen Lisbeth Rem , Guardabassi Luca , Damborg Peter
Published: May 2018

Background

Staphylococcus pseudintermedius is genotypically diverse within the canine population and multiple strains may colonize individual dogs at any given time. If multiple strains with distinct antimicrobial resistance profiles are present in superficial bacterial folliculitis (SBF), sampling a single skin lesion for culture and antimicrobial susceptibility testing (AST) might be inadequate to select effective therapy.

Hypothesis/Objectives

To investigate S. pseudintermedius diversity in carriage sites and lesions of dogs with SBF.

Animals

Fourteen dogs with SBF.

Methods

Staphylococcus pseudintermedius isolates obtained from perineum, gingiva and four to six skin lesions per dog were subjected to pulsed‐field gel electrophoresis (PFGE) and AST to assess diversity between lesions. For two dogs, 14–16 isolates per lesion were included in the analysis to assess diversity within lesions.

Results

Analysis of one isolate per lesion revealed one to four strains displaying unique PFGE profiles, and up to three unique antimicrobial resistance (AMR) profiles for each dog. Multiple pustules from the same dog always harboured the same strain, whereas papules, crusts and collarettes did not. Up to four strains with distinct AMR profiles were isolated from the same lesion in two dogs. In 12 dogs, at least one carriage site strain also was represented in lesions.

Conclusions and clinical importance

Lesions of SBF may harbour multiple S. pseudintermedius strains with distinct antimicrobial resistance profiles. Pustules are the best target for bacterial culture. It remains unclear whether isolation of different strains from other lesion types is a consequence of contamination or co‐infection by multiple strains.
Assessment of porcine endogenous retrovirus transmission across an alginate barrier used for the encapsulation of porcine islets
Authors: Crossan Claire , Mourad Nizar I. , Smith Karen , Gianello Pierre , Scobie Linda
Published: May 2018

Background

Subcutaneous implantation of a macroencapsulated patch containing human allogenic islets has been successfully used to alleviate type 1 diabetes mellitus (T1DM) in a human recipient without the need for immunosuppression. The use of encapsulated porcine islets to treat T1DM has also been reported. Although no evidence of pathogen transfer using this technology has been reported to date, we deemed it appropriate to determine if the encapsulation technology would prevent the release of virus, in particular, the porcine endogenous retrovirus (PERV).

Methods

HEK293 (human epithelial kidney) and swine testis (ST) cells were co‐cultured with macroencapsulated pig islets embedded in an alginate patch, macroencapsulated PK15 (swine kidney epithelial) cells embedded in an alginate patch and free PK15 cells. Cells and supernatant were harvested at weekly time points from the cultures for up to 60 days and screened for evidence of PERV release using qRT‐PCR to detect PERV RNA and SG‐PERT to detect reverse transcriptase (RT).

Results

No PERV virus, or evidence of PERV replication, was detected in the culture medium of HEK293 or pig cells cultured with encapsulated porcine islets. Increased PERV activity relative to the background was not detected in ST cells cultured with encapsulated PK15 cells. However, PERV was detected in 1 of the 3 experimental replicates of HEK293 cells cultured with encapsulated PK15 cells. Both HEK293 and ST cells cultured with free PK15 cells showed an increase in RT detection.

Conclusions

With the exception of 1 replicate, there does not appear to be evidence of transmission of replication competent PERV from the encapsulated islet cells or the positive control PK15 cells across the alginate barrier. The detection of PERV would suggest the alginate barrier of this replicate may have become compromised, emphasizing the importance of quality control when producing encapsulated islet patches.
EVALUATION OF BACTERIAL CELLULOSE-SODIUM ALGINATE FORWARD OSMOSIS MEMBRANE FOR WATER RECOVERY
Authors: T. B. Dang Ngan , B. Patacsil Liza , H. Orbecido Aileen , P. Eusebio Ramon Christian , B. Beltran Arnel
Published: May 2018

Water resources are very important to sustain life. However, these resources have been subjected to stress due to population growth, economic and industrial growth, pollution and climate change. With these, the recovery of water from sources such as wastewater, dirty water, floodwater and seawater is a sustainable alternative. The potential of recovering water from these sources could be done by utilizing forward osmosis, a membrane process that exploits the natural osmotic pressure gradient between solutions which requires low energy operation. This study evaluated the potential of forward osmosis (FO) composite membranes fabricated from bacterial cellulose (BC) and modified with sodium alginate. The membranes were evaluated for water flux and salt rejection. The effect of alginate concentrations and impregnation temperatures were evaluated using 0.6 M sodium chloride solution as feed and 2 M glucose solution as the draw solution. The membranes were characterized by Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), and Contact Angle Meter (CAM). The use of sodium alginate in BC membrane showed a thicker membrane (38.3 μm to 67.6 μm), denser structure (shown in the SEM images), and more hydrophilic (contact angle ranges from 28.39° to 32.97°) compared to the pristine BC membrane (thickness = 12.8 μm and contact angle = 66.13°). Furthermore, the alginate modification lowered the water flux of the BC membrane from 9.283 L/m2-h (LMH) to value ranging from 2.314 to 4.797 LMH but the improvement in salt rejection was prominent (up to 98.57%).
EFFECT OF AGAR-KAOLIN INTERACTION IN GELCASTING MIXTURES ON FORMING OF ALUMINA MEMBRANE SUPPORT
Authors: Lertwittayanon Kowit
Published: May 2018

Disc alumina membrane supports were formed through agar gelcasting method. The agar gelcasting was expected to be environmentally-friendly forming technique using simple equipment. Final agar amounts (0.25 – 0.75wt%) in gelcasting mixtures were varied to find the optimum condition of shaping and the desired microstructure of sintered supports. The gelcasting mixtures were prepared from non-reactive grade Al2O3 and porcelain at the ratio of 98.5:1.5 by weight. The porcelain addition allowed the membrane support to have high strength at lower sintering temperature. When the final agar amounts increased from 0.25 to 0.75wt%, the dried, gelcast supports tended to have rough surface and subsequently resulting in crack. TGA profiles confirmed that there was interaction between agar chains and kaolin particles on cooling the gelcast supports leading to different microstructures after sintering. The final agar amount of 0.5 wt% provided the highest porosity of 48.9% and the highest relative density of 61.5%. Additionally, the average pore size of 1.5 µm was obtained at the final agar amount of 0.5 wt% suitable for using as asymmetric membrane support or microfiltration membrane.
The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on MIC Determination
Authors: Smith Kenneth P. , Kirby James E.
Published: May 2018

The observed MIC may depend on the number of bacteria initially inoculated into the assay. This phenomenon is termed the inoculum effect (IE) and is often most pronounced for β-lactams in strains expressing β-lactamase enzymes. The Clinical and Laboratory Standards Institute (CLSI)-recommended inoculum is 5 × 10
5
CFU ml
−1
with an acceptable range of 2 × 10
5
to 8 × 10
5
CFU ml
−1
. IE testing is typically performed using an inoculum 100-fold greater than the CLSI-recommended inoculum. Therefore, it remains unknown whether the IE influences MICs during testing performed according to CLSI guidelines. Here, we utilized inkjet printing technology to test the IE on cefepime, meropenem, and ceftazidime-avibactam. First, we determined that the inkjet dispense volume correlated well with the number of bacteria delivered to microwells in 2-fold (
R
2
= 0.99) or 1.1-fold (
R
2
= 0.98) serial dilutions. We then quantified the IE by dispensing orthogonal titrations of bacterial cells and antibiotics. For cefepime-resistant and susceptible dose-dependent strains, a 2-fold increase in inoculum resulted in a 1.6 log
2
-fold increase in MIC. For carbapenemase-producing strains, each 2-fold reduction in inoculum resulted in a 1.26 log
2
-fold reduction in meropenem MIC. At the lower end of the CLSI-allowable inoculum range, minor error rates of 34.8% were observed for meropenem when testing a resistant-strain set. Ceftazidime-avibactam was not subject to an appreciable IE. Our results suggest that IE is sufficiently pronounced for meropenem and cefepime in multidrug-resistant Gram-negative pathogens to affect categorical interpretations during standard laboratory testing.
Carbapenem-Nonsusceptible Haemophilus influenzae with Penicillin-Binding Protein 3 Containing an Amino Acid Insertion
Authors: Kitaoka Kazuki , Kimura Kouji , Kitanaka Hiromitsu , Banno Hirotsugu , Jin Wanchun , Wachino Jun-ichi , Arakawa Yoshichika
Published: May 2018

The prevalence of β-lactamase-negative ampicillin-resistant (BLNAR)
Haemophilus influenzae
has become a clinical concern. In BLNAR isolates, amino acid substitutions in penicillin-binding protein 3 (PBP3) are relevant to the β-lactam resistance. Carbapenem-nonsusceptible
H. influenzae
isolates have been rarely reported. Through antimicrobial susceptibility testing, nucleotide sequence analysis of
ftsI
, encoding PBP3, and the utilization of a collection of
H. influenzae
clinical isolates in our laboratory, we obtained a carbapenem-nonsusceptible clinical isolate (NUBL1772) that possesses an altered PBP3 containing V525_N526insM. The aim of this study was to reveal the effect of altered PBP3 containing V525_N526insM on reduced carbapenem susceptibility. After generating recombinant strains with altered
ftsI
, we performed antimicrobial susceptibility testing and competitive binding assays with fluorescent penicillin (Bocillin FL) and carbapenems. Elevated carbapenem MICs were found for the recombinant strain harboring the entire
ftsI
gene of NUBL1772. The recombinant PBP3 of NUBL1772 also exhibited reduced binding to carbapenems. These results demonstrate that altered PBP3 containing V525_N526insM influences the reduced carbapenem susceptibility. The revertant mutant lacking the V525_N526insM exhibited lower MICs for carbapenems than NUBL1772, suggesting that this insertion affects reduced carbapenem susceptibility. The MICs of β-lactams for NUBL1772 were higher than those for the recombinant possessing
ftsI
of NUBL1772. NUBL1772 harbored AcrR with early termination, resulting in low-level transcription of
acrB
and high efflux pump activity. These findings suggest that the disruption of AcrR also contributes to the reduced carbapenem susceptibility found in NUBL1772. Our results provide the first evidence that the altered PBP3 containing V525_N526insM is responsible for the reduced susceptibility to carbapenems in
H. influenzae
.
Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity
Authors: Yew Wing Wai , Chang Kwok Chiu , Chan Denise P.
Published: May 2018

Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even, rarely, mortality. This form of toxicity potentially impacts the treatment outcome of tuberculosis in some patients. Covering only first-line antituberculosis drugs, this review addresses whether and how oxidative stress and, more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic hepatitis B infection, HIV infection, and preexisting liver disease. Importantly, these comorbid conditions are associated with oxidative stress and drugs related to antioxidants, especially those for management of mitochondrial dysfunction. Thus, the shared pathogenetic mechanism(s) for liver injury might be in operation due to disease-drug interaction. Our current ability to predict, prevent, or treat hepatotoxicity (other than removing potentially hepatotoxic drugs) remains limited. More translational research to unravel the pathogenesis, inclusive of the underlying molecular bases, regarding antituberculosis drug-induced hepatotoxicity is needed, and so is clinical research pertaining to the advances in therapy, with antioxidants and beyond. The role of pharmacogenetics in the clinical management of drug-induced hepatotoxicity also likely merits further evaluation.
Candida glabrata Med3 Plays a Role in Altering Cell Size and Budding Index To Coordinate Cell Growth
Authors: Liu Hui , Kong Lulin , Qi Yanli , Chen Xiulai , Liu Liming
Published: May 2018

This study demonstrates that
Cg
Med3AB can regulate cell growth in
C. glabrata
by coordinating the homeostasis of cellular acetyl-CoA metabolism and the cell cycle cyclin
Cg
Cln3. Specifically, we report that
Cg
Med3AB regulates the cellular acetyl-CoA level, which induces the transcription of
Cgcln3
, finally resulting in alterations to the cell size and budding index. In conclusion, we report that
Cg
Med3AB functions as a wheel responsible for driving cellular acetyl-CoA metabolism, indirectly inducing the transcription of
Cgcln3
and coordinating cell growth. We propose that Mediator subunits may represent a vital regulatory target modulating cell growth in
C. glabrata
.
PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani
Authors: Habib Samar , El Andaloussi Abdeljabar , Elmasry Khaled , Handoussa Aya , Azab Manar , Elsawey Aliaa , Al-Hendy Ayman , Ismail Nahed
Published: May 2018

Leishmania donovaniis a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective immunity against VL depends on CD4+Th1 cell-mediated immunity. Studies have shown that progression of VL is due to exhaustion of T cells; however, the mechanism involved is not clearly understood. Here, we examined the role of PD1/PDL-1 in the pathogenesis of VL by using a murine model of VL. Our data indicate thatL. donovaniis able to elicit initial expansion of gamma interferon-producing CD4+Th1 and CD8+T cells at day 7 postinfection (p.i.); however, the frequency of those cells and inflammatory response decreased at day 21 p.i., despite persistence of parasites. Persistent infection-induced expansion of interleukin-10+FOXP3+Treg and CD4+and CD8+T cells expressing PD1. Blocking of PDL-1 signalingin vivoresulted in restoration of protective type 1 responses by both CD4+and CD8+T cells, which resulted in a significant decrease in the parasite burden. Mechanistically, PDL-1 blocking inhibited autophagy, a cellular degradation process hijacked byLeishmaniato acquire host cell nutrients for their survival. Inhibition of autophagy was marked by decreased lipidation of microtubule-associated protein 1 light chain 3, a marker of autophagosome formation, and P62 accumulation. Together, our findings show for the first time that anti-PDL-1 antibody is an effective therapeutic approach for restoration of effector arms of protective immunity against VL and subsequent parasite clearance.
Small Bottleneck Size in a Highly Multipartite Virus during a Complete Infection Cycle
Authors: Gallet Romain , Fabre Frédéric , Thébaud Gaël , Sofonea Mircea T. , Sicard Anne , Blanc Stéphane , Michalakis Yannis
Published: May 2018

Multipartite viruses package their genomic segments independently and thus incur the risk of being unable to transmit their entire genome during host-to-host transmission if they undergo severe bottlenecks. In this paper, we estimated the bottleneck size during one infection cycle of
Faba bean necrotic stunt virus
(FBNSV), an octopartite nanovirus whose segments have been previously shown to converge to particular and unequal relative frequencies within host plants and aphid vectors. Two methods were used to derive this estimate, one based on the probability of transmission of the virus and the other based on the temporal evolution of the relative frequency of markers for two genomic segments, one frequent and one rare (segment N and S, respectively), both in plants and vectors. Our results show that FBNSV undergoes severe bottlenecks during aphid transmission. Further, even though the bottlenecks are always narrow under our experimental conditions, they slightly widen with the number of transmitting aphids. In particular, when several aphids are used for transmission, the bottleneck size of the segments is also affected by within-plant processes and, importantly, significantly differs across segments. These results indicate that genetic drift not only must be an important process affecting the evolution of these viruses but also that these effects vary across genomic segments and, thus, across viral genes, a rather unique and intriguing situation. We further discuss the potential consequences of our findings for the transmission of multipartite viruses.

IMPORTANCE
Multipartite viruses package their genomic segments in independent capsids. The most obvious cost of such genomic structure is the risk of losing at least one segment during host-to-host transmission. A theoretical study has shown that for nanoviruses, composed of 6 to 8 segments, hundreds of copies of each segment need to be transmitted to ensure that at least one copy of each segment was present in the host. These estimations seem to be very high compared to the size of the bottlenecks measured with other viruses. Here, we estimated the bottleneck size during one infection cycle of FBNSV, an octopartite nanovirus. We show that these bottlenecks are always narrow (few viral particles) and slightly widen with the number of transmitting aphids. These results contrast with theoretical predictions and illustrate the fact that a new conceptual framework is probably needed to understand the transmission of highly multipartite viruses.
The Case for an Expanded Concept of Trained Immunity
Authors: Cassone Antonio
Published: May 2018

Trained immunity was originally proposed as a program of innate immunity memory by innate immunity cells of hematopoietic origin such as the monocytes/macrophages and the NK cells. Here I discuss some old and new data justifying this program and some specific, still unanswered, questions it raises regarding the model fungus
Candida albicans
and the chronic, inflammatory vulvovaginal disease it causes. Building upon this well-established program, the recent reports that epithelial cells of mammals can also acquire memory from previous stimulations, and the apparent intrinsic ability of many living cells from bacteria to mammals to learn from experience, I suggest an expansion of the concept of trained immunity to include all cells of different lineages with the potential of memorizing previous microbial encounters. This expansion would better fit the complexity of innate immunity and the role it plays in infectious and inflammatory diseases.
Wolbachia w
Stri Blocks Zika Virus Growth at Two Independent Stages of Viral Replication
Authors: Schultz M. J. , Tan A. L. , Gray C. N. , Isern S. , Michael S. F. , Frydman H. M. , Connor J. H.
Published: May 2018

Mosquito-transmitted viruses are spread globally and present a great risk to human health. Among the many approaches investigated to limit the diseases caused by these viruses are attempts to make mosquitos resistant to virus infection. Coinfection of mosquitos with the bacterium
Wolbachia pipientis
from supergroup A is a recent strategy employed to reduce the capacity for major vectors in the
Aedes
mosquito genus to transmit viruses, including dengue virus (DENV), Chikungunya virus (CHIKV), and Zika virus (ZIKV). Recently, a supergroup B
Wolbachia w
Stri, isolated from
Laodelphax striatellus
, was shown to inhibit multiple lineages of ZIKV in
Aedes albopictus
cells. Here, we show that
w
Stri blocks the growth of positive-sense RNA viruses DENV, CHIKV, ZIKV, and yellow fever virus by greater than 99.9%.
w
Stri presence did not affect the growth of the negative-sense RNA viruses LaCrosse virus or vesicular stomatitis virus. Investigation of the stages of the ZIKV life cycle inhibited by
w
Stri identified two distinct blocks in viral replication. We found a reduction of ZIKV entry into
w
Stri-infected cells. This was partially rescued by the addition of a cholesterol-lipid supplement. Independent of entry, transfected viral genome was unable to replicate in
Wolbachia
-infected cells. RNA transfection and metabolic labeling studies suggested that this replication defect is at the level of RNA translation, where we saw a 66% reduction in mosquito protein synthesis in
w
Stri-infected cells. This study’s findings increase the potential for application of
w
Stri to block additional arboviruses and also identify specific blocks in viral infection caused by
Wolbachia
coinfection.

IMPORTANCE
Dengue, Zika, and yellow fever viruses are mosquito-transmitted diseases that have spread throughout the world, causing millions of infections and thousands of deaths each year. Existing programs that seek to contain these diseases through elimination of the mosquito population have so far failed, making it crucial to explore new ways of limiting the spread of these viruses. Here, we show that introduction of an insect symbiont,
Wolbachia w
Stri, into mosquito cells is highly effective at reducing yellow fever virus, dengue virus, Zika virus, and Chikungunya virus production. Reduction of virus replication was attributable to decreases in entry and a strong block of virus gene expression at the translational level. These findings expand the potential use of
Wolbachia w
Stri to block viruses and identify two separate steps for limiting virus replication in mosquitos that could be targeted via microbes or other means as an antiviral strategy.
A Single-Domain Response Regulator Functions as an Integrating Hub To Coordinate General Stress Response and Development in Alphaproteobacteria
Authors: Lori C. , Kaczmarczyk A. , de Jong I. , Jenal U.
Published: May 2018

The alphaproteobacterial general stress response is governed by a conserved partner-switching mechanism that is triggered by phosphorylation of the response regulator PhyR. In the model organism
Caulobacter crescentus
, PhyR was proposed to be phosphorylated by the histidine kinase PhyK, but biochemical evidence in support of such a role of PhyK is missing. Here, we identify a single-domain response regulator, MrrA, that is essential for general stress response activation in
C. crescentus
. We demonstrate that PhyK does not function as a kinase but accepts phosphoryl groups from MrrA and passes them on to PhyR, adopting the role of a histidine phosphotransferase. MrrA is phosphorylated by at least six histidine kinases that likely serve as stress sensors. MrrA also transfers phosphate to LovK, a histidine kinase involved in
C. crescentus
holdfast production and attachment, which also negatively regulates the general stress response. We show that LovK together with the response regulator LovR acts as a phosphate sink to redirect phosphate flux away from the PhyKR branch. In agreement with the biochemical data, an
mrrA
mutant is unable to activate the general stress response and shows a hyperattachment phenotype, which is linked to decreased expression of the major holdfast inhibitory protein HfiA. We propose that MrrA serves as a central phosphorylation hub that coordinates the general stress response with
C. crescentus
development and other adaptive behaviors. The characteristic bow-tie architecture of this phosphorylation network with MrrA as the central knot may expedite the evolvability and species-specific niche adaptation of this group of bacteria.

IMPORTANCE
Two-component systems (TCSs) consisting of a histidine kinase and a cognate response regulator are predominant signal transduction systems in bacteria. To avoid cross talk, TCSs are generally thought to be highly insulated from each other. However, this notion is based largely on studies of the HisKA subfamily of histidine kinases, while little information is available for the HWE and HisKA2 subfamilies. The latter have been implicated in the alphaproteobacterial general stress response. Here, we show that in the model organism
Caulobacter crescentus
an atypical FATGUY-type single-domain response regulator, MrrA, is highly promiscuous in accepting and transferring phosphoryl groups from and to multiple up- and downstream kinases, challenging the current view of strictly insulated TCSs. Instead, we propose that FATGUY response regulators have evolved in alphaproteobacteria as central phosphorylation hubs to broadly sample information and distribute phosphoryl groups between the general stress response pathway and other TCSs, thereby coordinating multiple cellular behaviors.
Patients’ perspectives on social and goal-based comparisons regarding their diabetes health status
Authors: Martinez William , Wallston Kenneth A , Schlundt David G , Hickson Gerald B , Bonnet Kemberlee R , Trochez Ricardo J , Elasy Tom A
Published: May 2018

Objective

Social comparisons (ie, self-evaluation in comparison with others) influence patients’ perspectives of their disease and may impact motivation and health behavior; however, little is known about patients’ perspectives toward receiving such information in a clinical context (eg, from their doctor’s office or health system). This study aims to understand patients’ perspectives and anticipated responses to receiving social comparison information regarding measures of their diabetes-related health status (eg, A1C) and how receiving such information would compare with goal-based comparisons (ie, self-evaluation in comparison with goal).

Research design and methods

We conducted semistructured interviews with 25 patients with type 2 diabetes mellitus (T2DM) regarding social and goal-based comparisons involving their diabetes health status and qualitatively analyzed interviews for themes.

Results

We identified seven major themes: self-relevance, motivation, self-concept, emotions, information seeking, medical care, and self-care. Participants commonly anticipated increased motivation and improved health behaviors in response to both social and goal-based comparisons. Subthemes unique to social comparisons included belief that this information would be motivating by engaging some patients’ competitiveness, perception that this information was more ‘personalized’ than comparisons with a standard goal (eg, A1C<7), and desire to learn from individuals similar to oneself who were doing better.

Conclusions

Our findings provide significant insights into the anticipated response of patients with T2DM to receiving social and goal-based comparison information regarding their diabetes health status. Providing patients with diabetes with social and goal-based comparison information may affect motivation, mood, and self-concept in ways that may improve or sustain diabetes self-care behaviors for some patients.
Validity of the Japan Acuity and Triage Scale in adults: a cohort study
Authors: Kuriyama Akira , Ikegami Tetsunori , Kaihara Toshie , Fukuoka Toshio , Nakayama Takeo
Published: May 2018

Objective

The Japan Acuity and Triage Scale (JTAS) was developed based on Canadian Triage and Acuity Scale in 2012 and has been implemented in many Japanese EDs. We assessed the validity of JTAS by examining the association between JTAS triage levels and throughput and clinical outcomes in adult patients.

Methods

We conducted a retrospective analysis of prospectively collected clinical data in the ED of a Japanese tertiary-care hospital. We included self-presenting patients who were ≥16 years of age and triaged between June 2013 and May 2014. We assessed the association between the triage level and overall admission and admission to the intensive care units (ICUs) with multivariable logistic regression analysis adjusted with patients’ age and the time of visit and ED length of stay using the Kruskal-Wallis rank-sum test. We examined the predictive ability of JTAS for determining overall and ICU admission using receiver operating characteristic curves.

Results

We included a total of 27 120 adult patients in our study. The OR for overall admission was greater with a higher triage level compared with the lowest urgency levels. ED length of stay was significantly longer with a higher JTAS level (p<0.001). The OR for ICU admission was greater in JTAS 1 (117.93 (95% CI 69.07 to 201.38)) and JTAS 2 (9.43 (95% CI 13.74 to 29.30)) compared with the lowest urgency levels. The areas under the curve for the predictive ability of JTAS for overall and ICU admission were 0.726 and 0.792, respectively.

Conclusion

Our study suggests an association of JTAS acuity with overall admission, ICU admission and ED length of stay, thereby demonstrating the predictive validity of JTAS.
Inflammatory bowel disease increases the risk of Parkinson’s disease: a Danish nationwide cohort study 1977–2014
Authors: Villumsen Marie , Aznar Susana , Pakkenberg Bente , Jess Tine , Brudek Tomasz
Published: May 2018

Objective

Intestinal inflammation has been suggested to play a role in development of Parkinson’s disease (PD) and multiple system atrophy (MSA). To test the hypothesis that IBD is associated with risk of PD and MSA, we performed a nationwide population-based cohort study.

Design

The cohort consisted of all individuals diagnosed with IBD in Denmark during 1977–2014 (n=76 477) and non-IBD individuals from the general population, who were comparable in terms of gender, age and vital status (n=7 548 259). All cohort members were followed from IBD diagnosis/index date to occurrence of PD and MSA (according to the Danish National Patient Register).

Results

Patients with IBD had a 22% increased risk of PD as compared with non-IBD individuals (HR=1.22; 95% CI 1.09 to 1.35). The increased risk was present independently of age at IBD diagnosis, gender or length of follow-up. The overall incidence of MSA was low in our study, and the regression analysis suggested a tendency towards higher risk of developing MSA in patients with IBD as compared with non-IBD individuals (HR=1.41; 95% CI 0.82 to 2.44). Estimates were similar for women and men. The increased risk of parkinsonism was significantly higher among patients with UC (HR=1.35; 95% CI 1.20 to 1.52) and not significantly different among patients with Crohn’s disease (HR=1.12; 95% CI 0.89 to 1.40).

Conclusions

This nationwide, unselected, cohort study shows a significant association between IBD and later occurrence of PD, which is consistent with recent basic scientific findings of a potential role of GI inflammation in development of parkinsonian disorders.
Using alternatives to the car and risk of all-cause, cardiovascular and cancer mortality
Authors: Panter Jenna , Mytton Oliver , Sharp Stephen , Brage Søren , Cummins Steven , Laverty Anthony A , Wijndaele Katrien , Ogilvie David
Published: May 2018

Objective

To investigate the associations between using alternatives to the car which are more active for commuting and non-commuting purposes, and morbidity and mortality.

Methods

We conducted a prospective study using data from 3 58 799 participants, aged 37–73 years, from UK Biobank. Commute and non-commute travel were assessed at baseline in 2006–2010. We classified participants according to whether they relied exclusively on the car or used alternative modes of transport that were more active at least some of the time. The main outcome measures were incident cardiovascular disease (CVD) and cancer, and CVD, cancer and all-cause mortality. We excluded events in the first 2 years and conducted analyses separately for those who regularly commuted and those who did not.

Results

In maximally adjusted models, regular commuters with more active patterns of travel on the commute had a lower risk of incident (HR 0.89, 95% CI 0.79 to 1.00) and fatal (HR 0.70, 95% CI 0.51 to 0.95) CVD. Those regular commuters who also had more active patterns of non-commute travel had an even lower risk of fatal CVD (HR 0.57, 95% CI 0.39 to 0.85). Among those who were not regular commuters, more active patterns of travel were associated with a lower risk of all-cause mortality (HR 0.92, 95% CI 0.86 to 0.99).

Conclusions

More active patterns of travel were associated with a reduced risk of incident and fatal CVD and all-cause mortality in adults. This is an important message for clinicians advising people about how to be physically active and reduce their risk of disease.