bluuebunny/crossref_metadata_2025 huggingface dataset:
Erythema nodosum‐like panniculitis mimicking disease recurrence: A novel toxicity from immune checkpoint blockade therapy—Report of 2 patients
Authors: Tetzlaff Michael T. , Jazaeri Amir A. , Torres‐Cabala Carlos A. , Korivi Brinda R. , Landon Genie A. , Nagarajan Priyadharsini , Choksi Adrienne , Chen Leon , Uemura Marc , Aung Phyu P. , Diab Adi , Sharma Padmanee , Davies Michael A. , Amaria Rodabe , Prieto Victor G. , Curry Jonathan L.
Published: September 2017

Immunotherapies targeting cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and the programmed cell death 1 (PD‐1) receptor and its ligand (PD‐L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum‐like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients’ cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management.
Referral population studies underestimate differences between human papillomavirus assays in primary cervical screening
Authors: Rebolj M. , Njor S. , Lynge E. , Preisler S. , Ejegod D. , Rygaard C. , Bonde J.
Published: September 2017

Objective

We studied how representative cytologically abnormal women (“referral populations”) are with respect to uncovering differences between human papillomavirus (HPV) assays in the primary screening where most women are cytologically normal.

Methods

A total of 4997 women were tested with SurePath® cytology, and Hybrid Capture 2 (HC2), cobas, CLART and APTIMA HPV assays. Women with positive test results were offered a follow‐up. For all detected HPV infections and HPV‐positive high‐grade cervical intraepithelial neoplasia (≥CIN2), we studied the distributions of assay‐specific signal strengths in the baseline samples as documented by the assays’ automatically generated reports. We calculated the likelihood of test result discordance as the proportion of HPV‐positive samples that were not confirmed by all four assays.

Results

Median signal strengths for HPV infections were weaker in normal than abnormal cytology (P<.001, adjusted for women's age, multiple infections and the reason for taking the sample). For HC2, they were RLU/CO 11.0 (interquartile range, IQR: 3.3‐52.8) vs 124.2 (IQR: 22.8‐506.9), respectively; for cobas, Ct 33.5 (IQR: 29.6‐37.5) vs 26.9 (IQR: 23.7‐31.3), respectively; for APTIMA, S/CO 10.2 (IQR: 5.8‐11.3) vs 11.1 (IQR: 9.4‐15.5), respectively. Similar patterns were observed for HPV‐positive ≥CIN2. The four HPV assays more frequently returned discordant test results in normal than in abnormal cytology. Relative frequency of discordance in detecting HPV infections was 0.39 (95% confidence interval: 0.33‐0.48) for abnormal vs normal cytology.

Conclusions

These data suggest that referral population studies, by not including sufficient numbers of cytology normal women, underestimate the differences between HPV assays that would become apparent in primary screening.
The developmental trajectory of children's auditory and visual statistical learning abilities: modality‐based differences in the effect of age
Authors: Raviv Limor , Arnon Inbal
Published: September 2017

Infants, children and adults are capable of extracting recurring patterns from their environment through statistical learning (SL), an implicit learning mechanism that is considered to have an important role in language acquisition. Research over the past 20 years has shown that SL is present from very early infancy and found in a variety of tasks and across modalities (e.g., auditory, visual), raising questions on the domain generality of SL. However, while SL is well established for infants and adults, only little is known about its developmental trajectory during childhood, leaving two important questions unanswered: (1) Is SL an early‐maturing capacity that is fully developed in infancy, or does it improve with age like other cognitive capacities (e.g., memory)? and (2) Will SL have similar developmental trajectories across modalities? Only few studies have looked at SL across development, with conflicting results: some find age‐related improvements while others do not. Importantly, no study to date has examined auditory SL across childhood, nor compared it to visual SL to see if there are modality‐based differences in the developmental trajectory of SL abilities. We addressed these issues by conducting a large‐scale study of children's performance on matching auditory and visual SL tasks across a wide age range (5–12y). Results show modality‐based differences in the development of SL abilities: while children's learning in the visual domain improved with age, learning in the auditory domain did not change in the tested age range. We examine these findings in light of previous studies and discuss their implications for modality‐based differences in SL and for the role of auditory SL in language acquisition. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=3kg35hoF0pw.
The role of local adaptation in shaping fish‐mussel coevolution
Authors: Douda Karel , Liu Huan‐Zhang , Yu Dan , Rouchet Romain , Liu Fei , Tang Qiong‐Ying , Methling Caroline , Smith Carl , Reichard Martin
Published: September 2017

The survival of affiliate (dependent) species in a changing environment is determined by the interactions between the affiliate species and their available hosts. However, the patterns of spatial and temporal changes in host compatibility are often unknown despite host shifts having direct impact on the persistence of local populations. Bivalves of the order Unionida (freshwater mussels) are a functionally important but declining group of affiliate species, which are dependent on freshwater fish to host their parasitic larvae. The role of local adaptations and host fish resistance in shaping freshwater mussel host relationships remains poorly understood.

We used an invasive East Asian unionid bivalve,Sinanodonta woodiana, and its potential host fishes to study the mechanisms shaping fish‐mussel coevolution using a combination of laboratory cross‐exposure methods and field‐collected data. We tested whether generalist host use ofS. woodianais pertinent to native host species, with special attention to bitterling fishes (Cyprinidae: Acheilognathinae) that are characterised by a mutual association with freshwater mussels. We also tested whether the pattern of the parasite–host association varies temporally (between areas of ancient and recent sympatry) and spatially (at a sub‐basin level in its native range).

Results revealed the ability ofS. woodianato widely exploit non‐bitterling host fishes at a global scale. In contrast, the ability ofS. woodianato exploit closely associated bitterling fishes was low in its native range (with ancient sympatry). In areas of recent sympatry (non‐nativeS. woodianarange in Europe),S. woodianaglochidia were demonstrated to readily parasitise local, evolutionarily naive bitterling species at high density.

The results of a population‐level experiment with three native populations ofS. woodianaand rose bitterling,Rhodeus ocellatus, from various sub‐basins of the River Yangtze confirmed that mussel populations vary in their compatibility with particular host populations. However, there was no evidence of population‐specific adaptive coevolution.

This study provides the first evidence for a role of fish counter‐adaptations against freshwater mussel glochidia, and documents the importance of population‐level variation in shaping compatibility between glochidia and their host fishes. This outcome can inform predictions on the impact of biotic homogenisation on endangered affiliate species in general and freshwater mussels in particular.
Current status of portal vein thrombosis in Japan: Results of a questionnaire survey by the Japan Society for Portal Hypertension
Authors: Kojima Seiichiro , Watanabe Norihito , Koizumi Jun , Kokubu Shigehiro , Murashima Naoya , Matsutani Shoichi , Obara Katsutoshi
Published: September 2017

Aim

To investigate the current status of portal vein thrombosis (PVT) in Japan, the Clinical Research Committee of the Japan Society of Portal Hypertension undertook a questionnaire survey.

Methods

A questionnaire survey of 539 cases of PVT over the previous 10 years was carried out at institutions affiliated with the Board of Trustees of the Japan Society of Portal Hypertension.

Results

The most frequent underlying etiology of PVT was liver cirrhosis in 75.3% of patients. Other causes included inflammatory diseases of the hepatobiliary system and the pancreas, malignant tumors, and hematologic diseases. The most frequent site was the main trunk of the portal vein (MPV) in 70.5%, and complete obstruction of the MPV was present in 11.5%. Among the medications for PVT, danaparoid was given to 45.8%, warfarin to 26.2%, heparin to 17.3%, and anti‐thrombin III to 16.9%. Observation of the course was practiced in 22.4%. Factors contributing to therapeutic efficacy were implementation of various medications, thrombi localized to either the right or left portal vein only, non‐complete obstruction of the MPV and Child–Pugh class A liver function. A survival analysis showed that the prognosis was favorable with PVT disappearance regardless of treatment.

Conclusion

The questionnaire survey showed the current status of PVT in Japan. Any appropriate medication should be given to a patient with PVT when PVT is recognized. It is necessary to compile a large amount of information and reach a consensus on safe and highly effective management of PVT.
One‐piece zirconia oral implants for single‐tooth replacement: Three‐year results from a long‐term prospective cohort study
Authors: Kohal Ralf‐Joachim , Spies Benedikt C. , Bauer Annalena , Butz Frank
Published: September 2017

Aim

This 3‐year report of a prospective long‐term cohort investigation aimed to evaluate the clinical and radiographic outcomes of a one‐piece zirconia oral implant for single‐tooth replacement.

Materials and Methods

Sixty‐five patients received a 1‐stage implant surgery with immediate temporization. Standardized radiographs were taken at implant insertion, after 1 year, and after 3 years to monitor peri‐implant bone levels. A univariate analysis of the association of different baseline parameters on marginal bone loss from implant insertion to 36 months was performed. Soft‐tissue parameters were evaluated at prosthesis insertion, after 6 months, after 1 year, and at the 3‐year follow‐up.

Results

After 3 years, six posterior site implants were lost, giving a cumulative survival rate of 90.8%. The mean marginal bone loss was 1.45 mm; 35% of the implants lost at least 2 mm bone, and 22% more than 3 mm. The univariate analysis did not identify any parameter associated with marginal bone loss. Probing depth, clinical attachment level, and bleeding index increased over 3 years, and plaque index decreased.

Conclusions

The low survival rate of the presented ceramic implant and especially the high frequency of advanced bone loss are noticeable but remain unexplained.
How much vitamin D is needed for healthy bones?
Authors: Bouillon R.
Published: September 2017

Click here to view the Original Article by Dr. I. R. Reid et al.
Rewriting the rules of the British economy
Authors: Kibasi Tom
Published: September 2017

The British economy suffers from deep structural problems and is not generating rising prosperity for the majority of the population. Underpinned by an understanding of what makes economies successful in the 21st century, a new settlement must now be forged.
Location and Emergency Inventory Pre‐Positioning for Disaster Response Operations: Min‐Max Robust Model and a Case Study of Yushu Earthquake
Authors: Ni Wenjun , Shu Jia , Song Miao
Published: September 2017

Pre‐positioning emergency inventory in selected facilities is commonly adopted to prepare for potential disaster threat. In this study, we simultaneously optimize the decisions of facility location, emergency inventory pre‐positioning, and relief delivery operations within a single‐commodity disaster relief network. A min‐max robust model is proposed to capture the uncertainties in both the left‐ and right‐hand‐side parameters in the constraints. The former corresponds to the proportions of the pre‐positioned inventories usable after a disaster attack, while the latter represents the demands of the inventories and the road capacities in the disaster‐affected areas. We study how to solve the robust model efficiently and analyze a special case that minimizes the deprivation cost. The application of the model is illustrated by a case study of the 2010 earthquake attack at Yushu County in Qinghai Province of PR China. The advantage of the min‐max robust model is demonstrated through comparison with the deterministic model and the two‐stage stochastic model for the same problem. Experiment variants also show that the robust model outperforms the other two approaches for instances with significantly larger scales.
The Long Shadow of Police Racial Treatment: Racial Disparity in Criminal Justice Processing
Authors: Kim Jaeok , Kiesel André
Published: September 2017

This article explores racial disproportionality in criminal justice processing in an era of punitive criminal justice policies and mass incarceration. Using arrest data from New York State, the authors compare the racial disparity in prison sentencing with the disparity at arrest while controlling for crime type and criminal history of the arrest population. Findings show that the racial disparity in prison sentencing at the state level is established before courts begin criminal case proceedings. Scholars and policy makers interested in the sources of racial disparity in incarceration should concentrate on the processes that generate crime and arrests. However, a decrease in racial disparity at prison sentencing, relative to arrest, suggests that the practices of courtroom actors still merit scholarly attention.
Treating OSA: Current and emerging therapies beyond CPAP
Authors: Lorenzi‐Filho Geraldo , Almeida Fernanda R. , Strollo Patrick J.
Published: September 2017

ABSTRACT

Continuous positive airway pressure (CPAP) is the standard treatment for moderate‐to‐severe obstructive sleep apnoea (OSA). However, adherence to CPAP is limited and non‐CPAP therapies are frequently explored. Oral appliance (OA) therapy is currently widely used for the treatment of snoring, mild, moderate and severe OSA. The most commonly used and studied OA consists of a maxillary and mandibular splint which hold the lower jaw forward during sleep. The efficacy of OA is inferior to CPAP; however, the effectiveness as measured by sleepiness, quality of life, endothelial function and blood pressure is similar likely due to higher acceptance and subjective adherence. Upper airway stimulation augments neural drive by unilaterally stimulating the hypoglossal nerve. The Stimulation Therapy for Apnea Reduction (STAR) study enrolled 126 patients and demonstrated a 68% reduction in OSA severity. A high upfront cost and variable response are the main limitations. Oropharyngeal exercises consist of a set of isometric and isotonic exercises involving the tongue, soft palate and lateral pharyngeal wall. The collective reported trials (n = 120) showed that oropharyngeal exercises can ameliorate OSA and snoring (~30–40%). Nasal EPAP devices consist of disposable one‐way resister valve. A systematic review (n = 345) showed that nasal EPAP reduced OSA severity by 53%. The Winx device consists of a mouthpiece placed inside the oral cavity that is connected by tubing to a console that generates negative pressure. Winx may provide successful therapy for ~30–40% of OSA patients. In conclusion, several non‐CPAP therapies to treat OSA are currently available.
The truncated NLR protein TIR‐NBS13 is a MOS6/IMPORTIN‐α3 interaction partner required for plant immunity
Authors: Roth Charlotte , Lüdke Daniel , Klenke Melanie , Quathamer Annalena , Valerius Oliver , Braus Gerhard H. , Wiermer Marcel
Published: September 2017

Importin‐α proteins mediate the translocation of nuclear localization signal (NLS)‐containing proteins from the cytoplasm into the nucleus through nuclear pore complexes (NPCs). Genetically, Arabidopsis IMPORTIN‐α3/MOS6 (MODIFIER OF SNC1, 6) is required for basal plant immunity and constitutive disease resistance activated in the autoimmune mutant snc1 (suppressor of npr1‐1, constitutive 1), suggesting that MOS6 plays a role in the nuclear import of proteins involved in plant defense signaling. Here, we sought to identify and characterize defense‐regulatory cargo proteins and interaction partners of MOS6. We conducted both in silico database analyses and affinity purification of functional epitope‐tagged MOS6 from pathogen‐challenged stable transgenic plants coupled with mass spectrometry. We show that among the 13 candidate MOS6 interactors we selected for further functional characterization, the TIR‐NBS‐type protein TN13 is required for resistance against Pseudomonas syringae pv. tomato (Pst) DC3000 lacking the type‐III effector proteins AvrPto and AvrPtoB. When expressed transiently in N. benthamiana leaves, TN13 co‐immunoprecipitates with MOS6, but not with its closest homolog IMPORTIN‐α6, and localizes to the endoplasmic reticulum (ER), consistent with a predicted N‐terminal transmembrane domain in TN13. Our work uncovered the truncated NLR protein TN13 as a component of plant innate immunity that selectively binds to MOS6/IMPORTIN‐α3 in planta. We speculate that the release of TN13 from the ER membrane in response to pathogen stimulus, and its subsequent nuclear translocation, is important for plant defense signal transduction.
Plasmatic coagulation and fibrinolysis in healthy and Otostrongylus‐affected Northern elephant seals (Mirounga angustirostris)
Authors: Kaye Sarrah , Johnson Shawn , Rios Carlos , Fletcher Daniel J.
Published: September 2017

Background

Prepatent Otostrongylus arteritis results in hemorrhagic diathesis in free‐ranging Northern elephant seals (Mirounga angustirostris) attributed to aberrant larval migration of the lungworm, Otostrongylus circumlitus. Clinical signs are often nonspecific, including lethargy, anorexia, and blepharospasm, but can progress to spontaneous frank hemorrhage and death within 72 hours of onset. Previously published case reports describe coagulopathy with prolonged PT and APTT, normal to elevated platelet counts, normal antithrombin concentrations, and low concentrations of fibrinogen degradation products. Disseminated intravascular coagulation was proposed as the cause of hemorrhage, but is inconsistent with some of the reported clinicopathologic changes.

Objective

The purpose of this study was to compare plasmatic coagulation and fibrinolysis in healthy and Otostrongylus‐affected elephant seals, in order to identify potential therapy. We hypothesized that hyperfibrinolysis contributed to hemorrhage in these cases.

Methods

Citrated plasma samples were collected from 3‐ to 4‐month‐old Northern elephant seals in a wildlife rehabilitation hospital. The sampled population included 25 healthy, prerelease seals and 32 clinically ill seals diagnosed with presumptive Otostrongylus arteritis. Twenty‐one of the included seals had Otostrongylus infestation confirmed at necropsy. Standard coagulation tests and plasma thromboelastography were performed for a complete assessment of coagulation and fibrinolysis.

Results

Northern elephant seals with definitive Otostrongylus infestation were hypocoagulable and hypofibrinolytic compared to healthy controls.

Conclusions

Results were most consistent with disseminated intravascular coagulation. Treatment with antifibrinolytic drugs to control hemorrhage may be unrewarding; alternative therapies such as plasma transfusions or coagulation factor concentrates should be investigated.
Evaluation of the correlation between Scoring Feline Allergic Dermatitis and Feline Extent and Severity Index and skin hydration in atopic cats
Authors: Szczepanik Marcin P. , Wilkołek Piotr M. , Adamek Łukasz R. , Zając Marcin , Gołyński Marcin , Sitkowski Wiesław , Taszkun Iwona
Published: September 2017

Background

Evaluation of the severity of clinical signs of cats with allergic skin diseases has used two scoring systems: Scoring Feline Allergic Dermatitis (SCORFAD) and the Feline Extent and Severity Index (FeDESI). The integrity of the cutaneous barrier can also be evaluated by measuring skin hydration. A correlation between the clinical score and skin hydration has been observed in humans and dogs with atopic dermatitis (AD).

Hypothesis

To demonstrate a correlation between the clinical score and skin hydration of cats affected with presumed AD.

Animals

European short hair cats (n = 18): 11 females and seven males with a confirmed diagnosis of AD.

Methods

SCORFAD and FeDESI scores were calculated and the measurements of skin hydration were assessed from seven body sites using corneometry. The correlation between the SCORFAD and FeDESI systems and skin hydration of each site, and the average skin hydration was calculated.

Results

There was a positive correlation between the SCORFAD score and skin hydration for the axilla, thorax and forelimb; for FeDESI and axilla and lumbar sites. There was a negative correlation between the FeDESI and skin hydration for the pinna (r = −0.47).

Conclusions and clinical importance

Measurements of skin hydration could be a useful tool for the evaluation of allergic cats. There is limited evidence of any useful correlation between clinical scoring systems and measurements of hydration. The pinna may be a suitable region for the assessment of skin barrier function in normal and allergic cats.
Cylindrical Borehole Failure in a Transversely Isotropic Poroelastic Medium
Authors: Gao Yue , Liu Zhanli , Zhuang Zhuo , Gao Deli , Hwang Keh-Chih
Published: September 2017

Rocks underground often have pores and bedding planes, which are appropriate to be described by the transversely isotropic poroelastic constitutive model. Drilling boreholes in these rocks must be careful, since stresses and pore pressure would change with time, because of the inherent time dependent property of poroelasticity as well as pore fluid diffusion. In order to correlate the behavior of transversely isotropic poroelastic model of borehole in plane strain with the behavior of isotropic poroelastic model, an equivalent isotropic material is built with carefully chosen material constants, and correlation rules are successfully developed. With the solutions for the borehole problem in an isotropic model obtained previously, the solutions to transversely isotropic model can be obtained. Two cases of tensile failure and six cases of shear failure for the borehole are considered. As a result, the allowable borehole working pressure range is formulated by explicit expressions. The failure case, time, and location could also be obtained for any given drilling pressure. Results obtained from the Hooke’s traditional elastic model are compared, and it is found that poroelastic model is necessary in borehole safety check, while Hooke’s model is not on the safe side.
Verification Assessment of Piston Boundary Conditions for Lagrangian Simulation of the Guderley Problem
Authors: Ramsey Scott D. , Lilieholm Jennifer F.
Published: September 2017

This work is concerned with the use of Guderley's converging shock wave solution of the inviscid compressible flow equations as a verification test problem for compressible flow simulation software. In practice, this effort is complicated by both the semi-analytical nature and infinite spatial/temporal extent of this solution. Methods can be devised with the intention of ameliorating this inconsistency with the finite nature of computational simulation; the exact strategy will depend on the code and problem archetypes under investigation. For example, scale-invariant shock wave propagation can be represented in Lagrangian compressible flow simulations as rigid boundary-driven flow, even if no such “piston” is present in the counterpart mathematical similarity solution. The purpose of this work is to investigate in detail the methodology of representing scale-invariant shock wave propagation as a piston-driven flow in the context of the Guderley problem, which features a semi-analytical solution of infinite spatial/temporal extent. The semi-analytical solution allows for the derivation of a similarly semi-analytical piston boundary condition (BC) for use in Lagrangian compressible flow solvers. The consequences of utilizing this BC (as opposed to directly initializing the Guderley solution in a computational spatial grid at a fixed time) are investigated in terms of common code verification analysis metrics (e.g., shock strength/position errors, global convergence rates). For the examples considered in this work, the piston-driven initialization approach is demonstrated to be a viable alternative to the more traditional, direct initialization approach.
Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin’s glucose-lowering effects
Authors: Hwangbo Cheol , Wu Jingxia , Papangeli Irinna , Adachi Takaomi , Sharma Bikram , Park Saejeong , Zhao Lina , Ju Hyekyung , Go Gwang-woong , Cui Guoliang , Inayathullah Mohammed , Job Judith K. , Rajadas Jayakumar , Kwei Stephanie L. , Li Ming O. , Morrison Alan R. , Quertermous Thomas , Mani Arya , Red-Horse Kristy , Chun Hyung J.
Published: September 2017

Inhibition of FABP4 rescues defective apelin signaling, decreases fatty acid accumulation, and promotes insulin sensitivity.
Targeted inhibition of G
q
signaling induces airway relaxation in mouse models of asthma
Authors: Matthey Michaela , Roberts Richard , Seidinger Alexander , Simon Annika , Schröder Ralf , Kuschak Markus , Annala Suvi , König Gabriele M. , Müller Christa E. , Hall Ian P. , Kostenis Evi , Fleischmann Bernd K. , Wenzel Daniela
Published: September 2017

Local pharmacological inhibition of G
q
results in airway relaxation in mouse models of asthma.
Fat chance for creatine deficiency
Authors: Charneski Catherine A.
Published: September 2017

Creatine metabolism in adipose tissue is necessary to burn off extra dietary calories and helps prevent obesity.
Psp Stress Response Proteins Form a Complex with Mislocalized Secretins in the
Yersinia enterocolitica
Cytoplasmic Membrane
Authors: Srivastava Disha , Moumene Amal , Flores-Kim Josué , Darwin Andrew J.
Published: September 2017

The bacterial phage shock protein system (Psp) is a conserved extracytoplasmic stress response that is essential for the virulence of some pathogens, including
Yersinia enterocolitica
. It is induced by events that can compromise inner membrane (IM) integrity, including the mislocalization of outer membrane pore-forming proteins called secretins. In the absence of the Psp system, secretin mislocalization permeabilizes the IM and causes rapid cell death. The Psp proteins PspB and PspC form an integral IM complex with two independent roles. First, the PspBC complex is required to activate the Psp response in response to some inducing triggers, including a mislocalized secretin. Second, PspBC are sufficient to counteract mislocalized secretin toxicity. Remarkably, secretin mislocalization into the IM induces
psp
gene expression without significantly affecting the expression of any other genes. Furthermore,
psp
null strains are killed by mislocalized secretins, whereas no other null mutants have been found to share this specific secretin sensitivity. This suggests an exquisitely specific relationship between secretins and the Psp system, but there has been no mechanism described to explain this. In this study, we addressed this deficiency by using a coimmunoprecipitation approach to show that the Psp proteins form a specific complex with mislocalized secretins in the
Y. enterocolitica
IM. Importantly, analysis of different secretin mutant proteins also revealed that this interaction is absolutely dependent on a secretin adopting a multimeric state. Therefore, the Psp system has evolved with the ability to detect and detoxify dangerous secretin multimers while ignoring the presence of innocuous monomers.

IMPORTANCE
The phage shock protein (Psp) response has been linked to important phenotypes in diverse bacteria, including those related to antibiotic resistance, biofilm formation, and virulence. This has generated widespread interest in understanding various aspects of its function. Outer membrane secretin proteins are essential components of export systems required for the virulence of many bacterial pathogens. However, secretins can mislocalize into the inner membrane, and this induces the Psp response in a highly specific manner and kills Psp-defective strains with similar specificity. There has been no mechanism described to explain this exquisitely specific relationship between secretins and the Psp system. Therefore, this study provides a critical advance by discovering that Psp effector proteins form a complex with secretins in the
Yersinia enterocolitica
inner membrane. Remarkably, this interaction is absolutely dependent on a secretin adopting its multimeric state. Therefore, the Psp system detects and detoxifies dangerous secretin multimers, while ignoring the presence of innocuous secretin monomers.
Distinct Spatiotemporal Dynamics of Peptidoglycan Synthesis between
Mycobacterium smegmatis
and
Mycobacterium tuberculosis
Authors: Botella Helene , Yang Guangli , Ouerfelli Ouathek , Ehrt Sabine , Nathan Carl F. , Vaubourgeix Julien
Published: September 2017

Peptidoglycan (PG), a polymer cross-linked by
d
-amino acid-containing peptides, is an essential component of the bacterial cell wall. We found that a fluorescent
d
-alanine analog (FDAA) incorporates chiefly at one of the two poles in
Mycobacterium smegmatis
but that polar dominance varies as a function of the cell cycle in
Mycobacterium tuberculosis
: immediately after cytokinesis, FDAAs are incorporated chiefly at one of the two poles, but just before cytokinesis, FDAAs are incorporated comparably at both. These observations suggest that mycobacterial PG-synthesizing enzymes are localized in functional compartments at the poles and septum and that the capacity for PG synthesis matures at the new pole in
M. tuberculosis
. Deeper knowledge of the biology of mycobacterial PG synthesis may help in discovering drugs that disable previously unappreciated steps in the process.

IMPORTANCE
People are dying all over the world because of the rise of antimicrobial resistance to medicines that could previously treat bacterial infections, including tuberculosis. Here, we used fluorescent
d
-alanine analogs (FDAAs) that incorporate into peptidoglycan (PG)—the synthesis of which is an attractive drug target—combined with high- and super-resolution microscopy to investigate the spatiotemporal dynamics of PG synthesis in
M. smegmatis
and
M. tuberculosis
. FDAA incorporation predominates at one of the two poles in
M. smegmatis
. In contrast, while FDAA incorporation into
M. tuberculosis
is also polar, there are striking variations in polar dominance as a function of the cell cycle. This suggests that enzymes involved in PG synthesis are localized in functional compartments in mycobacteria and that
M. tuberculosis
possesses a mechanism for maturation of the capacity for PG synthesis at the new pole. This may help in discovering drugs that cripple previously unappreciated steps in the process.
Petrobactin Is Exported from
Bacillus anthracis
by the RND-Type Exporter ApeX
Authors: Hagan A. K. , Tripathi A. , Berger D. , Sherman D. H. , Hanna P. C.
Published: September 2017

Bacillus anthracis
—a Gram-positive, spore-forming bacterium—causes anthrax, a highly lethal disease with high bacteremia titers. Such rapid growth requires ample access to nutrients, including iron. However, access to this critical metal is heavily restricted in mammals, which requires
B. anthracis
to employ petrobactin, an iron-scavenging small molecule known as a siderophore. Petrobactin biosynthesis is mediated by
asb
gene products, and import of the iron-bound (holo)-siderophore into the bacterium has been well studied. In contrast, little is known about the mechanism of petrobactin export following its production in
B. anthracis
cells. Using a combination of bioinformatics data, gene deletions, and laser ablation electrospray ionization mass spectrometry (LAESI-MS), we identified a resistance-nodulation-cell division (RND)-type transporter, termed ApeX, as a putative petrobactin exporter. Deletion of
apeX
abrogated export of intact petrobactin, which accumulated inside the cell. However, growth of Δ
apeX
mutants in iron-depleted medium was not affected, and virulence in mice was not attenuated. Instead, petrobactin components were determined to be exported through a different protein, which enables iron transport sufficient for growth, albeit with a slightly lower affinity for iron. This is the first report to identify a functional siderophore exporter in
B. anthracis
and the
in vivo
functionality of siderophore components. Moreover, this is the first application of LAESI-MS to sample a virulence factor/metabolite directly from bacterial culture media and cell pellets of a human pathogen.

IMPORTANCE
Bacillus anthracis
requires iron for growth and employs the siderophore petrobactin to scavenge this trace metal during infections. While we understand much about petrobactin biosynthesis and ferric petrobactin import, how apo-petrobactin (iron free) is exported remains unknown. This study used a combination of bioinformatics, genetics, and mass spectrometry to identify the petrobactin exporter. After screening 17 mutants with mutations of candidate exporter genes, we identified the
a
po-
p
etrobactin
ex
porter (termed ApeX) as a member of the resistance-nodulation-cell division (RND) family of transporters. In the absence of ApeX, petrobactin accumulates inside the cell while continuing to export petrobactin components that are capable of transporting iron. Thus, the loss of ApeX does not affect the ability of
B. anthracis
to cause disease in mice. This has implications for treatment strategies designed to target and control pathogenicity of
B. anthracis
in humans.
Genome-Enabled Insights into the Ecophysiology of the Comammox Bacterium “
Candidatus
Nitrospira nitrosa”
Authors: Camejo Pamela Y. , Santo Domingo Jorge , McMahon Katherine D. , Noguera Daniel R.
Published: September 2017

Nitrospira
-like bacteria are among the most diverse and widespread nitrifiers in natural ecosystems and the dominant nitrite oxidizers in wastewater treatment plants (WWTPs). The recent discovery of comammox-like
Nitrospira
strains, capable of complete oxidation of ammonia to nitrate, raises new questions about specific traits responsible for the functional versatility and adaptation of this genus to a variety of environments. The availability of new
Nitrospira
genome sequences from both nitrite-oxidizing and comammox bacteria offers a way to analyze traits in different
Nitrospira
functional groups. Our comparative genomics analysis provided new insights into the adaptation of
Nitrospira
strains to specific lifestyles and environmental niches.
Strategies for research engagement of clinicians in allied health (STRETCH): a mixed methods research protocol
Authors: Mickan Sharon , Wenke Rachel , Weir Kelly , Bialocerkowski Andrea , Noble Christy
Published: September 2017

Introduction

Allied health professionals (AHPs) report positive attitudes to using research evidence in clinical practice, yet often lack time, confidence and skills to use, participate in and conduct research. A range of multifaceted strategies including education, mentoring and guidance have been implemented to increase AHPs’ use of and participation in research. Emerging evidence suggests that knowledge brokering activities have the potential to support research engagement, but it is not clear which knowledge brokering strategies are most effective and in what contexts they work best to support and maintain clinicians’ research engagement.

Methods and analysis

This protocol describes an exploratory concurrent mixed methods study that is designed to understand how allied health research fellows use knowledge brokering strategies within tailored evidence-based interventions, to facilitate research engagement by allied health clinicians. Simultaneously, a realist approach will guide a systematic process evaluation of the research fellows’ pattern of use of knowledge brokering strategies within each case study to build a programme theory explaining which knowledge brokering strategies work best, in what contexts and why. Learning and behavioural theories will inform this critical explanation.

Ethics and dissemination

An explanation of how locally tailored evidence-based interventions improve AHPs use of, participation in and leadership of research projects will be summarised and shared with all participating clinicians and within each case study. It is expected that local recommendations will be developed and shared with medical and nursing professionals in and beyond the health service, to facilitate building research capacity in a systematic and effective way.
Changes in admission thresholds in English emergency departments
Authors: Wyatt Steven , Child Kieran , Hood Andrew , Cooke Matthew , Mohammed Mohammed A
Published: September 2017

Background

The most common route to a hospital bed in an emergency is via an Emergency Department (ED). Many recent initiatives and interventions have the objective of reducing the number of unnecessary emergency admissions. We aimed to assess whether ED admission thresholds had changed over time taking account of the casemix of patients arriving at ED.

Methods

We conducted a retrospective cross-sectional analysis of more than 20 million attendances at 47 consultant-led EDs in England between April 2010 and March 2015. We used mixed-effects logistic regression to estimate the odds of a patient being admitted to hospital and the impact of a range of potential explanatory variables. Models were developed and validated for four attendance subgroups: ambulance-conveyed children, walk-in children, ambulance-conveyed adults and walk-in adults.

Results

23.8% of attendances were for children aged under 18 years, 49.7% were female and 30.0% were conveyed by ambulance. The number of ED attendances increased by 1.8% per annum between April 2010–March 2011 (year 1) and April 2014–March 2015 (year 5). The proportion of these attendances that were admitted to hospital changed negligiblybetween year 1 (27.0%) and year 5 (27.5%). However, after adjusting for patient and attendance characteristics, the odds of admission over the 5-year period had reduced by 15.2% (95% CI 13.4% to 17.0%) for ambulance-conveyed children, 22.6% (95% CI 21.7% to 23.5%) for walk-in children, 20.9% (95% CI 20.4% to 21.5%) for ambulance conveyed adults and 22.9% (95% CI 22.4% to 23.5%) for walk-in adults.

Conclusions

The casemix-adjusted odds of admission via ED to NHS hospitals in England have decreased since April 2010. EDs are admitting a similar proportion of patients to hospital despite increases in the complexity and acuity of presenting patients. Without these threshold changes, the number of emergency admissions would have been 11.9% higher than was the case in year 5.
TP73DNA methylation and upregulation of ΔNp73 are associated with an adverse prognosis in breast cancer
Authors: Gomez Laura C , Sottile Mayra L , Guerrero-Gimenez Martin E , Zoppino Felipe C M , Redondo Analia L , Gago Francisco E , Orozco Javier I , Tello Olga M , Roqué Maria , Nadin Silvina B , Marzese Diego M , Vargas-Roig Laura M
Published: September 2017

Aim

Accumulated evidence suggests that aberrant methylation of theTP73gene and increased levels of ΔNp73 in primary tumours correlate with poor prognosis. However, little is known regarding the transcriptional and functional regulation of theTP73gene in breast cancer. The aim of the present study was to determine the expression of the ΔNp73 isoform, its relationship with DNA methylation ofTP73and their clinical prognostic significance in breast cancer patients.

Methods

TP73gene methylation was studied in TCGA datasets and in 70 invasive ductal breast carcinomas (IDCs). The expression of p73 isoforms was evaluated by immunohistochemistry (IHC) and Western blot and correlated with clinicopathological variables and clinical outcome.

Results

We observed that the methylation of diverse CpG islands ofTP73differed significantly between molecular subtypes. An inverse correlation was found between p73 protein expression and the methylation status of theTP73gene. The expression of exon 3’ of p73 (only expressed in ΔNp73) was significantly higher in patients with wild-type p53. Immunohistochemical analysis revealed that all p73 isoforms were localised in both the nuclear and cytoplasmic compartments. We confirmed a positive association between the expression of ∆Np73 and high histological grade.

Conclusions

Our findings suggest that high expression of ΔNp73 could be used to determine the aggressiveness of IDCs and could be incorporated in the pathologist’s report.
Sustainability of TNF-blocker tapering in rheumatoid arthritis over 3 years: long-term follow-up of the STRASS (Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study) randomised controlled trial
Authors: Sigaux Johanna , Bailly Florian , Hajage David , Mariette Xavier , Morel Jacques , Gandjbakhch Frédérique , Foltz Violaine , Gossec Laure , Tubach Florence , Fautrel Bruno
Published: September 2017

Introduction

We have limited data on the sustainability of tumour necrosis factor (TNF)-blocker tapering in rheumatoid arthritis (RA) in remission over the long term in real-life settings. This study aimed to assess the probability of sustained dose reduction of TNF-blockers in an observational 3-year extended follow-up of the Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study (STRASS), a randomised controlled trial comparing progressive TNF-blocker injections (spacing arm (S-arm) to maintenance arm (M-arm)) in patients with RA in stable remission.

Methods

In 2015, clinical data for the completer population were retrospectively collected at 1, 2 and 3 years after the end of the trial. The endpoints were the proportion of patients free of a biological disease-modifying antirheumatic drug (bDMARD) treatment, a sustainably spaced injection of TNF-blockers and a full-dose regimen as well as the mean dose of bDMARD intake and treatment switch rate.

Results

Overall, 96 patients (76.8% of the completers) had data available up to 3 years; 11.5% discontinued TNF-blockers (5.8% vs 18.2% in the M-arm and S-arm, p=0.06), 30.2% had a tapered regimen (28.8% vs 31.8%, p=0.76) and 37.5% retained a full dose (44.2% vs 29.5%, p=0.14). The mean TNF-blocker dose quotient was 66% of the full dose (74% vs 58% in the M-arm and S-arm, p=0.06); 20.8% switched to another bDMARD (21.2% vs 20.5%, p=0.94).

Conclusion

Sustained TNF-blocker de-escalation or withdrawal is achievable in 41% of patients over 3 years with limited dose reduction. Optimal strategies remain to be determined to maintain remission after TNF-blocker tapering or discontinuation.
Two cases of embolic pneumonia associated with udder cleft dermatitis in dairy cattle from the same farm
Authors: Turner Andrea , Wood Sarah , Millar Michael
Published: September 2017

Two Holstein cows from the same farm were presented within eight months of each other with malaise, milk drop and dyspnoea. Both cows had active or historic udder cleft dermatitis (UCD) lesions. Clinical examination and diagnostic tests led to an initial diagnosis of chronic suppurative pneumonia in both cows. The cases were poorly responsive to antibiotic treatment and died or were euthanased, 18 and 16 days respectively, after presentation. Postmortem examination of each case resulted in the diagnosis of embolic pneumonia associated with UCD. In both cases, UCD lesions, which were considered insignificant by the farmer and the veterinarian, are thought to have been the initiating source of infection. It is important that both farmers and vets are made aware of the possible severe consequences of udder cleft lesions and that early detection strategies for UCD and udder cleft lesions are adopted and implemented on‐farm.
Orchiectomy of a Cape porcupine (Hystrix africaeaustralis)
Authors: Baldrey Vicki
Published: September 2017

A Cape porcupine (Hystrix africaeaustralis) was presented for surgical castration to prevent inbreeding within the family group. A literature review found limited information on relevant anatomy and surgical approach, with a single report describing the need for CT to locate the testes. Anaesthesia was induced by hand injection of a combination of 0.03 mg/kg medetomidine and 4 mg/kg ketamine. Analgesia was provided with buprenorphine, meloxicam and local infiltration of lidocaine. The surgical approach was similar to other hystricomorph rodents, with testes located subcutaneously, lateral to the prepuce; however, in contrast to other rodents, the skin was notably fragile and prone to tearing when handled. Recovery and wound healing were uneventful. The surgical technique and minor complications are discussed.
Internal phosphorus loading in Canadian fresh waters: a critical review and data analysis
Authors: Orihel Diane M. , Baulch Helen M. , Casson Nora J. , North Rebecca L. , Parsons Chris T. , Seckar Dalila C.M. , Venkiteswaran Jason J.
Published: September 2017

Many physical, chemical, and biological processes in freshwater ecosystems mobilize the nutrient phosphorus (P) from sediments, which in turn may contribute to the formation of harmful algal blooms. Here, we critically reviewed internal P loading in Canadian fresh waters to understand the geographic patterns and environmental drivers of this important process. From 43 publications, we consolidated 618 estimates of internal P loading from Canadian freshwater ponds, lakes, reservoirs, and coastal wetlands (n = 70). Expressed in terms of total P, short-term gross rates in sediment samples (Lgross) ranged from −27 to 54 mg·m−2·day−1(n = 461), while long-term net rates in whole ecosystems (Lnet) ranged from −1694 to 10 640 mg·m−2·year−1(n = 157). The main environmental drivers of this variation were oxygen, pH, geology, and trophic state. Internal P loading tended to be higher during the open-water season and most prominent in small prairie lakes. Priorities for future research on internal P loading should include resolving methodological problems, assessing the relative importance of different mechanisms, examining the influence of anthropogenic activities, and quantifying rates in understudied ecosystems.