bluuebunny/crossref_metadata_2025 huggingface dataset:
Melanoma exosomes deliver a complex biological payload that upregulates PTPN11 to suppress T lymphocyte function
Authors: Wu Yueting , Deng Wentao , McGinley Emily Chambers , Klinke David J.
Published: December 2016

As exosomes are emerging as a new mode of intercellular communication, we hypothesized that the payload contained within exosomes is shaped by somatic evolution. To test this, we assayed the impact on primary CD8+ T‐cell function, a key mechanism for antitumor immunity, of exosomes derived from three melanoma‐related cell lines. While morphologically similar, exosomes from each cell line were functionally different, as B16F0 exosomes dose‐dependently suppressed T‐cell proliferation. In contrast, Cloudman S91 exosomes promoted T‐cell proliferation and Melan‐A exosomes had a negligible effect on primary CD8+ T cells. Mechanistically, transcript profiling suggested that exosomal mRNA is enriched for full‐length mRNAs that target immune‐related pathways. Interestingly, B16F0 exosomes were unique in that they contained both protein and mRNA for PTPN11, which inhibited T‐cell proliferation. Collectively, the results suggest that upregulation of PTPN11 by B16F0 exosomes to tumor infiltrating lymphocytes would bypass the extracellular control of the immune checkpoints.
Patient involvement in own rehabilitation after early discharge
Authors: Hørdam Britta , Boolsen Merete Watt
Published: December 2016

Background

A European Union Commission report in 2015 concluded that the concept of patient involvement refers specially to the right of patients to have a central position in the healthcare process (EU Commission 2012, http://ec.europa.eu/public_opinion/archives/quali/ql_5937_patient_en.pdf). Recent research suggests that patient involvement after hip replacement is a very effective strategy in older adults with regard to improving walking ability and reducing pain and thereby lessening loss of physical, mental and social aspects of the quality of life. The growing number of older adults all over the world will increase the need for hip surgery.

Hypothesis

Older adults’ involvement in own rehabilitation improves their health and quality of life after hip replacement.

Aim

To involve and coach older adults with a hip replacement to self‐care after early discharge in transition between hospital and home.

Population

Empirical data were collected by carrying out three randomised clinical trials (RCT) focusing on self‐rated health and involvement of patients undergoing total hip replacement in three Danish orthopaedic clinics. Based on power calculation, 260 patients (mean age 67.5 years) were invited to participate. In this third study in 2010–2013, patients were randomised to either an intervention group or a control group.

Methodology

Randomised clinical trials (RCT). Questionnaire SF‐36 a generic tool measuring patients’ self‐rated health status and quality of life. All patients filled out SF‐36 before surgery and again 3, 6, 9 and 12 months after surgery. Patients in the intervention group had an additional follow‐up 1, 3 and 7 weeks after discharge by nurses from orthopaedic clinic in hospital. The nurses used a semi‐structured interview guide as intervention model to coach, counsel and involve patients to improve their self‐care and planned rehabilitation after hip replacement.

Results

Older adults benefit through involvement based on an intervention model of expectations, measurement of self‐rated health and quality of life. The results of the randomised trials one and two documented that patients’ self‐rated health status in the intervention group reached their habitual level 3 months after hip replacement vs. 9 months in the control group. Since our working hypothesis ‘patient involvement in own rehabilitation improves health and quality of life after hip replacement’ was found valid, our ambition is now based on results from this third study to contribute to further research and development within patient involvement.

Relevance to clinical practice

To follow new evidence‐based research, results concluded that walking ability is very necessary in order to increase physical activity to benefit the health of older adults and prevent disease.
An open trial of mindfulness‐based stress reduction for young adults with social anxiety disorder
Authors: Hjeltnes Aslak , Molde Helge , Schanche Elisabeth , Vøllestad Jon , Lillebostad Svendsen Julie , Moltu Christian , Binder Per‐Einar
Published: December 2016

The present study investigated mindfulness‐based stress reduction (MBSR) for young adults with a social anxiety disorder (SAD) in an open trial. Fifty‐three young adults in a higher education setting underwent a standard eight‐week MBSR program. Eight participants (15%) did not complete the program. Participants reported significant reductions in SAD symptoms and global psychological distress, as well as increases in mindfulness, self‐compassion, and self‐esteem. Using intention‐to‐treat (ITT) analyses, effect sizes ranged from large to moderate for SAD symptoms (Cohen's d = 0.80) and global psychological distress (d = 0.61). Completer analyses yielded large effect sizes for SAD symptoms (d = 0.96) and global psychological distress (d = 0.81). The largest effect sizes were found for self‐compassion (d = 1.49) and mindfulness (d = 1.35). Two thirds of the participants who were in the clinical range at pretreatment reported either clinically significant change (37%) or reliable improvement (31%) on SAD symptoms after completing the MBSR program, and almost two thirds reported either clinically significant change (37%) or reliable improvement (26%) on global psychological distress. MBSR may be a beneficial intervention for young adults in higher education with SAD, and there is a need for more research on mindfulness and acceptance‐based interventions for SAD.
A molecular approach to arthrotardigrade phylogeny (Heterotardigrada, Tardigrada)
Authors: Fujimoto Shinta , Jørgensen Aslak , Hansen Jesper G.
Published: December 2016

The marine order Arthrotardigrada (class Heterotardigrada, phylum Tardigrada) is known for its conspicuously high morphological diversity and has been traditionally recognized as the most ancestral group within the phylum. Despite its potential importance in understanding the evolution of the phylum, the phylogenetic relationships of Arthrotardigrada have not been clarified. This study conducted molecular phylogenetic analyses of the order encompassing all families except Neoarctidae using nuclear 18S and 28S rRNA fragments. Data from two rare families, Coronarctidae and Renaudarctidae, were included for the first time. The analyses confirmed the monophyly of Heterotardigrada and inferred Coronarctidae as the sister group to all other heterotardigrade taxa. Furthermore, the results support a monophyletic Renaudarctidae + Stygarctidae clade, which has been previously suggested on morphology. Our data indicated that two subfamilies currently placed in Halechiniscidae are only distantly related to this family. We propose that these taxa are each elevated to family level (Styraconyxidae (new rank) and Tanarctidae (new rank)). The morphology of tardigrades is discussed in the context of the inferred phylogeny.
Exact Frequency Equation of a Linear Structure Carrying Lumped Elements Using the Assumed Modes Method
Authors: Cha Philip D. , Hu Siyi
Published: December 2016

Combined systems consisting of linear structures carrying lumped attachments have received considerable attention over the years. In this paper, the assumed modes method is first used to formulate the governing equations of the combined system, and the corresponding generalized eigenvalue problem is then manipulated into a frequency equation. As the number of modes used in the assumed modes method increases, the approximate eigenvalues converge to the exact solutions. Interestingly, under certain conditions, as the number of component modes goes to infinity, the infinite sum term in the frequency equation can be reduced to a finite sum using digamma function. The conditions that must be met in order to reduce an infinite sum to a finite sum are specified, and the closed-form expressions for the infinite sum are derived for certain linear structures. Knowing these expressions allows one to easily formulate the exact frequency equations of various combined systems, including a uniform fixed–fixed or fixed-free rod carrying lumped translational elements, a simply supported beam carrying any combination of lumped translational and torsional attachments, or a cantilever beam carrying lumped translational and/or torsional elements at the beam's tip. The scheme developed in this paper is easy to implement and simple to code. More importantly, numerical experiments show that the eigenvalues obtained using the proposed method match those found by solving a boundary value problem.
Study of Water Impact and Entry of a Free Falling Wedge Using Computational Fluid Dynamics Simulations
Authors: Kamath Arun , Bihs Hans , Arntsen Øivind A.
Published: December 2016

Many offshore constructions and operations involve water impact problems such as water slamming onto a structure or free fall of objects with subsequent water entry and emergence. Wave slamming on semisubmersibles, vertical members of jacket structures, crane operation of a diving bell, and dropping of free fall lifeboats are some notable examples. The slamming and water entry problems lead to large instantaneous impact pressures on the structure, accompanied with complex free surface deformations. These need to be studied in detail in order to obtain a better understanding of the fluid physics involved and develop safe and economical design. Numerical modeling of a free falling body into water involves several complex hydrodynamic features after its free fall such as water entry, submergence into water and resurfacing. The water entry and submergence lead to formation of water jets and air cavities in the water resulting in large impact forces on the object. In order to evaluate the forces and hydrodynamics involved, the numerical model should be able to account for the complex free surface features and the instantaneous pressure changes. The water entry of a free falling wedge into water is studied in this paper using the open source computational fluid dynamics (CFD) model REEF3D. The vertical velocity of the wedge during the process of free fall and water impact are calculated for different cases and the free surface deformations are captured in detail. Numerical results are compared with experimental data and a good agreement is seen.
Effect of Thermal Softening on Anisotropy and Ductile Mode Cutting of Sapphire Using Micro-Laser Assisted Machining
Authors: Mohammadi Hossein , Patten John A.
Published: December 2016

Ceramics and semiconductors have many applications in optics, micro-electro-mechanical systems, and electronic industries due to their desirable properties. In most of these applications, these materials should have a smooth surface without any surface and subsurface damages. Avoiding these damages yet achieving high material removal rate in the machining of them is very challenging as they are extremely hard and brittle. Materials such as single crystal silicon and sapphire have a crystal orientation or anisotropy effect. Because of this characteristic, their mechanical properties vary significantly by orientation that makes their machining even more difficult. In previous works, it has been shown that it is possible to machine brittle materials in ductile mode. In the present study, scratch tests were accomplished on the monocrystal sapphire in four different perpendicular directions. A laser is transmitted to a diamond cutting tool to heat and soften the material to either enhance the ductility, resulting in a deeper cut, or reducing brittleness leading to decreased fracture damage. Results such as depth of cut and also nature of cut (ductile or brittle) for different directions, laser powers, and cutting loads are compared. Also, influence of thermal softening on ductile response and its correlation to the anisotropy properties of sapphire is investigated. The effect of thermal softening on cuts is studied by analyzing the image of cuts and verifying the depth of cuts which were made by using varying thrust load and laser power. Macroscopic plastic deformation (chips and surface) occurring under high contract pressures and high temperatures is presented.
Prediction of Nonlinear Evolution of Fatigue Damage Accumulation From an Energy-Based Model
Authors: Herman Shen M.-H. , Akanda Sajedur R.
Published: December 2016

An energy-based framework is developed for welded steel and AL6061-T6 for assessment of nonlinear evolution of fatigue damage accumulation along fatigue life. The framework involves interrogation at continuum using a newly developed experimental procedure to determine the cyclic damaging energy to reveal that the accumulated fatigue damage evolves nonlinearly along cycle in case of low cycle fatigue but has somewhat linear relationship with cycle in case of high cycle fatigue. The accumulated fatigue damage is defined as the ratio of the accumulated cyclic damaging energy to the fatigue toughness, a material property and hence remains the same at all applied stress ranges. Based on the experimental data, a model is developed in order to predict cyclic damaging energy history at any applied stress range. The predicted fatigue damage evolution from the energy-based model are found to agree well with the experimental data.
Optimization of Shift Control Trajectories for Step Gear Automatic Transmissions
Authors: Čorić Mirko , Ranogajec Vanja , Deur Joško , Ivanović Vladimir , Eric Tseng H.
Published: December 2016

New generation of torque converter automatic transmissions (ATs) include a large number of gears for improved fuel economy and performance. Control requirements for such a transmission become more demanding, which calls for the development of new shift control optimization tools. A pseudospectral collocation method is used in the paper to optimize AT clutch and engine control trajectories for comfortable and efficient shifts. Since the optimization method requires a smooth formulation of plant model, the emphasized clutch model nonlinearity around the zero slip speed has been found to be a major difficulty to be resolved through proper modeling of the optimization problem. Therefore, different approaches of describing the friction behavior are considered and assessed, starting from simple static models, through dynamics models, toward torque-source approaches subject to the clutch passivity constraint. Apart from the conventional optimization approach based on minimizing the cost function (including the vehicle jerk and clutch energy loss terms), the so-called feasibility approach based on restricting the cost through an inequality constraint is considered, as well. The proposed optimization method has been verified on a characteristic example of 10-speed AT for both single- and double-transition shifts (DTSs). It has been found out that the clutch passivity constraint-based approach results in numerically most efficient optimizations for a wide range of shift tasks and scenarios.
Ultrathin high-resolution flexographic printing using nanoporous stamps
Authors: Kim Sanha , Sojoudi Hossein , Zhao Hangbo , Mariappan Dhanushkodi , McKinley Gareth H. , Gleason Karen K. , Hart A. John
Published: December 2016

Nanoporous stamps enable flexographic printing with uniform nanoscale thickness and micrometer-scale lateral resolution.
Carbon monoxide, the silent killer, may have met its match
Authors: Yan Wudan
Published: December 2016

Repurposed molecule saves rodents from gas poisoning.
The broadening reach of frustrated Lewis pair chemistry
Authors: Stephan Douglas W.
Published: December 2016

Cooperation between frustrated partners

What might you do with a hat that had so many decorations dangling from the brim that you couldn't put it on? Lewis acids and bases are the molecular versions of hats and heads. Stephan reviews the surprising chemistry of so-called frustrated Lewis pairs (FLPs), which cannot form their natural complex together. Over the past decade, such systems (most often comprising a borane with a nitrogen or phosphorus partner) have been used to catalyze hydrogenation reactions, activate a number of other small molecules, and generally promote a wide range of cooperative chemical reactivity.

Science
, this issue p.
10.1126/science.aaf7229
Enhancing reproducibility for computational methods
Authors: Stodden Victoria , McNutt Marcia , Bailey David H. , Deelman Ewa , Gil Yolanda , Hanson Brooks , Heroux Michael A. , Ioannidis John P.A. , Taufer Michela
Published: December 2016

Data, code, and workflows should be available and cited
Functional and Antigen-Specific Serum Antibody Levels as Correlates of Protection against Shigellosis in a Controlled Human Challenge Study
Authors: Shimanovich Avital A. , Buskirk Amanda D. , Heine Shannon J. , Blackwelder William C. , Wahid Rezwanul , Kotloff Karen L. , Pasetti Marcela F.
Published: December 2016

Shigellais an important cause of diarrheal disease in young children living in developing countries. No approved vaccines are available, and the development of vaccine candidates has been hindered by the lack of firm immunological correlates of protection, among other reasons. To address this gap in knowledge, we established quantitative assays to measureShigella-specific serum bactericidal antibody (SBA) and opsonophagocytic killing antibody (OPKA) activities and investigated their potential association with protection against disease in humans. SBA, OPKA, and Ipa-, VirG (IscA)-, andShigella flexneri2a lipopolysaccharide-specific serum IgG titers were determined in adult volunteers who receivedShigellavaccine candidate EcSf2a-2 and in unvaccinated controls, all of whom were challenged with virulentShigella flexneri2a. Prechallenge antibody titers were compared with disease severity after challenge. SBA and OPKA, as well as IpaB- and VirG-specific IgG, significantly correlated with reduced illness. SBA and OPKA assays were also used to evaluate the immunogenicity of leading live attenuated vaccine candidatesShigellaCVD 1204 and CVD 1208S in humans. A single oral immunization with CVD 1204 or CVD 1208S resulted in SBA seroconversion rates of 71% and 47% and OPKA seroconversion rates of 57% and 35%, respectively. Higher functional antibody responses were induced by CVD 1204, which is consistent with its lower attenuation. This is the first demonstration of SBA, OPKA, and IpaB- and VirG-specific IgG levels as potential serological correlates of protection against shigellosis in humans. These results warrant further studies to establish their capacity to predict protective immunity and vaccine efficacy.
Mycobacterial Taxonomy
Authors: Forbes Betty A.
Published: December 2016

This article summarizes the most recent (since 2012) taxonomic changes in the genus
Mycobacterium
. Only those mycobacteria that have been isolated from human specimens are included in this summary.
Field Validation of SYBR Green- and TaqMan-Based Real-Time PCR Using Biopsy and Swab Samples To Diagnose American Tegumentary Leishmaniasis in an Area Where Leishmania (Viannia) braziliensis Is Endemic
Authors: Gomes Ciro Martins , Cesetti Mariana Vicente , de Paula Natália Aparecida , Vernal Sebastián , Gupta Gaurav , Sampaio Raimunda Nonata Ribeiro , Roselino Ana Maria
Published: December 2016

The precise diagnosis of American tegumentary leishmaniasis (ATL) is an essential task due to the disease's associated morbidity. A noninvasive, extremely sensitive, and highly specific exam is critical, particularly for mucosal leishmaniasis (ML), in which a low parasite quantity is expected. We aimed to compare the diagnostic accuracy of swab and biopsy sample analysis using SYBR Green- and TaqMan-based real-time PCR (qPCR) assays with that of a composite reference standard consisting of the Montenegro skin test, serology, histopathology, smears, culture, and conventional PCR. In total, 55 patients with ATL (ML, 18 patients; cutaneous leishmaniasis [CL], 37 patients) and 36 patients without ATL were studied. qPCR analysis of swabs was more accurate when using SYBR Green (87.88%; 95% confidence interval [CI], 77.86 to 93.73 patients) than when using TaqMan (78.79%; 95% CI, 67.49 to 86.92%) (P= 0.031). SYBR Green (84.72%; 95% CI, 74.68 to 91.25%) was also more accurate than TaqMan (73.61%; 95% CI, 62.42 to 82.41%) for biopsy samples (P= 0.008). All qPCR methods were 100% specific. Swabs and biopsy specimens had similar sensitivity when using the same chemistry (P= 0.125 for SYBR Green andP= 0.625 for TaqMan). Moreover, qPCR achieved better performance than most existing techniques used for the diagnosis of ATL and also detected theLeishmaniaparasite in a greater proportion of patients than the associated histopathology, smear, culture, and conventional PCR techniques did. Swabs therefore represent a useful diagnostic tool because they not only are noninvasive but also can achieve an accuracy similar to that of biopsy samples. The high accuracy of SYBR Green-based qPCR may also reduce the requirement for associated parasitological tests for ATL diagnosis.
Stability Study of Cervical Specimens Collected by Swab and Stored Dry Followed by Human Papillomavirus DNA Detection Using the cobas 4800 Test
Authors: Lin Chun-Qing , Zeng Xi , Cui Jian-Feng , Liao Guang-Dong , Wu Ze-Ni , Gao Qian-Qian , Zhang Xun , Yu Xiu-Zhang , Chen Wen , Xi Ming-Rong , Qiao You-Lin
Published: December 2016

Safer, more convenient methods for cervical sample collection and storage are necessary to facilitate human papillomavirus (HPV) DNA testing in low-resource settings. Our study aimed to evaluate the stability of cervical specimens collected with dry swabs and stored dry, compared to liquid-based cytology (LBC) samples, as detected by HPV DNA testing. Women with abnormal cytological findings or HPV-positive results at colposcopy were recruited from the West China Second University Hospital, Sichuan University, between October 2013 and March 2014. From each woman, physicians collected cervical specimens with a swab placed into a Sarstedt tube and a CytoBrush placed into LBC medium. Samples were randomly assigned to be stored at uncontrolled ambient temperature for 2, 7, 14, or 28 days and then were tested for 14 high-risk HPV (HR-HPV) types using the cobas HPV test. The rates of agreement between dry swab and LBC samples for any HR-HPV type, HPV16, HPV18, and the 12 pooled HR-HPV types were 93.8%, 97.8%, 99.4%, and 93.2%, respectively, with kappa values of 0.87 (95% confidence interval [CI], 0.83 to 0.91), 0.94 (95% CI, 0.91 to 0.97), 0.94 (95% CI, 0.87 to 1.00), and 0.86 (95% CI, 0.82 to 0.90). The performance of swab samples for detection of cervical precancerous lesions by means of cobas HPV testing was equal to that of LBC samples, even with stratification by storage time. Dry storage of swab-collected cervical samples can last for 1 month without loss of test performance by cobas HPV testing, compared to LBC samples, which may offer a simple inexpensive approach for cervical cancer screening in low-resource settings.
Validation of Autoclave Protocols for Successful Decontamination of Category A Medical Waste Generated from Care of Patients with Serious Communicable Diseases
Authors: Garibaldi Brian T. , Reimers Mallory , Ernst Neysa , Bova Gregory , Nowakowski Elaine , Bukowski James , Ellis Brandon C. , Smith Chris , Sauer Lauren , Dionne Kim , Carroll Karen C. , Maragakis Lisa L. , Parrish Nicole M.
Published: December 2016

In response to the Ebola outbreak in 2014, many hospitals designated specific areas to care for patients with Ebola and other highly infectious diseases. The safe handling of category A infectious substances is a unique challenge in this environment. One solution is on-site waste treatment with a steam sterilizer or autoclave. The Johns Hopkins Hospital (JHH) installed two pass-through autoclaves in its biocontainment unit (BCU). The JHH BCU and The Johns Hopkins biosafety level 3 (BSL-3) clinical microbiology laboratory designed and validated waste-handling protocols with simulated patient trash to ensure adequate sterilization. The results of the validation process revealed that autoclave factory default settings are potentially ineffective for certain types of medical waste and highlighted the critical role of waste packaging in successful sterilization. The lessons learned from the JHH validation process can inform the design of waste management protocols to ensure effective treatment of highly infectious medical waste.
Emergence of a Viral RNA Polymerase Variant during Gene Copy Number Amplification Promotes Rapid Evolution of Vaccinia Virus
Authors: Cone Kelsey R. , Kronenberg Zev N. , Yandell Mark , Elde Nels C.
Published: December 2016

Viruses are under relentless selective pressure from host immune defenses. To study how poxviruses adapt to innate immune detection pathways, we performed serial vaccinia virus infections in primary human cells. Independent courses of experimental evolution with a recombinant strain lacking E3L revealed several high-frequency point mutations in conserved poxvirus genes, suggesting important roles for essential poxvirus proteins in innate immune subversion. Two distinct mutations were identified in the viral RNA polymerase gene A24R, which seem to act through different mechanisms to increase virus replication. Specifically, a Leu18Phe substitution encoded within A24R conferred fitness trade-offs, including increased activation of the antiviral factor protein kinase R (PKR). Intriguingly, this A24R variant underwent a drastic selective sweep during passaging, despite enhanced PKR activity. We showed that the sweep of this variant could be accelerated by the presence of copy number variation (CNV) at the K3L locus, which in multiple copies strongly reduced PKR activation. Therefore, adaptive cases of CNV can facilitate the accumulation of point mutations separate from the expanded locus. This study reveals how rapid bouts of gene copy number amplification during accrual of distant point mutations can potently facilitate poxvirus adaptation to host defenses.

IMPORTANCE
Viruses can evolve quickly to defeat host immune functions. For poxviruses, little is known about how multiple adaptive mutations emerge in populations at the same time. In this study, we uncovered a means of vaccinia virus adaptation involving the accumulation of distinct genetic variants within a single population. We identified adaptive point mutations in the viral RNA polymerase gene A24R and, surprisingly, found that one of these mutations activates the nucleic acid sensing factor PKR. We also found that gene copy number variation (CNV) can provide dual benefits to evolving virus populations, including evidence that CNV facilitates the accumulation of a point mutation distant from the expanded locus. Our data suggest that transient CNV can accelerate the fixation of mutations conferring modest benefits, or even fitness trade-offs, and highlight how structural variation might aid poxvirus adaptation through both direct and indirect actions.
Influence of Plasma Cell Niche Factors on the Recruitment and Maintenance of IRF4
hi
Plasma Cells and Plasmablasts in Vaccinated, Simian Immunodeficiency Virus-Infected Rhesus Macaques with Low and High Viremia
Authors: Shaw Julia M. , Miller-Novak Leia K. , Mohanram Venkatramanan , McKinnon Katherine , Demberg Thorsten , Vargas-Inchaustegui Diego A. , Venzon David , Robert-Guroff Marjorie
Published: December 2016

In a recent study, we found that protection following simian immunodeficiency virus (SIV) exposure correlated with rectal plasma cell frequency in vaccinated female rhesus macaques. We sought to determine if the same macaques maintained high mucosal plasma cell frequencies postinfection and if this translated to reduced viremia. Although delayed SIV acquisition did not predict subsequent viral control, alterations existed in the distribution of plasma cells and plasmablasts between macaques that exhibited high or low viremia. Flow cytometric analysis of cells from rectal biopsy specimens, bone marrow, and mesenteric lymph nodes of vaccinated infected, unvaccinated infected, and uninfected macaques identified two main IRF4
hi
subsets of interest: CD138
+
plasma cells, and CD138
−
plasmablasts. In rectal tissue, plasma cell frequency positively correlated with plasma viremia and unvaccinated macaques had increased plasma cells and plasmablasts compared to vaccinated animals. Likewise, plasmablast frequency in the mesenteric lymph node correlated with viremia. However, in bone marrow, plasmablast frequency negatively correlated with viremia. Accordingly, low-viremic macaques had a higher frequency of both bone marrow IRF4
hi
subsets than did animals with high viremia. Significant reciprocal relationships between rectal and bone marrow plasmablasts suggested that efficient trafficking to the bone marrow as opposed to the rectal mucosa was linked to viral control. mRNA expression analysis of proteins involved in establishment of plasma cell niches in sorted bone marrow and rectal cell populations further supported this model and revealed differential mRNA expression patterns in these tissues.

IMPORTANCE
As key antibody producers, plasma cells and plasmablasts are critical components of vaccine-induced immunity to human immunodeficiency virus type 1 (HIV-1) in humans and SIV in the macaque model; however, few have attempted to examine the role of these cells in viral suppression postinfection. Our results suggest that plasmablast trafficking to and retention in the bone marrow play a previously unappreciated role in viral control and contrast the potential contribution of mucosal plasma cells to mediate protection at sites of infection with that of bone marrow plasmablasts and plasma cells to control viremia during chronic infection. Manipulation of niche factors influencing the distribution and maintenance of these critical antibody-secreting cells may serve as potential therapeutic targets to enhance antiviral responses postvaccination and postinfection.
Herpes Simplex Virus 1 UL41 Protein Suppresses the IRE1/XBP1 Signal Pathway of the Unfolded Protein Response via Its RNase Activity
Authors: Zhang Pengchao , Su Chenhe , Jiang Zhangtao , Zheng Chunfu
Published: December 2016

During viral infection, accumulation of viral proteins can cause stress in the endoplasmic reticulum (ER) and trigger the unfolded protein response (UPR) to restore ER homeostasis. The inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved of the three UPR signal pathways. Upon activation, IRE1 splices out an intron from the unspliced inactive form of X box binding protein 1 [XBP1(u)] mRNA and produces a transcriptionally potent spliced form [XBP1(s)]. Previous studies have reported that the IRE1/XBP1 pathway is inhibited upon herpes simplex virus 1 (HSV-1) infection; however, the underlying molecular mechanism is still elusive. Here, we uncovered a role of the HSV-1 UL41 protein in inhibiting the IRE1/XBP1 signal pathway. Ectopic expression of UL41 decreased the expression of XBP1 and blocked XBP1 splicing activation induced by the ER stress inducer thapsigargin. Wild-type (WT) HSV-1, but not the UL41-null mutant HSV-1 (R2621), decreased XBP1 mRNA induced by thapsigargin. Nevertheless, infection with both WT HSV-1 and R2621 without drug pretreatment could reduce the mRNA and protein levels of XBP1(s), and additional mechanisms might contribute to this inhibition of XBP1(s) during R2621 infection. Taking these findings together, our results reveal XBP1 as a novel target of UL41 and provide insights into the mechanism by which HSV-1 modulates the IRE1/XBP1 pathway.

IMPORTANCE
During viral infection, viruses hijack the host translation apparatus to produce large amounts of viral proteins, which leads to ER stress. To restore ER homeostasis, cells initiate the UPR to alleviate the effects of ER stress. The IRE1/XBP1 pathway is the most conserved UPR branch, and it activates ER-associated protein degradation (ERAD) to reduce the ER load. The IRE1/XBP1 branch is repressed during HSV-1 infection, but little is known about the underlying molecular mechanism. Our results show for the first time that UL41 suppresses the IRE1/XBP1 signal pathway by reducing the accumulation of XBP1 mRNA, and characterization of the underlying molecular mechanism provides new insight into the modulation of UPR by HSV-1.
Strain-Dependent Recognition of a Unique Degradation Motif by ClpXP in Streptococcus mutans
Authors: Jana Biswanath , Tao Liang , Biswas Indranil
Published: December 2016

Regulated proteolysis in bacteria is an important biological process that maintains protein homeostasis. ClpXP, an intracellular proteolytic complex, is the primary protease that is responsible for protein turnover. While the substrates for ClpXP were identified in
Escherichia coli
, the substrates for vast majority of bacteria are currently unknown. In this study, we identified a unique substrate for ClpXP-mediated degradation in
Streptococcus mutans
, a dental pathogen. We also found that a small motif composed of 3 amino acids is sufficient for ClpXP-mediated degradation. Identification of this motif will clearly help us to understand the pathogenesis of this organism and other related pathogens.
Temporal ocular coherence tomography-measured changes in anterior chamber angle and diurnal intraocular pressure after laser iridoplasty: IMPACT study
Authors: Bourne Rupert R A , Zhekov Ivailo , Pardhan Shahina
Published: December 2016

Aims

To evaluate temporal change in anterior chamber angle anatomy following argon laser peripheral iridoplasty (ALPI) in eyes with occludable angles postlaser peripheral iridotomy (LPI) compared with control eyes. Additionally, the effect on diurnal intraocular pressure (DIOP) fluctuation (maximum-minimum IOP) was investigated.

Methods

Twenty-two patients with bilateral primary angle closure/suspects with gonioscopically occludable anterior chamber angles following LPI were randomised to receive ALPI (n=11) or no further treatment (n=11). Angle opening distance (AOD), trabecular-iris angle, angle recess area and trabecular-iris space area were measured over eight sections with swept-source anterior segment optical coherence tomography and DIOP was measured pre-LPI and repeated at 3 months after ALPI (hourly measures).

Results

All angle parameters increased following ALPI. This change was maintained for 3 months in seven of the eight sections (eg, inferotemporal AOD500 increased by 0.063 mm, p=0.004 at 1 day; 0.051 mm, p=0.029 at 1 week; 0.059 mm, p=0.006 at 6 weeks and 0.056 mm, p=0.011 at 3 months). The only exception was in the inferior sector (eg, AOD500 increased by 0.041 mm, p=0.025 at 1 day and by 0.029 mm, p=0.054 at 3 months). DIOP at 3 months was significantly reduced (5.04 mm Hg; ±1.61 mm Hg) compared with controls (6.61 mm Hg; ±1.63 mm Hg). Maximum IOP was significantly greater in the non-ALPI group (1.87 mm Hg, p=0.026).

Conclusions

ALPI widened all angle sections in eyes that remained occludable post-LPI. Changes were maintained for 3 months. ALPI decreased DIOP fluctuation in the treated eyes by lowering the maximum IOP value.
Effect of prehabilitation in gastro-oesophageal adenocarcinoma: study protocol of a multicentric, randomised, control trial—the PREHAB study
Authors: Le Roy Bertrand , Pereira Bruno , Bouteloup Corinne , Costes Frédéric , Richard Ruddy , Selvy Marie , Pétorin Caroline , Gagnière Johan , Futier Emmanuel , Slim Karem , Meunier Bernard , Mabrut Jean-Yves , Mariette Christophe , Pezet Denis
Published: December 2016

Introduction

Perioperative chemotherapy is the gold standard treatment of the resectable gastro-oesophageal adenocarcinoma. However, 70% of patients cannot receive the complete sequence because of a postoperative complication or a decrease in functional and nutritional reserves. Recently, a new concept appeared in digestive surgery: prehabilitation. This interventional process consists of patient preparation, between surgical consultation and surgery, and is based on 3 components: (1) physical management, (2) nutritional care and (3) psychological care. Prehabilitation should decrease postoperative complications and improve nutritional and physical status during the preoperative and postoperative periods. Therefore, it is becoming essential to evaluate the effect of prehabilitation, compared to conventional care, on the percentage of patients reaching the complete oncological treatment.

Methods and analysis

The PREHAB trial aimed to evaluate the efficacy of prehabilitation compared to conventional care, in patients with gastro-oesophageal cancer with perioperative chemotherapy. This trial is a prospective, randomised, controlled, open-blind and interventional study in 4 centres. Patients (n=60 per group) will be randomly assigned for management with either prehabilitation or conventional care. The primary outcome is the percentage of patients reaching the complete oncological treatment decided in a multidisciplinary tumour board. The secondary outcomes are the postoperative morbidity, disease-free survival, overall survival, feasibility of the protocol, length of stay, variation of the functional reserve after the preoperative chemotherapy (defined by the VO2peak, ventilatory threshold and 6-min walk test), preoperative and postoperative nutritional status, preoperative anxiety, quality of life, 30-day and 90-day mortality and cumulative dose of cytotoxic treatment received.

Ethics and dissemination

The study was approved by an independent medical ethics committee (IRB00008526, CPP Sud-Est VI, Clermont-Ferrand, France) and by the competent French authority (ANSM, Saint Denis, France) and registered onClinicaltrial.gov. The results will be disseminated in a peer-reviewed journal.

Trial registration number

NCT02780921.
Differences among primary care patients with different mechanical patterns of low back pain: a cross-sectional investigation
Authors: Della Mora Lauren S , Perruccio Anthony V , Badley Elizabeth M , Rampersaud Y Raja
Published: December 2016

Objectives

To characterise and compare a persistent low back pain (LBP) population based on 4 clinical pain patterns.

Design

Cross-sectional analysis of patient-reported data.

Setting

Patients from 220 primary care practitioners in 3 cities in Ontario, Canada.

Participants

1020 individuals seeking LBP care. Inclusion criteria: LBP symptoms lasting 1½–12 months, or unmanageable recurrent symptoms; ages 18+years. Exclusion criteria: pregnant/1-year postpartum; involved in active litigation or motor vehicle injury; emergent spinal presentations; pain disorder diagnosis; work injury claim; or constant symptoms persisting >12 months postonset.

Main outcome measure

Hall pain pattern subgroups: back dominant pain aggravated by flexion (P1) or extension (P2), or leg dominant constant (P3) or intermittent (P4) pain (multinomial logistic outcome; referent: P1).

Results

Groups P1 and P2 had the highest proportion of women. P2 and P4 had higher mean ages and comorbidity counts. P3 and P4 had higher proportions of overweight/obese individuals and lower general health scores. Adjusted models: being male and overweight/obese was associated with increased odds of being in P3 (OR 1.64 (95% CI 1.10 to 2.46), and OR 1.74 (1.13 to 2.68), respectively) and P4 (OR 1.87 (1.11 to 3.15) and OR 1.91 (1.06 to 3.42), respectively), and increasing age with increased odds of being in P2 (OR 1.02 (1.01 to 1.03)) and P4 (OR 1.06 (1.04 to 1.08)). Increasing comorbidity count was associated with increased odds of being in P2 (OR 1.14 (1.0 to 1.3)), and better general health scores with decreased odds of being in P3 (OR 0.40 (0.18 to 0.93)).

Conclusions

This is the first study to examine the ‘Hall system’ in a non-rehab primary care population. Subgroups classified according to this system appear to have distinct profiles. Further research is needed to better characterise and determine the prognostic implication of these clinically derived subgroups.
Development of a model of dementia support and pathway for culturally and linguistically diverse communities using co-creation and participatory action research
Authors: Goeman Dianne , King Jordan , Koch Susan
Published: December 2016

Objective

To develop an inclusive model of culturally sensitive support, using a specialist dementia nurse (SDN), to assist people with dementia from culturally and linguistically diverse (CALD) communities and their carers to overcome barriers to accessing health and social care services.

Design

Co-creation and participatory action research, based on reflection, data collection, interaction and feedback from participants and stakeholders.

Setting

An SDN support model embedded within a home nursing service in Melbourne, Australia was implemented between October 2013 and October 2015.

Participants

People experiencing memory loss or with a diagnosis of dementia from CALD backgrounds and their carers and family living in the community setting and expert stakeholders.

Data collection and analysis

Reflections from the SDN on interactions with participants and expert stakeholder opinion informed the CALD dementia support model and pathway.

Results

Interaction with 62 people living with memory loss or dementia from CALD backgrounds, carers or family members receiving support from the SDN and feedback from 13 expert stakeholders from community aged-care services, consumer advocacy organisations and ethnic community group representatives informed the development and refinement of the CALD dementia model of care and pathway. We delineate the three components of the ‘SDN’ model: the organisational support; a description of the role; and the competencies needed. Additionally, we provide an accompanying pathway for use by health professionals delivering care to consumers with dementia from CALD backgrounds.

Conclusions

Our culturally sensitive model of dementia care and accompanying pathway allows for the tailoring of health and social support to assist people from CALD backgrounds, their carers and families to adjust to living with memory loss and remain living in the community as long as possible. The model and accompanying pathway also have the potential to be rolled out nationally for use by health professionals across a variety of health services.
Quantifying the hospitalised morbidity and mortality attributable to traumatic injury using a population-based matched cohort in Australia
Authors: Mitchell Rebecca J , Cameron Cate M , McClure Rod
Published: December 2016

Objectives

To quantify the 12-month hospitalised morbidity and mortality attributable to traumatic injury using a population-based matched cohort in Australia.

Setting

New South Wales, Queensland and South Australia, Australia.

Participants

Individuals ≥18 years who had an injury-related hospital admission in 2009 formed the injured cohort. The non-injured comparison cohort was randomly selected from the electoral roll and was matched 1:1 on age, gender and postcode of residence at the date of the index injury admission of their matched counterpart.

Primary outcome measures

Using linked emergency department presentation, hospital admission and mortality records from 1 January 2008 to 31 December 2010 for both the injured and non-injured cohorts, 12-month mortality and pre-index and post-index injury hospital service use was examined. Adjusted rate ratios and attributable risk were calculated.

Results

There were 167 600 individuals injured in 2009 and admitted to hospital in New South Wales, South Australia or Queensland with a matched comparison. The injured cohort had 3 times higher proportion of having ≥1 comorbidity preinjury, higher preinjury hospital service use, and a higher 12-month mortality compared with a non-injured comparison group. The injured cohort had 2.20 (95% CI 2.12 to 2.28) times higher rate of hospital admissions in the 12 months post the index injury admission compared with the non-injured comparison cohort. Injury was a likely contributory factor in at least 55% of hospitalisations within 12 months of the index injury hospitalisation.

Conclusions

Individuals who had an injury-related hospitalisation had higher mortality and are hospitalised at increased rates for many months postinjury. While comorbid conditions are significant, they do not account for the differences in outcomes. This study contributes to informing research efforts on better quantifying the attributable burden of hospitalised injury-related disability and mortality in Australia.
Th9 cytokines response and its possible implications in the immunopathogenesis of leprosy
Authors: de Sousa Jorge Rodrigues , Pagliari Carla , de Almeida Dandara Simone Maia , Barros Luiz Fernando Lima , Carneiro Francisca Regina Oliveira , Dias Leonidas Braga , de Souza Aarão Tinara Leila , Quaresma Juarez Antonio Simões
Published: December 2016

Aims

Leprosy is an infectious-contagious disease whose clinical evolution depends on the interaction of the infectious agent with the immune response of the host, leading to a clinical spectrum that ranges from lepromatous leprosy (susceptibility, LL) to tuberculoid leprosy (resistance, TT). The immune response profile will depend on the pattern of cytokine production and on the activity of macrophages during infection. Classically, the clinical evolution of leprosy has been associated with Th1/Th2 cytokine profiles, but the role of new cytokine profiles such as T helper 9 (Th9) remains to be elucidated.

Methods

To evaluate the tissue expression profile of these cytokines, a cross-sectional study was conducted using a sample of 30 leprosy skin lesion biopsies obtained from patients with leprosy, 16 TT and 14 lepromatous LL.

Results

Immunohistochemical analysis revealed a significant difference in interleukin (IL)-9, IL-4 transforming growth factor (TGF)-β and IL-10 levels between the two groups. IL-9 was more expressed in TT lesions compared with LL lesions. Higher expression of IL-4, IL-10 and TGF-β was observed in LL compared with TT. IL-4, IL-10 and TGF-β tended to be negatively correlated with the expression of IL-9, indicating a possible antagonistic activity in tissue.

Conclusions

The results suggest that Th9 lymphocytes may be involved in the response toMycobacterium leprae, positively or negatively regulating microbicidal activity of the local immune system in the disease.
Can you reduce the dose of meloxicam in dogs with osteoarthritis?
Authors: Doit Hannah , Wareham Kathryn
Published: December 2016

BestBETs for Vets are generated by the Centre for Evidence‐based Veterinary Medicine at the University of Nottingham to help answer specific questions and assist in clinical decision making. Although evidence is often limited, they aim to find, present and draw conclusions from the best available evidence, using a standardised framework. A more detailed description of how BestBETs for Vets are produced was published in a previous issue of Veterinary Record (VR, April 4, 2015, pp 354‐356)
Third‐year student diary
Authors: Perrett Rosie
Published: December 2016

The stress of finding somewhere to live and a couple of health issues have been occupying our diarist Rosie Perrett recently. However, she has also been fascinated by anaesthesia and animal behaviour.
Bulk Current Model for GaN-on-Si High Electron Mobility Transistors
Authors: Islam Mirwazul , Simin Grigory
Published: December 2016

Drain to substrate current is an important parameter affecting loss, breakdown and reliability of power GaN HEMTs on Si substrates; however, no clear model of the current has been established. This work proposes a novel approach describing the drain to substrate current as a function of equivalent Si/GaN interface barrier. The modeling results are in close agreement with experimental observations; they reveal an important role of space charge injection from Si substrate into GaN buffer. Compact model closely reproducing experimental data is presented. The results are important for GaN on Si power switches development.