bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the JNK Pathway in Varicella-Zoster Virus Lytic Infection and Reactivation
Authors: Kurapati Sravya , Sadaoka Tomohiko , Rajbhandari Labchan , Jagdish Balaji , Shukla Priya , Ali Mir A. , Kim Yong Jun , Lee Gabsang , Cohen Jeffrey I. , Venkatesan Arun 
Published: June 2017

ABSTRACT
Mechanisms of neuronal infection by varicella-zoster virus (VZV) have been challenging to study due to the relatively strict human tropism of the virus and the paucity of tractable experimental models. Cellular mitogen-activated protein kinases (MAPKs) have been shown to play a role in VZV infection of nonneuronal cells, with distinct consequences for infectivity in different cell types. Here, we utilize several human neuronal culture systems to investigate the role of one such MAPK, the c-Jun N-terminal kinase (JNK), in VZV lytic infection and reactivation. We find that the JNK pathway is specifically activated following infection of human embryonic stem cell-derived neurons and that this activation of JNK is essential for efficient viral protein expression and replication. Inhibition of the JNK pathway blocked viral replication in a manner distinct from that of acyclovir, and an acyclovir-resistant VZV isolate was as sensitive to the effects of JNK inhibition as an acyclovir-sensitive VZV isolate in neurons. Moreover, in a microfluidic-based human neuronal model of viral latency and reactivation, we found that inhibition of the JNK pathway resulted in a marked reduction in reactivation of VZV. Finally, we utilized a novel technique to efficiently generate cells expressing markers of human sensory neurons from neural crest cells and established a critical role for the JNK pathway in infection of these cells. In summary, the JNK pathway plays an important role in lytic infection and reactivation of VZV in physiologically relevant cell types and may provide an alternative target for antiviral therapy.

IMPORTANCE
Varicella-zoster virus (VZV) has infected over 90% of people worldwide. While primary infection leads to the typically self-limiting condition of chickenpox, the virus can remain dormant in the nervous system and may reactivate later in life, leading to shingles or inflammatory diseases of the nervous system and eye with potentially severe consequences. Here, we take advantage of newer stem cell-based technologies to study the mechanisms by which VZV infects human neurons. We find that the c-Jun N-terminal kinase (JNK) pathway is activated by VZV infection and that blockade of this pathway limits lytic replication (as occurs during primary infection). In addition, JNK inhibition limits viral reactivation, exhibiting parallels with herpes simplex virus reactivation. The identification of the role of the JNK pathway in VZV infection of neurons reveals potential avenues for the development of alternate antiviral drugs.
Interplay of PA-X and NS1 Proteins in Replication and Pathogenesis of a Temperature-Sensitive 2009 Pandemic H1N1 Influenza A Virus
Authors: Nogales Aitor , Rodriguez Laura , DeDiego Marta L. , Topham David J. , Martínez-Sobrido Luis 
Published: June 2017

ABSTRACT

Influenza A viruses (IAVs) cause seasonal epidemics and occasional pandemics, representing a serious public health concern. It has been described that one mechanism used by some IAV strains to escape the host innate immune responses and modulate virus pathogenicity involves the ability of the PA-X and NS1 proteins to inhibit the host protein synthesis in infected cells. It was reported that for the 2009 pandemic H1N1 IAV (pH1N1) only the PA-X protein had this inhibiting capability, while the NS1 protein did not. In this work, we have evaluated, for the first time, the combined effect of PA-X- and NS1-mediated inhibition of general gene expression on virus pathogenesis, using a temperature-sensitive, live-attenuated 2009 pandemic H1N1 IAV (pH1N1 LAIV). We found that viruses containing PA-X and NS1 proteins that simultaneously have (PA
WT
+
/NS1
MUT
+
) or do not have (PA
MUT
−
/NS1
WT
−
) the ability to block host gene expression showed reduced pathogenicity
in vivo
. However, a virus where the ability to inhibit host protein expression was switched between PA-X and NS1 (PA
MUT
−
/NS1
MUT
+
) presented pathogenicity similar to that of a virus containing both wild-type proteins (PA
WT
+
/NS1
WT
−
). Our findings suggest that inhibition of host protein expression is subject to a strict balance, which can determine the successful progression of IAV infection. Importantly, knowledge obtained from our studies could be used for the development of new and more effective vaccine approaches against IAV.

IMPORTANCE
Influenza A viruses (IAVs) are one of the most common causes of respiratory infections in humans, resulting in thousands of deaths annually. Furthermore, IAVs can cause unpredictable pandemics of great consequence when viruses not previously circulating in humans are introduced into humans. The defense machinery provided by the host innate immune system limits IAV replication; however, to counteract host antiviral activities, IAVs have developed different inhibition mechanisms, including prevention of host gene expression mediated by the viral PA-X and NS1 proteins. Here, we provide evidence demonstrating that optimal control of host protein synthesis by IAV PA-X and/or NS1 proteins is required for efficient IAV replication in the host. Moreover, we demonstrate the feasibility of genetically controlling the ability of IAV PA-X and NS1 proteins to inhibit host immune responses, providing an approach to develop more effective vaccines to combat disease caused by this important respiratory pathogen.
A protocol for prospective studies of 25-hydroxyvitamin D, leptin and body mass index in relation to cutaneous melanoma incidence and survival
Authors: Stenehjem Jo Steinson , Grimsrud Tom K , Rees Judith R , Vos Linda , Babigumira Ronnie , Veierød Marit B , Robsahm Trude Eid 
Published: June 2017

IntroductionThe incidence and mortality rates of cutaneous melanoma (CM) are increasing among fair-skinned populations worldwide. Ultraviolet radiation (UVR) is the principal risk factor for CM, but is also the main source of 25-hydroxyvitamin D (25(OH)D), which has been associated with reduced risk and better prognosis of some cancer types. However, both low and high 25(OH)D levels have been associated with increased risk of CM. Obesity as measured by body mass index (BMI) is associated with risk of several cancers and has also been suggested as a risk factor for CM, and may also be related to insufficient 25(OH)D and/or high leptin levels. Moreover, contracting a CM diagnosis has been associated with increased risk of developing second cancer. We aim to study whether low prediagnostic serum levels of 25(OH)D, high prediagnostic levels of BMI and high serum leptin levels influence CM incidence, Breslow thickness and CM mortality, and risk of second cancer and survival after a CM diagnosis.Methods and analysisCohort and nested case–control studies will be carried out using the population-based Janus Serum Bank Cohort (archival prediagnostic sera, BMI, smoking and physical activity), with follow-up from 1972 to 2014. Additional data will be received from the Cancer Registry of Norway, the national Cause of Death Registry, Statistics Norway (education and occupation) and exposure matrices of UVR. Time-to-event regression models will be used to analyse the cohort data, while the nested case–control studies will be analysed by conditional logistic regression. A multilevel approach will be applied when incorporating group-level data.Ethics and disseminationThe project is approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer-reviewed journals, at scientific conferences and in the news media.
Does attendance at a specialist antenatal clinic improve clinical outcomes in women with class III obesity compared with standard care? A retrospective case-note analysis
Authors: Denison Fiona C , MacGregor Heather , Stirrat Laura I , Stevenson Kerrie , Norman Jane E , Reynolds Rebecca M 
Published: June 2017

ObjectivesTo determine whether attendance at a specialised multidisciplinary antenatal clinic for women with class III obesity (BMI >40 kg/m2) is associated with improved clinical outcomes compared with standard antenatal care.DesignRetrospective cohort study using routinely collected data from electronic patient record.SettingCommunity and hospital based antenatal care.ParticipantsWomen with a singleton pregnancy with class III obesity booked for antenatal care and delivered in one of two hospitals in NHS Lothian, Scotland, UK between 2008 and 2014. Maternal and offspring outcomes were compared in women who attended a specialised obesity clinic (n=511) compared with standard antenatal care (n=502).Main outcome measuresIncluded stillbirth, low birth weight, gestational diabetes, induction of labour and caesarean section.ResultsCompared with standard care, women receiving specialist care were less likely to have a stillbirth (OR 0.12, 95% CI 0.06 to 0.97) and a low birthweight baby (OR 0.57, 95% CI 0.33 to 0.99) and more likely to be screened for (100% vs 73.6%; p<0.001) and diagnosed with (26.0% vs 12.5%; p<0.001) gestational diabetes, to require induction of labour (38.4% vs 29.9%; p=0.009), an elective (20.3% vs 17.7%; p<0.001) and emergency (23.9% vs 20.3%; p<0.001) caesarean section and attend antenatal triage one or more times during pregnancy (77.7% vs 53.1%; p<0.001). Women attending the specialist clinic had a higher BMI (44.5 kg/m2(4.3) vs 43.2 kg/m2(3.1); p<0.001) and were more likely to be nulliparous (46.0% vs 24.9%; p<0.001). There were no other differences in maternal demographic or maternal and offspring outcomes between groups.ConclusionsAttendance at a specialised antenatal clinic for obesity is associated with reduced rates of stillbirth and low birth weight and improved detection of gestational diabetes. The improvement in clinical outcomes is associated with an increase in healthcare attendance to obstetric triage and clinical interventions including induction of labour and caesarean section.
The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients
Authors: Rol Mary-Luz , Venet Fabienne , Rimmele Thomas , Moucadel Virginie , Cortez Pierre , Quemeneur Laurence , Gardiner David , Griffiths Andrew , Pachot Alexandre , Textoris Julien , Monneret Guillaume 
Published: June 2017

IntroductionThe host response to septic shock is dynamic and complex. A sepsis-induced immunosuppression phase has recently been acknowledged and linked to bad outcomes and increased healthcare costs. Moreover, a marked suppression of the immune response has also been partially described in patients hospitalized in intensive care unit (ICU) for severe trauma or burns. It has been hypothesized that immune monitoring could enable identification of patients who might most benefit from novel, adjunctive immune-stimulating therapies. However, there is currently neither a clear definition for such injury-induced immunosuppression nor a stratification biomarker compatible with clinical constraints.Methods and analysisWe set up a prospective, longitudinal single-centre clinical study to determine the incidence, severity and persistency of innate and adaptive immune alterations in ICU patients. We optimized a workflow to describe and follow the immunoinflammatory status of 550 patients (septic shock, severe trauma/burn and major surgery) during the first 2 months after their initial injury. On each time point, two immune functional tests will be performed to determine whole-blood TNF-α production in response toex vivolipopolysaccharide stimulation and the T lymphocyte proliferation in response to phytohaemagglutinin. In addition, a complete immunophenotyping using flow cytometry including monocyte HLA-DR expression and lymphocyte subsets will be obtained. New markers (ie, levels of expression of host mRNA and viral reactivation) will be also evaluated. Reference intervals will be determined from a cohort of 150 age-matched healthy volunteers. This clinical study will provide, for the first time, data describing the immune status of severe ICU patients over time.Ethics and disseminationEthical approval has been obtained from the institutional review board (no 69HCL15_0379) and the French National Security agency for drugs and health-related products. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals.Trial registration numberClinicaltrials.gov Registration number:NCT02638779. Pre-results.
Intrathecal baclofen therapy in paediatrics: a study protocol for an Australian multicentre, 10-year prospective audit
Authors: Stewart Kirsty , Hutana Gavin , Kentish Megan 
Published: June 2017

IntroductionIncreasing clinical use of Intrathecal baclofen (ITB) in Australian tertiary paediatric hospitals, along with the need for standardised assessment and reporting of adverse events, saw the formation of the Australian Paediatric ITB Research Group (APIRG). APIRG developed a National ITB Audit tool designed to capture clinical outcomes and adverse events data for all Australian children and adolescents receiving ITB therapy.Methods and analysisThe Australian ITB Audit is a 10 year, longitudinal, prospective, clinical audit collecting all adverse events and assessment data across body functions and structure, participation and activity level domains of the ICF. Data will be collected at baseline, 6 and 12 months with ongoing capture of all adverse event data. This is the first Australian study that aims to capture clinical and adverse event data from a complete population of children with neurological impairment receiving a specific intervention between 2011 and 2021. This multi-centre study will inform ITB clinical practice in children and adolescents, direct patient selection, record and aid decision making regarding adverse events and investigate the impact of ITB therapy on family and patient quality of life.Ethics and disseminationThis project was approved by the individual Human Research Ethics committees at the six Australian tertiary hospitals involved in the study. Results will be published in various peer reviewed journals and presented at national and international conferences.Trial registration numberACTRN 12610000323022; Pre-results.
Primary prevention implantable cardioverter defibrillator in patients with non-ischaemic cardiomyopathy: a meta-analysis of randomised controlled trials
Authors: Barakat Amr F , Saad Marwan , Elgendy Akram Y , Mentias Amgad , Abuzaid Ahmed , Mahmoud Ahmed N , Elgendy Islam Y 
Published: June 2017

ObjectivesThe objective of this meta-analysis of randomised controlled trials (RCTs) is to evaluate the role of primary prevention implantable cardioverter defibrillator (ICD) in patients with non-ischaemic cardiomyopathy (NICM).SettingA meta-analysis of RCTs performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.Data sourcesThe PubMed, MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases were searched for relevant articles.ParticipantsA total of 5 RCTs with 2573 patients with NICM were included.InterventionPrimary prevention ICD, compared with medical therapy alone.Primary and secondary outcome measuresAll-cause mortality (primary outcome) and sudden cardiac death (SCD, secondary outcome).Data analysisSummary estimate HR were constructed using the random-effect DerSimonian and Laird’s model. Multiple study-level subgroup analyses were performed, and interaction was tested using random-effect analysis.ResultsCompared with medical therapy alone, ICD placement was associated with lower risk of all-cause mortality (HR 0.79; 95% CI 0.64 to 0.93; p<0.001; I2=0%) at a mean follow-up of 4.2 years. The risk of SCD was also lower with ICD placement (RR 0.47; 95% CI 0.30 to 0.73; p=0.001; I2=0%) compared with control. On subgroup analyses, there was a suggestion of possible effect modification by age, in which benefit was observed in age group <60 years (HR 0.64; 95% CI 0.47 to 0.89), but not with age ≥60 years (HR 0.82; 95% CI 0.65 to 1.03) (Pinteraction=0.058), but not with other study-level variables.ConclusionsCompared with medical therapy alone, primary prevention ICD therapy in patients with NICM is associated with a significant reduction in all-cause mortality, especially in younger patients. Future dedicated studies are needed to investigate the role of primary prevention ICD in the elderly population.PROSPEROregistrationnumberPROSPERO CRD42016052010.
Group clinics for young adults with diabetes in an ethnically diverse, socioeconomically deprived setting (TOGETHER study): protocol for a realist review, co-design and mixed methods, participatory evaluation of a new care model
Authors: Papoutsi Chrysanthi , Hargreaves Dougal , Colligan Grainne , Hagell Ann , Patel Anita , Campbell-Richards Desirée , Viner Russell M , Vijayaraghavan Shanti , Marshall Martin , Greenhalgh Trisha , Finer Sarah 
Published: June 2017

IntroductionYoung adults with diabetes often report dissatisfaction with care and have poor diabetes-related health outcomes. As diabetes prevalence continues to rise, group-based care could provide a sustainable alternative to traditional one-to-one consultations, by engaging young people through life stage-, context- and culturally-sensitive approaches. In this study, we will co-design and evaluate a group-based care model for young adults with diabetes and complex health and social needs in socioeconomically deprived areas.Methods and analysisThis participatory study will include three phases. In phase 1, we will carry out a realist review to synthesise the literature on group-based care for young adults with diabetes. This theory-driven understanding will provide the basis for phase 2, where we will draw on experience-based co-design methodologies to develop a new, group-based care model for young adults (aged <25 years, under the care of adult diabetes services). In phase 3, we will use a researcher-in-residence approach to implement and evaluate the co-designed group clinic model and compare with traditional care. We will employ qualitative (observations in clinics, patient and staff interviews and document analysis) and quantitative methods (eg, biological markers, patient enablement instrument and diabetes distress scale), including a cost analysis.Ethics and disseminationNational Health Service ethics approval has been granted (reference 17/NI/0019). The project will directly inform service redesign to better meet the needs of young adults with diabetes in socioeconomically deprived areas and may guide a possible cluster-randomised trial, powered to clinical and cost-effectiveness outcomes. Findings from this study may be transferable to other long-term conditions and/or age groups. Project outputs will include briefing statements, summaries and academic papers, tailored for different audiences, including people living with diabetes, clinicians, policy makers and strategic decision makers.Registration detailsPROSPERO (CRD42017058726).
Racial Differences in Arterial Stiffness are Mainly Determined by Blood Pressure Levels: Results From the ELSA‐Brasil Study
Authors: Baldo Marcelo P. , Cunha Roberto S. , Ribeiro Antônio L.P. , Lotufo Paulo A. , Chor Dora , Barreto Sandhi M. , Bensenor Isabela M. , Pereira Alexandre C. , Mill José Geraldo 
Published: June 2017

Background
Black people have a higher risk of developing hypertension and presenting higher vascular stiffening. Our aim was to investigate whether the association between race and aortic stiffness could be explained by differences in the primary risk factors.

Methods and Results

We analyzed data from 11 472 adults (mean age, 51.9±8.9; 53.8% female) self‐reported as white (n=6173), brown (n=3364), or black (n=1935). Their carotid‐to‐femoral pulse wave velocity (cf‐PWV) as well as clinical and anthropometric parameters were measured. cf‐PWV was higher in blacks than in whites or browns (men: white, 9.63±1.81; brown, 9.63±1.88; black, 9.98±1.99; women: white, 8.84±1.64; brown, 9.02±1.68; black, 9.34±1.91;
P
<0.05). However, this difference disappeared after adjustments for age, mean arterial pressure, heart rate, waist circumference, fasting glucose, and glomerular filtration rate (men: white, 9.68±1.54; brown, 9.68±1.50; black, 9.73±1.52; women: white, 8.93±1.32; brown, 8.98±1.29; black, 9.02±1.32;
P
>0.05). The association between race and arterial stiffness was significant for brown and black women in the highest cf‐PWV quartile, even after controlling for covariates. There were no differences in the age‐related increase in cf‐PWV among the racial groups after adjustment, confirming the strong effect of age and mean arterial pressure on cf‐PWV revealed by the multiple linear regression.

Conclusions
Racial differences in cf‐PWV were mainly attributed to differences in mean arterial pressure and age, although they cannot fully explain the association between race and cf‐PWV in women in the highest cf‐PWV values. This suggests that therapeutic approaches to overcome the effects of aging on the vascular system should focus on blood pressure control, especially in the black population.
Aircraft Observations of Cumulus Microphysics Ranging from the Tropics to Midlatitudes: Implications for a “New” Secondary Ice Process
Authors: Lawson Paul , Gurganus Colin , Woods Sarah , Bruintjes Roelof 
Published: June 2017

AbstractIn situ data collected by three research aircraft in four geographical locations are analyzed to determine the relationship between cloud-base temperature, drop size distribution, and the development of supercooled water drops and ice in strong updraft cores of convective clouds. Data were collected in towering cumulus and feeder cells in the Caribbean, over the Gulf of Mexico, over land near the Gulf Coast, over land in the southeastern United States, and the high plains in Colorado and Wyoming. Convective clouds in the Caribbean, over the Gulf of Mexico and its coast, and over the southeastern United States all develop millimeter-diameter supercooled drops in updraft cores. Clouds over the high plains do not generate supercooled large drops, and rarely are drops >70 μm observed in updraft cores. Commensurate with the production of supercooled large drops, ice is generated and rapidly glaciates updraft cores through a hypothesized secondary ice process that is based on laboratory observations of large drops freezing and emitting tiny ice particles. Clouds over the high plains do not experience the secondary ice process and significant concentrations of supercooled liquid in the form of small drops are carried much higher (up to −35.5°C) in the updraft cores. An empirical relationship that estimates the maximum level to which supercooled liquid water will be transported, based on cloud-base drop size distribution and temperature, is developed. Implications have applications for modeling the transport of water vapor and particles into the upper troposphere and hygroscopic seeding of cumulus clouds.