bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type I Interferon Protects Mice from Fatal Neurotropic Infection with Langat Virus by Systemic and Local Antiviral Responses
Authors: Weber Elvira , Finsterbusch Katja , Lindquist Richard , Nair Sharmila , Lienenklaus Stefan , Gekara Nelson O , Janik Dirk , Weiss Siegfried , Kalinke Ulrich , Överby Anna K. , Kröger Andrea 
Published: August 2014

ABSTRACT
Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of infections in humans. TBEV causes a broad range of pathological symptoms, ranging from meningitis to severe encephalitis or even hemorrhagic fever, with high mortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis.

IMPORTANCE
The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system, is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection. The first phase is in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). In the second phase, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis.
Epitope Mapping of the Hemagglutinin Molecule of A/(H1N1)pdm09 Influenza Virus by Using Monoclonal Antibody Escape Mutants
Authors: Matsuzaki Yoko , Sugawara Kanetsu , Nakauchi Mina , Takahashi Yoshimasa , Onodera Taishi , Tsunetsugu-Yokota Yasuko , Matsumura Takayuki , Ato Manabu , Kobayashi Kazuo , Shimotai Yoshitaka , Mizuta Katsumi , Hongo Seiji , Tashiro Masato , Nobusawa Eri 
Published: August 2014

ABSTRACT
We determined the antigenic structure of pandemic influenza A(H1N1)pdm09 virus hemagglutinin (HA) using 599 escape mutants that were selected using 16 anti-HA monoclonal antibodies (MAbs) against A/Narita/1/2009. The sequencing of mutant HA genes revealed 43 amino acid substitutions at 24 positions in three antigenic sites, Sa, Sb, and Ca2, which were previously mapped onto A/Puerto Rico/8/34 (A/PR/8/34) HA (A. J. Caton, G. G. Brownlee, J. W. Yewdell, and W. Gerhard, Cell 31:417–427, 1982), and an undesignated site, i.e., amino acid residues 141, 142, 143, 171, 172, 174, 177, and 180 in the Sa site, residues 170, 173, 202, 206, 210, 211, and 212 in the Sb site, residues 151, 154, 156, 157, 158, 159, 200, and 238 in the Ca2 site, and residue 147 in the undesignated site (numbering begins at the first methionine). Sixteen MAbs were classified into four groups based on their cross-reactivity with the panel of escape mutants in the hemagglutination inhibition test. Among them, six MAbs targeting the Sa and Sb sites recognized both residues at positions 172 and 173. MAb n2 lost reactivity when mutations were introduced at positions 147, 159 (site Ca2), 170 (site Sb), and 172 (site Sa). We designated the site consisting of these residues as site Pa. From 2009 to 2013, no antigenic drift was detected for the A(H1N1)pdm09 viruses. However, if a novel variant carrying a mutation at a position involved in the epitopes of several MAbs, such as 172, appeared, such a virus would have the advantage of becoming a drift strain.

IMPORTANCE
The first influenza pandemic of the 21st century occurred in 2009 with the emergence of a novel virus originating with swine influenza, A(H1N1)pdm09. Although HA of A(H1N1)pdm09 has a common origin (1918 H1N1) with seasonal H1N1, the antigenic divergence of HA between the seasonal H1N1 and A(H1N1)pdm09 viruses gave rise to the influenza pandemic in 2009. To take precautions against the antigenic drift of the A(H1N1)pdm09 virus in the near future, it is important to identify its precise antigenic structure. To obtain various mutants that are not neutralized by MAbs, it is important to neutralize several plaque-cloned parent viruses rather than only a single parent virus. We characterized 599 escape mutants that were obtained by neutralizing four parent viruses of A(H1N1)pdm09 in the presence of 16 MAbs. Consequently, we were able to determine the details of the antigenic structure of HA, including a novel epitope.
DESC1 and MSPL Activate Influenza A Viruses and Emerging Coronaviruses for Host Cell Entry
Authors: Zmora Pawel , Blazejewska Paulina , Moldenhauer Anna-Sophie , Welsch Kathrin , Nehlmeier Inga , Wu Qingyu , Schneider Heike , Pöhlmann Stefan , Bertram Stephanie 
Published: August 2014

ABSTRACT
The type II transmembrane serine protease (TTSP) TMPRSS2 cleaves and activates the influenza virus and coronavirus surface proteins. Expression of TMPRSS2 is essential for the spread and pathogenesis of H1N1 influenza viruses in mice. In contrast, H3N2 viruses are less dependent on TMPRSS2 for viral amplification, suggesting that these viruses might employ other TTSPs for their activation. Here, we analyzed TTSPs, reported to be expressed in the respiratory system, for the ability to activate influenza viruses and coronaviruses. We found that MSPL and, to a lesser degree, DESC1 are expressed in human lung tissue and cleave and activate the spike proteins of the Middle East respiratory syndrome and severe acute respiratory syndrome coronaviruses for cell-cell and virus-cell fusion. In addition, we show that these proteases support the spread of all influenza virus subtypes previously pandemic in humans. In sum, we identified two host cell proteases that could promote the amplification of influenza viruses and emerging coronaviruses in humans and might constitute targets for antiviral intervention.

IMPORTANCE
Activation of influenza viruses by host cell proteases is essential for viral infectivity and the enzymes responsible are potential targets for antiviral intervention. The present study demonstrates that two cellular serine proteases, DESC1 and MSPL, activate influenza viruses and emerging coronaviruses in cell culture and, because of their expression in human lung tissue, might promote viral spread in the infected host. Antiviral strategies aiming to prevent viral activation might thus need to encompass inhibitors targeting MSPL and DESC1.
Emergence of Broadly Neutralizing Antibodies and Viral Coevolution in Two Subjects during the Early Stages of Infection with Human Immunodeficiency Virus Type 1
Authors: Sather D. Noah , Carbonetti Sara , Malherbe Delphine C. , Pissani Franco , Stuart Andrew B. , Hessell Ann J. , Gray Mathew D. , Mikell Iliyana , Kalams Spyros A. , Haigwood Nancy L. , Stamatatos Leonidas 
Published: August 2014

ABSTRACT
Delineating the key early events that lead to the development of broadly neutralizing anti-HIV-1 antibodies during natural infection may help guide the development of immunogens and vaccine regimens to prevent HIV-1 infection. In this study, we monitored two HIV-1-positive subjects, VC20013 and VC10014, over the course of infection from before they developed broadly neutralizing antibody (bNAb) activity until several years after neutralizing breadth was detected in plasma. Both subjects developed bNAb activity after approximately 1 year postinfection, which ultimately mapped to the membrane-proximal external region (MPER) in VC20013 and an epitope that overlaps the CD4 receptor binding site in VC10014. In subject VC20013, we were able to identify anti-MPER activity in the earliest plasma sample that exhibited no bNAb activity, indicating that this epitope specificity was acquired very early on, but that it was initially not able to mediate neutralization. Escape mutations within the bNAb epitopes did not arise in the circulating envelopes until bNAb activity was detectable in plasma, indicating that this early response was not sufficient to drive viral escape. As bNAb activity began to emerge in both subjects, we observed a simultaneous increase in autologous antienvelope antibody binding affinity, indicating that antibody maturation was occurring as breadth was developing. Our findings illustrate one potential mechanism by which bNAbs develop during natural infection in which an epitope target is acquired very early on during the course of infection but require time and maturation to develop into broadly neutralizing activity.

IMPORTANCE
One major goal of HIV-1 vaccine research is the development of a vaccine that can elicit broadly neutralizing antibodies (bNAbs). Although no such vaccine exists, bNAbs develop in approximately 20% of HIV-1-infected subjects, providing a prototype of the bNAbs that must be reelicited by vaccine. Thus, there is significant interest in understanding the mechanisms by which bNAbs develop during the course of infection. We studied the timing, epitope specificity, and evolution of the bNAb responses in two HIV-1-positive patients who developed bNAb activity within the first several years after infection. In one subject, antibodies to a broadly neutralizing epitope developed very early but were nonneutralizing. After several months, neutralizing activity developed, and the virus mutated to escape their activity. Our study highlights one mechanism for the development of bNAbs where early epitope acquisition followed by sufficient time for antibody maturation drives the epitope-specific antibody response toward broadly neutralizing activity.
Elevated 1 h postload plasma glucose levels identify adults with normal glucose tolerance but increased risk of non-alcoholic fatty liver disease
Authors: Sesti Giorgio , Hribal Marta Letizia , Fiorentino Teresa Vanessa , Sciacqua Angela , Perticone Francesco 
Published: August 2014

ObjectiveTo determine the ability of the proposed diagnostic value of a 1-h OGTT glucose ≥155mg/dL to identify individuals with non-alcoholic fatty liver disease (NAFLD) diagnosed by ultrasonography in a cohort of adult white individuals.DesignThe study group comprised 710 white individuals participating to the CATAnzaro MEtabolic RIsk factors (CATAMERI) Study, a cross-sectional study assessing cardio-metabolic risk factors in individuals carrying at least one risk factor including dysglycemia, overweight/obesity, hypertension, dyslipidemia. a 75 g oral Oral Glucose Tolerance Test (OGTT) was performed with 0, 30, 60, 90 and 120 min sampling for plasma glucose and insulin measurements. Cardio-metabolic risk factors including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were assessed in the whole cohort.ResultsOf the 710 participants examined, 295 had normal glucose tolerance (NGT) with 1-hour post-load plasma glucose <155 mg/dL (NGT 1h-low), 109 individuals had NGT 1h-high, 104 had isolated impaired fasting glucose (IFG), and 202 had impaired glucose tolerance (IGT). As compared with NGT 1h-low, NGT 1h-high and IGT subjects exhibited significantly higher body mass index (BMI), triglycerides, high sensitivity C reactive protein, ALT, GGT, and hepatic insulin resistance (IR), assessed by the liver IR index, as well as lower high density lipoprotein, and insulin-like growth factor-1 (IGF-1) levels. In a logistic regression analysis adjusted for age, gender, and BMI, NGT 1h-high participants had a 1.5-fold increased risk of having NAFLD and an even increased risk was observed in subjects with IGT (1.8-fold), but not in the isolated IFG group (1.01-fold).ConclusionsThese data suggest that the value of a 1-hour OGTT glucose ≥155 mg/dL may be helpful to identify a subset of NGT individuals at risk for NAFLD.
Current and future use of point-of-care tests in primary care: an international survey in Australia, Belgium, The Netherlands, the UK and the USA
Authors: Howick Jeremy , Cals Jochen W L , Jones Caroline , Price Christopher P , Plüddemann Annette , Heneghan Carl , Berger Marjolein Y , Buntinx Frank , Hickner John , Pace Wilson , Badrick Tony , Van den Bruel Ann , Laurence Caroline , van Weert Henk C , van Severen Evie , Parrella Adriana , Thompson Matthew 
Published: August 2014

ObjectiveDespite the growing number of point-of-care (POC) tests available, little research has assessed primary care clinician need for such tests. We therefore aimed to determine which POC tests they actually use or would like to use (if not currently available in their practice).DesignCross-sectional survey.SettingPrimary care in Australia, Belgium (Flanders region only), the Netherlands, the UK and the USA.ParticipantsPrimary care doctors (general practitioners, family physicians).Main measuresWe asked respondents to (1) identify conditions for which a POC test could help inform diagnosis, (2) from a list of tests provided: evaluate which POC tests they currently use (and how frequently) and (3) determine which tests (from that same list) they would like to use in the future (and how frequently).Results2770 primary care clinicians across five countries responded. Respondents in all countries wanted POC tests to help them diagnose acute conditions (infections, acute cardiac disease, pulmonary embolism/deep vein thrombosis), and some chronic conditions (diabetes, anaemia). Based on the list of POC tests provided, the most common tests currently used were: urine pregnancy, urine leucocytes or nitrite and blood glucose. The most commonly reported tests respondents expressed a wish to use in the future were: D-dimer, troponin and chlamydia. The UK and the USA reported a higher actual and desired use for POC tests than Australia, Belgium and the Netherlands. Our limited data suggest (but do not confirm) representativeness.ConclusionsPrimary care clinicians in all five countries expressed a desire for POC tests to help them diagnose a range of acute and chronic conditions. Rates of current reported use and desired future use were generally high for a small selection of POC tests, but varied across countries. Future research is warranted to explore how specific POC tests might improve primary care.
THE AHEAD STUDY: MANAGING ANTICOAGULATED PATIENTS WHO SUFFER HEAD INJURY
Authors: Mason Suzanne , Kuczawski Maxine , Teare Marion D , Stevenson Matthew , Holmes Michael , Ramlakhan Shammi , Goodacre Steve , Morris Francis , Harper Rosemary 
Published: August 2014

Objectives & BackgroundExisting practice in emergency departments (ED) in the UK for managing anticoagulated patients after blunt head trauma is variable and based on limited evidence. We aimed to determine the head injury complication rate within this group of patients and identify risk factors associated with a poor outcome.MethodsA prospective observational multi-centre study enrolled patients taking warfarin who attended 33 emergency departments in England and Scotland after blunt head trauma. ED attendance data and patient reported outcomes were collected over an 18-month period from October 2011. Head injury complication was defined by head injury-related death, neurosurgery resulting from injury, clinically-significant CT head scan or re-attendance with significant head injury complications. Factors including neurological status (Glasgow Coma Score, GCS), level of anticoagulation (INR) and neurological symptoms were entered into multivariate logistic regression analyses as predictors of a poor outcome.ResultsA total of 3566 patients were enrolled; anonymised clinical data was submitted for 99.1% of patients. The age range was 18 to 101 years (median 81 yrs, IQR 12), 48.7% were men. Mean initial INR was 2.67 (SD 1.34, IQR 1.1), 80.5% patients had a GCS of 15 and 68.1% did not report any associated neurological symptoms. 59.3% of patients had a CT head scan with a significant head injury-related finding identified in 5.6%. Reversal therapy was given to 5.3% of patients, only 19 (0.5%) patients underwent neurosurgery and 42 (1.2%) patients died of a head injury-related death. The overall rate of head injury complication was found to be 6.1%. Multivariate logistic regression modelling found GCS <13 (OR 12.7; 95% CI 2.41 to 67.2), vomiting (OR 3.09; 95% CI 1.71 to 5.61) and loss of consciousness (OR 2.53; 95% CI 1.54 to 4.15) to be significantly associated with a poor outcome. In univariate analyses an INR >4 was associated with an increased risk of an adverse outcome, however it made no significant contribution to the multivariable models.ConclusionThis is the largest cohort of anticoagulated head injury patients ever reported. The head injury complication rate was 6.1% which correlates well with previous findings. INR was not found to be associated with a poor outcome however GCS <13, vomiting and loss of consciousness were identified as significant risk factors for an adverse outcome in anticoagulated patients with a head injury.
ORAL PREDNISOLONE IN THE TREATMENT OF ACUTE GOUT: A PRAGMATIC, MULTI-CENTRE, DOUBLE-BLIND, RANDOMIZED, EQUIVALENCE TRIAL
Authors: Rainer Timothy H , Cheng Chi H , Graham Colin A , Janssens Hein J , Man Chi Y , Tam Lai S , Choi Yu F , Yau Wah H , Lee Ka H 
Published: August 2014

Objectives & BackgroundTo compare oral prednisolone with oral indomethacin in patients presenting to emergency departments (ED) with acute gout firstly for analgesic effectiveness, and secondly for safety.MethodsPragmatic, multi-centre, double-blind, randomized, equivalence trial. Each patient received either oral indomethacin plus placebo or prednisolone plus placebo for 5 days. Data were analysed in the first two hours in the ED, and from days 1 to 14.Results416 patients were recruited (208 patients in each arm), and 376 patients completed the study. Clinically significant reductions in mean pain score were observed within two hours of treatment with both indomethacin and prednisolone both at rest and with activity, and also over the subsequent 14 days. The margin of equivalence seta prioriat 13% between the two arms was not breached. There were no major adverse events during the ED or later phases of the study. In the first two hours, there were minor adverse events affecting 34 (18%) patients in the indomethacin group and 10 (5.3%) patients in the prednisolone group (P<0.001). From day 1 to day 14, 75 (39%) patients in the indomethacin group and 75 (40%) patients in the prednisolone group suffered from mild side effects (P=0.50).ConclusionPrednisolone and Indomethacin are equally effective first line treatments for acute gout in ED patients. There were no serious adverse event rates during a follow-up period of 14 days.
THE DIAGNOSTIC UTILITY OF D-DIMER, AND OTHER CLINICAL VARIABLES IN PREGNANT AND POSTPARTUM PATIENTS WITH SUSPECTED ACUTE PULMONARY EMBOLISM
Authors: Choi Hyun , Krishnamoorthy Dinesh 
Published: August 2014

Objectives & BackgroundPulmonary Embolism (PE) in pregnancy remains one of the leading causes of maternal morbidity and mortality in the developed world. However, there is a paucity of high quality evidence resulting in a lack of consensus in managing this group of patients. The aim of the study was to address the diagnostic utility of D dimer for suspected PE in pregnant and postpartum patients, and to identify any clinical presentation variables that are predictors of PE in this group of patients.MethodsA retrospective case note review of 152 pregnant and postpartum patients who underwent diagnostic imaging (Ventilation/Perfusion (V/Q) or computed tomographic pulmonary angiography (CTPA)) for suspected PE at a tertiary teaching hospital from 2007 to 2011 was conducted. The reference range for D-dimer was less than 0.5 mg/L as being normal. The following variables were also assessed in terms of their predictive capability for PE diagnosis in pregnancy; Heart Rate (HR), Mean Arterial Pressure (MAP), Shock Index (SI), and A-a gradient.ResultsThe application of D-dimer testing for suspected PE in this study population had a sensitivity of 100% (95% CI, 73%– 100%), specificity of 42% (95% CI, 31%–53%), and a likelihood negative ratio of 0. None of the clinical variables were significant predictors of PE according to regression analyses: d-dimer odds ratio (OR) 1.52 95% CI [0.95, 2.42], HR OR 1.02 95% CI [0.56, 1.85], MAP OR 1.54 95% CI [0.89, 2.66], SI OR 0.70 95% CI [0.33, 1.51] and A-a gradient OR 2.08 95% CI [0.93, 4.62].ConclusionAccording to our study, there is supportive evidence that a negative D-dimer result is useful as a means of ruling out PE in pregnant and post-partum patients. However, we need a larger prospective observational study to collaborate the findings.
EMERGENCIES BY APPOINTMENT: WOULD PATIENTS WITH MINOR INJURIES PREFER A BOOKED APPOINTMENT AT THEIR LOCAL EMERGENCY DEPARTMENT TO THE CURRENT WALK-IN SERVICE PROVISION
Authors: Roberts Lynn , Dykes Linda 
Published: August 2014

Objectives & BackgroundEmergency Departments (ED) typically offer walk-in services for minor injuries, and patients arriving at peak times may experience delays. Other NHS services (e.g. GP, dentists and GUM) utilise booked appointments even for urgent problems.We wished to ascertain whether patients attending our ED (a DGH with a very large rural catchment area) with minor injuries would find an appointment system accessed via phone/internet acceptable, and also their views on perhaps being asked to return for an appointment later the same (or following) day, should they arrive when waiting times are unacceptably long.MethodsA cross-sectional sample of 512 ED attendees with minor injuries/conditions were identified by the triage nurse. A questionnaire with a semi-structured design was used to determine the experiences, opinions and preferences of patients with minor injuries/conditions in relation to the proposed development of an appointment system. Ethical approval was obtained. Statistical analysis used mainly non-parametric tests plus descriptive statistics, with cluster analysis used to predict associations with patients' willingness to accept booked appointment.ResultsOverall, most participants (79%) indicated they were strongly supportive of the concept of booked appointments as an alternative to the current “walk-in” system, particularly those who would book by internet/phone (p=0.000).Younger patients, those in employment, and those with lower levels of anxiety and perceived urgency were also significantly more likely to find booked appointments acceptable.Being asked to return for a later appointment having already arrived at the ED was deemed less popular, although patients living closer to the hospital were more likely to find being asked to return for an appointment acceptable (p=0.012).ConclusionThis study confirms acceptance of the concept of ED offering appointments to minor injury patients. Participants would prefer pre-booked appointments over being asked to return later or next day, but they would accept either in preference to enduring excessive delays.