bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Guideline‐recommended Pain Medication Use Among Patients with Newly Diagnosed Fibromyalgia
Authors: Halpern Rachel , Shah Sonali N. , Cappelleri Joseph C. , Masters Elizabeth T. , Clair Andrew
Published: October 2015

Objectives

To compare pain medication treatment changes across cohorts of newly diagnosed patients with fibromyalgia (FM) treated with guideline‐recommended medications or opioids.

Methods and Design

Retrospective claims data analysis examined adult commercial health plan members newly diagnosed withFM(initial diagnosis = index date) from January 2008 to February 2012. Patients had 6‐month pre‐index and 12‐month postindex periods and received pain medication within 6 months postindex; cohorts were based on the first postindex medication. Guideline‐recommended medication cohorts were anti‐epileptic drug (AED), serotonin–norepinephrine reuptake inhibitor (SNRI), selective serotonin reuptake inhibitor (SSRI), and tricyclic antidepressant (TCA). Short‐acting and long‐acting opioid (SAO,LAO) cohorts were also identified. Pairwise comparisons with theSAOcohort were conducted. Cox proportional hazards regressions modeled the likelihood of receiving guideline‐recommended therapy.

Results

The final sample was 96,175 patients (mean age 47.3 years; 72.5% female), distributed intoSAO(57%),SSRI(22%),AED(10%),SNRI(6%),TCA(3%), andLAO(2%) cohorts. TheSAOcohort had the most discontinuation (49% vs. 6% to 22%,P< 0.01) and the least augmentation (29% vs. 35% to 50%,P< 0.01). Regression analyses indicated that patients with (vs. without) pre‐index guideline‐recommended medications were 2 to 4 times more likely to receive them postindex. Patients in the opioid cohorts were about half as likely to receive subsequent guideline‐recommended medications.

Conclusions

Opioid use was widespread among patients withFM. Once patients received opioids postdiagnosis, the likelihood of receiving guideline‐recommended medications was small. These real‐world results indicate an opportunity may exist for improvedFMmanagement using recommended therapies in clinical practice.
Development of a novel recessive genetic male sterility system for hybrid seed production in maize and other cross‐pollinating crops
Authors: Wu Yongzhong , Fox Tim W. , Trimnell Mary R. , Wang Lijuan , Xu Rui‐ji , Cigan A. Mark , Huffman Gary A. , Garnaat Carl W. , Hershey Howard , Albertsen Marc C.
Published: October 2015

We have developed a novel hybridization platform that utilizes nuclear male sterility to produce hybrids in maize and other cross‐pollinating crops. A key component of this platform is a process termed Seed Production Technology (SPT). This process incorporates a transgenic SPT maintainer line capable of propagating nontransgenic nuclear male‐sterile lines for use as female parents in hybrid production. The maize SPT maintainer line is a homozygous recessive male sterile transformed with a SPT construct containing (i) a complementary wild‐type male fertility gene to restore fertility, (ii) an α‐amylase gene to disrupt pollination and (iii) a seed colour marker gene. The sporophytic wild‐type allele complements the recessive mutation, enabling the development of pollen grains, all of which carry the recessive allele but with only half carrying the SPT transgenes. Pollen grains with the SPT transgenes exhibit starch depletion resulting from expression of α‐amylase and are unable to germinate. Pollen grains that do not carry the SPT transgenes are nontransgenic and are able to fertilize homozygous mutant plants, resulting in nontransgenic male‐sterile progeny for use as female parents. Because transgenic SPT maintainer seeds express a red fluorescent protein, they can be detected and efficiently separated from seeds that do not contain the SPT transgenes by mechanical colour sorting. The SPT process has the potential to replace current approaches to pollen control in commercial maize hybrid seed production. It also has important applications for other cross‐pollinating crops where it can unlock the potential for greater hybrid productivity through expanding the parental germplasm pool.
Permanent Deviation: Understanding Our Place in History with the Aid of Sartre's Critique, Volume Two
Authors: McBride William L.
Published: October 2015

The unfinished, posthumously published second volume of Jean‐Paul Sartre's Critique of Dialectical Reason consists for the most part of a study of the evolution of the Soviet Union under the reign of Stalin. Essentially, Sartre sees this history as amounting to a lengthy deviation from the goal of socialism, a deviation (‘detour’) that he regards as thoroughly intelligible in light of social and historical circumstances. Some ten years after abandoning his work on this book, on the occasion of the Soviet invasion of Czechoslovakia (1968), Sartre concluded that this ‘deviation’ was permanent. At the same time, Sartre believed, as he had stated already in Volume I of the Critique, that the post‐Stalinist era must be characterized as ‘One World’, a historical turning away from the plurality that had prevailed in all of past human history. The present essay attempts to capture Sartre's approach to history as ongoing ‘totalization’ – conflict‐filled, subject to contingency and chance and the frequent occurrence of ‘holes’, and nevertheless intelligible. Although Stalin died many decades ago (in 1953), and the Soviet Union itself no longer exists as such, it is argued here that Sartre's approach in this book is very useful as a key to the present time. Future history is indeed unpredictable, but Sartre's techniques of historical analysis remain valid. It is also contended, more controversially, that today the ideal of democracy may be in the process of following the path of socialism in the direction of permanent deviation.
Affectivity in Heidegger II: Temporality, Boredom, and Beyond
Authors: Freeman Lauren , Elpidorou Andreas
Published: October 2015

In ‘Affectivity in Heidegger I: Moods and Emotions in Being and Time’, we explicated the crucial role that Martin Heidegger assigns to our capacity to affectively find ourselves in the world. There, our discussion was restricted to Division I of Being and Time (BT). Specifically, we discussed how Befindlichkeit as a basic existential (i.e., a structure of Dasein's being that constitutes both the manner in which Dasein exists and discloses itself) and moods as the ontic counterparts of Befindlichkeit (i.e., the pre‐reflective ways in which Dasein relates to and discloses the world) make circumspective engagement with the world possible. Indeed, according to Heidegger, it is primarily through moods that the world is ‘opened up’ and revealed to us as a world that is suffused with values and entities that already matter to us. In this companion essay, our aim is to expand our analysis of affectivity in the following ways: first, we revisit our discussion of Befindlichkeit in light of Heidegger's discussion of temporality in Division II of BT; second, we discuss the basic or fundamental mood (Grundstimmung) of boredom (Langeweile) and its ontological significance; we conclude by providing a brief characterization of how Heidegger's notion of mood changes in his later thinking.
Differences in Media Preference Mediate the Link Between Personality and Political Orientation
Authors: Xu Xiaowen , Peterson Jordan B.
Published: October 2015

Research has consistently demonstrated that political liberalism is predicted by the personality trait Openness to Experience and conservatism by trait Conscientiousness. Less well studied, however, is how trait personality influences political orientation. The present study investigated whether differences in media preference might mediate the links between personality and political orientation. Participants completed measures of Big Five personality, media preferences, and political orientation. Results revealed that increased preferences for Dark/Alternative and Aesthetic/Musical media genres, as well as decreased preferences for Communal/Popular media genres, mediated the association between Openness to Experience and liberalism. In contrast, greater preferences for Communal/Popular and Thrilling/Action genres, as well as lower preferences for Dark/Alternative and Aesthetic/Musical genres mediated the link between Conscientiousness and conservatism.
Risk Factors for Stillbirth: Findings from a Population‐Based Case–Control Study, Haryana, India
Authors: Neogi Sutapa Bandyopadhyay , Negandhi Preeti , Chopra Sapna , Das Ankan Mukherjee , Zodpey Sanjay , Gupta Ravi Kant , Gupta Rakesh
Published: October 2015

Background

Stillbirth is a prevalent adverse outcome of pregnancy in India despite efforts to improve care of women during pregnancy. Risk factors for stillbirths include sociodemographic factors, medical complications during pregnancy, intake of harmful drugs, and complications during delivery. The objective of the study was to examine the risk factors for stillbirth with a focus on sex selection drugs (SSDs).

Methods

A population‐based case–control study was undertaken in Haryana. Cases of stillbirths were identified from the Maternal Infant Death Review System portal of Haryana state for the months of August–September 2014. A consecutive birth from the same geographical area as the case was selected as the control. The sample size was 325 per group. Mothers were interviewed using a validated tool. Bivariate analyses and logistic regression were conducted to examine the association between risk factors and stillbirth. Attributable risk proportions (ARP) and population attributable risk proportions (PARP) were estimated.

Results

The sociodemographic profiles of the cases and controls were similar. History of intake of SSDs [adjusted odds ratio (OR) 2.6, 95% confidence interval (CI) 1.5, 4.5] emerged as a risk factor. Other significant factors were preterm <37 weeks (OR 3.5, 95% CI 2.1, 6.0), history of previous stillbirths (OR 4.0, 95% CI 2.1, 7.8), and complications during labour (OR 3.3, 95% CI 2.1, 5.3). Estimates of the ARP and PARP for intake of SSDs were 0.60 (95% CI 0.32, 0.77) and 0.1 (95% CI −0.13, 0.28), respectively.

Conclusions

SSDs could be attributed as a risk factor in a fifth of the cases of stillbirths. The number needed to harm for the use of SSDs in causing adverse effect of stillbirths was 5, suggesting thereby that for every five mothers exposed to SSDs, one would have stillbirth. Greater efforts are required to inform people about the harmful effects of SSD consumption during pregnancy.
Laser‐cut Rb–Sr microsampling dating of deformational events in the Mont Blanc‐Aiguilles Rouges region (European Alps)
Authors: Egli Daniel , Müller Wolfgang , Mancktelow Neil
Published: October 2015

Spatial control for in situ dating of mineral phases in fine‐grained rocks is a significant challenge in geochronology, and the precision of microsampling is a crucial factor in obtaining accurate results. In this study, a new microsampling approach to Rb–Sr geochronology has been applied to greenschist facies mylonitic shear zones in the Mont Blanc‐Aiguille Rouges region of the western European Alps. Using a laser‐ablation system for microsampling by laser cutting followed by conventional TIMS Rb–Sr isotopic analysis of μg‐sized samples provides an improved workflow for texturally controlled, quasi in situ dating of mineral phases. The automated cutting process minimizes material loss and the risk of handling errors, while facilitating sampling of complex shapes of almost any size, a significant improvement over earlier microscope‐mounted microdrills. The new Rb–Sr white mica–calcite ages of between 27 and 30 Ma indicate Oligocene deformation in Alpine shear zones from two specific areas in the Mont Blanc‐Aiguilles Rouges region.
Ten‐year retrospective review of transfusion practices in beating‐heart organ donors
Authors: Coberly Emily A. , Booth Garrett S.
Published: October 2015

BACKGROUND

Recent studies suggest that restrictive transfusion strategies are equivocal or noninferior to liberal strategies in various patient populations; however, evidence for the optimal transfusion threshold or current transfusion practice in beating‐heart organ donors is lacking. A 10‐year retrospective analysis of blood product utilization in beating‐heart organ donors was performed to determine current transfusion practice.

STUDY DESIGN AND METHODS

An institutional review board–approved retrospective review of 439 beating‐heart organ donors from January 1, 2004, to October 1, 2014, was performed. For each donor, hemoglobin (Hb), platelet (PLT), prothrombin time/international normalized ratio (PT/INR), and fibrinogen levels as well as all transfusion reaction reports were recorded from the time of declaration of brain death to organ procurement.

RESULTS

Red blood cell transfusion occurred in 304 donors (69.2%), with a trough Hb level of more than 8 g/dL in 63.2% and more than 10 g/dL in 15.8%; final Hb was more than 10 g/dL in 44.1% of transfused donors. PLT transfusion occurred in 165 donors (37.6%), with a trough PLT count of more than 50 × 109/L in 113 (68.5%) and more than 100 × 109/L in 15 (9.1%). Plasma transfusion occurred in 217 donors (49.4%), with a peak INR of less than 1.5 in 75 donors (34.6%) and a peak INR of 1.6 to 2.0 in 112 donors (51.6%). Only 17.4% of donors who received cryoprecipitate had fibrinogen levels measured, and results were all more than 200 mg/dL. Transfusion reactions were underreported (p = 0.0001).

CONCLUSIONS

This study suggests potential suboptimal use of limited biologic resources in beating‐heart organ donors, as well as significant underreporting of suspected transfusion reactions. Additional studies are indicated to determine optimal transfusion thresholds in this population.
Genetic diversity of the weed species,Stellera chamaejasme, inChina inferred from amplified fragment length polymorphism analysis
Authors: Zhang Yong‐Hong , Zhang Jian‐Wen , Li Zhi‐Min , Sun Hang
Published: October 2015

Stellera chamaejasmeis a perennial weed with a wide geographic range that is found from theAltai of easternRussia, northernChina andMongolia southwards as far as the westernHimalayas of theQinghai–Tibet andYunguiPlateaus. The genetic diversity and population structure of 17 populations ofS. chamaejasme, represented by 349 individuals, were assessed by using amplified fragment length polymorphism markers. The results showed a relatively high level of genetic variation at the species level. The proportion of total diversity among populations was 0.4370, suggesting significant genetic differentiation and a low gene flow among the populations of this species. TheMantel test indicated that genetic differentiation among populations was significantly correlated with geographic distance. Genetic drift through range expansion and a low gene flow among populations might result in a lower diversity in peripheral populations, compared to central populations. ABayesian analysis revealed two potential gene pools inS. chamaejasme, which was confirmed by neighbor‐joining clustering and principal coordinate analysis. These results demonstrate that it is necessary to develop suitable biocontrol agents for populations with different gene pools.
Kv3.3 potassium channels and spinocerebellar ataxia
Authors: Zhang Yalan , Kaczmarek Leonard K.
Published: October 2015

The voltage‐dependent potassium channel subunit Kv3.3 is expressed at high levels in cerebellar Purkinje cells, in auditory brainstem nuclei and in many other neurons capable of firing at high rates. In the cerebellum, it helps to shape the very characteristic complex spike of Purkinje cells. Kv3.3 differs from other closely related channels in that human mutations in the gene encoding Kv3.3 (KCNC3) result in a unique neurodegenerative disease termed spinocerebellar ataxia type 13 (SCA13). This primarily affects the cerebellum, but also results in extracerebellar symptoms. Different mutations produce either early onset SCA13, associated with delayed motor and impaired cognitive skill acquisition, or late onset SCA13, which typically produces cerebellar degeneration in middle age. This review covers the localization and physiological function of Kv3.3 in the central nervous system and how the normal function of the channel is altered by the disease‐causing mutations. It also describes experimental approaches that are being used to understand how Kv3.3 mutations are linked to neuronal survival, and to develop strategies for treatment.

image
Ca2+ signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca2+ channel blockade
Authors: Gryshchenko Oleksiy , Gerasimenko Julia V. , Gerasimenko Oleg V. , Petersen Ole H.
Published: October 2015

Key points

Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions.

In this study, we have investigated bradykinin‐elicited Ca2+ signal generation in normal mouse pancreatic lobules.

We found complete separation of Ca2+ signalling between pancreatic acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked Ca2+ signals, via B2 receptors, in PSCs but never in neighbouring PACs, whereas cholecystokinin, consistently evoking Ca2+ signals in PACs, never elicited Ca2+ signals in PSCs.

The bradykinin‐elicited Ca2+ signals were due to initial Ca2+ release from inositol trisphosphate‐sensitive stores followed by Ca2+ entry through Ca2+ release‐activated channels (CRACs). The Ca2+ entry phase was effectively inhibited by a CRAC blocker.

B2 receptor blockade reduced the extent of PAC necrosis evoked by pancreatitis‐promoting agents and we therefore conclude that bradykinin plays a role in acute pancreatitis via specific actions on PSCs.

Normal pancreatic stellate cells (PSCs) are regarded as quiescent, only to become activated in chronic pancreatitis and pancreatic cancer. However, we now report that these cells in their normal microenvironment are far from quiescent, but are capable of generating substantial Ca2+ signals. We have compared Ca2+ signalling in PSCs and their better studied neighbouring acinar cells (PACs) and found complete separation of Ca2+ signalling in even closely neighbouring PACs and PSCs. Bradykinin (BK), at concentrations corresponding to the slightly elevated plasma BK levels that have been shown to occur in the auto‐digestive disease acute pancreatitis in vivo, consistently elicited substantial Ca2+ signals in PSCs, but never in neighbouring PACs, whereas the physiological PAC stimulant cholecystokinin failed to evoke Ca2+ signals in PSCs. The BK‐induced Ca2+ signals were mediated by B2 receptors and B2 receptor blockade protected against PAC necrosis evoked by agents causing acute pancreatitis. The initial Ca2+ rise in PSCs was due to inositol trisphosphate receptor‐mediated release from internal stores, whereas the sustained phase depended on external Ca2+ entry through Ca2+ release‐activated Ca2+ (CRAC) channels. CRAC channel inhibitors, which have been shown to protect PACs against damage caused by agents inducing pancreatitis, therefore also inhibit Ca2+ signal generation in PSCs and this may be helpful in treating acute pancreatitis.
Determination of Scattering and Absorption Coefficients of Porous Silica Aerogel Composites
Authors: Fu Tairan , Tang Jiaqi , Chen Kai , Zhang Fan
Published: October 2015

Silica aerogels are porous ultralight materials with exceptional physical properties that are promising materials for thermal insulation applications. This paper theoretically and experimentally investigates the spectral scattering and absorption coefficients of a porous silica aerogel. Silica aerogel samples were prepared with the same compositions and various thicknesses using the sol-gel technique and supercritical drying. The spectral normal-hemispherical transmittances and reflectances of the silica aerogel samples with various thicknesses were measured for wavelengths of 0.38–15 μm. The reflectance and transmittance are higher at short wavelengths than in the infrared region due to the strong scattering and weak absorption at short wavelengths. The thicker samples strongly attenuate the spectral normal-hemispherical transmittance, but have little effect on the spectral normal-hemispherical reflectance. A modified two-flux radiative transfer model was used to analyze the radiation propagation in the silica aerogel with a rough surface morphology and millimeter thicknesses to develop theoretical expressions for the spectral directional-hemispherical reflectance and transmittance. Then, the optical constants, including the absorption coefficient and the scattering coefficient, were determined for wavelengths of 0.38–15 μm based on experimental data by the least-squares algorithm. The results show that when considering the radiation propagation inside the sample, the surface reflection at the air–aerogel interface can be neglected for aerogel thicker than 1.1 mm when the absorbing and scattering effects inside the sample are quite important. The analysis provides valuable data for the optical properties for silica aerogel applications.
Experimental and Numerical Investigation of Fuel–Air Mixing in a Radial Swirler Slot of a Dry Low Emission Gas Turbine Combustor
Authors: Agbonzikilo Festus Eghe , Owen Ieuan , Stewart Jill , Sadasivuni Suresh Kumar , Riley Mike , Sanderson Victoria
Published: October 2015

This paper presents the results of an investigation in which the fuel/air mixing process in a single slot within the radial swirler of a dry low emission (DLE) combustion system is explored using air/air mixing. Experimental studies have been carried out on an atmospheric test facility in which the test domain is a large-scale representation of a swirler slot from a Siemens proprietary DLE combustion system. Hot air with a temperature of 300 °C is supplied to the slot, while the injected fuel gas is simulated using air jets with temperatures of about 25 °C. Temperature has been used as a scalar to measure the mixing of the jets with the cross-flow. The mixture temperatures were measured using thermocouples while Pitot probes were used to obtain local velocity measurements. The experimental data have been used to validate a computational fluid dynamics (CFD) mixing model. Numerical simulations were carried out using CFD software ansys-cfx. Due to the complex three-dimensional flow structure inside the swirler slot, different Reynolds-averaged Navier–Stokes (RANS) turbulence models were tested. The shear stress transport (SST) turbulence model was observed to give best agreement with the experimental data. The momentum flux ratio between the main air flow and the injected fuel jet, and the aerodynamics inside the slot were both identified by this study as major factors in determining the mixing characteristics. It has been shown that mixing in the swirler can be significantly improved by exploiting the aerodynamic characteristics of the flow inside the slot. The validated CFD model provides a tool which will be used in future studies to explore fuel/air mixing at engine conditions.
A Flight Dynamics Model for a Small-Scale Flybarless Helicopter
Authors: Taamallah Skander
Published: October 2015

We present a helicopter flight dynamics nonlinear model for a flybarless, articulated, pitch–lag–flap (P–L–F) main rotor (MR) with rigid blades, particularly suited for small-scale unmanned aerial vehicles (UAVs). The model incorporates the MR, tail rotor (TR), fuselage, and tails. This model is further applicable for high bandwidth control specifications and is valid for a range of flight conditions, including the vortex-ring-state (VRS) and autorotation. Additionally, the paper reviews all assumptions made in deriving the model, i.e., structural, aerodynamics, and dynamical simplifications. Simulation results show that this nonlinear model is in good agreement with an equivalent flightlab model, for both static (trim) and dynamic conditions.
The Transition of Medical Students Through Residency: Effects on Physical Activity and Other Lifestyle-Related Behaviors
Authors: Pardo Alba , Mitjans Anna , Baranda Lucía , Salamero Manel , McKenna James , Arteman Antoni , Violán Mariona
Published: October 2015

Background:

Little is known about lifestyle choices and preventive healthcare-seeking behaviors during the transition from medical school graduation to residency training, a period characterized by increased rates of stress and lack of free time due to demanding working conditions. All of these issues are likely to affect physical activity (PA) level. This study explored the evolution of PA and other lifestyle behaviors during this transition.

Methods:

A cross-sectional study and a cohort study were conducted with medical students (2010) and physicians before and after the first year of residency (2013 and 2014). A self-administered questionnaire assessed PA, health and lifestyle behaviors.

Results:

From a sample of 420 medical students and 478 residents, 74% comply with current PA guidelines. PA decreased by 16% during residency. Low levels of PA were found among (i) females and in respondents who reported (ii) poor self-perceived health and (iii) unhealthy body weight (P < .05). Low PA level was also significantly associated with poor mental health in first-year residents.

Conclusions:

The transition has a negative effect on physicians’ PA level that may affect physicians’ own health and patient care. Medical programs should encourage residents to engage in PA to assure physicians’ personal and mental health.
Objectively Measured School Day Physical Activity Among Elementary Students in the United States and Finland
Authors: Yli-Piipari Sami , Kulmala Janne Santeri , Jaakkola Timo , Hakonen Harto , Fish Joseph Cole , Tammelin Tuija
Published: October 2015

Background:

Schools are in a unique position to ensure that all students meet the current physical activity (PA) recommendations. This study aimed to examine 1st to 3rd grade elementary students’ accelerometer measured school day PA in the United States (U.S.) and Finland.

Methods:

The sample consisted of 200 students (107 girls, 93 boys; ages 6 to 8) and their school day PA was monitored with hip-worn ActiGraph GT3X+ accelerometers across a 5-day school week and the thresholds 100 and 2296 count per minute were used to separate sedentary time, light PA, and moderate-to-vigorous PA (MVPA).

Results:

On an average school day, students were engaged in MVPA for 20.0 min in the U.S. and 24.1 min in Finland. Students’ school-day MVPA was 9 to 16 minutes higher during physical education (PE) days compared with non-PE days (U.S: 25.8 vs. 16.6 min/day; Finland: 36.3 vs. 20.1 min/day). Girls had less MVPA and more sedentary time compared with boys in both samples.

Conclusion:

This study highlights both the role of PE and other school day physical activities in meeting PA guidelines. Policy measures are needed to change the structure of the school day and enhance PA to ensure that students meet the PA recommendations.
Neuronal PAC
1
receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine
Authors: Akerman Simon , Goadsby Peter J.
Published: October 2015

PACAP-38 action within the brain causes delayed activation and sensitization of central trigeminovascular neurons, a likely mechanism for migraine and target for therapeutics.
ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease
Authors: Zhang Jilu , Ramadan Abdulraouf M. , Griesenauer Brad , Li Wei , Turner Matthew J. , Liu Chen , Kapur Reuben , Hanenberg Helmut , Blazar Bruce R. , Tawara Isao , Paczesny Sophie
Published: October 2015

Blocking sST2 before transplant with a neutralizing monoclonal antibody reduced GVHD severity and mortality.
The difficult—and often delayed—diagnosis of CTCL
Authors: Weed Jason , Girardi Michael
Published: October 2015

High-throughput sequencing of T cell receptors to define and quantify T cell populations emerges as a diagnostic tool with the remarkable ability to discriminate between CTCL and benign inflammatory conditions (Kirsch
et al
., this issue).
Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota
Authors: Nunn Kenetta L. , Wang Ying-Ying , Harit Dimple , Humphrys Michael S. , Ma Bing , Cone Richard , Ravel Jacques , Lai Samuel K.
Published: October 2015

Cervicovaginal mucus (CVM) can provide a barrier that precludes HIV and other sexually transmitted virions from reaching target cells in the vaginal epithelium, thereby preventing or reducing infections. However, the barrier properties of CVM differ from woman to woman, and the causes of these variations are not yet well understood. Using high-resolution particle tracking of fluorescent HIV-1 pseudoviruses, we found that neither pH nor Nugent scores nor total lactic acid levels correlated significantly with virus trapping in unmodified CVM from diverse donors. Surprisingly, HIV-1 was generally trapped in CVM with relatively high concentrations of
d
-lactic acid and a
Lactobacillus crispatus
-dominant microbiota. In contrast, a substantial fraction of HIV-1 virions diffused rapidly through CVM with low concentrations of
d
-lactic acid that had a
Lactobacillus iners
-dominant microbiota or significant amounts of
Gardnerella vaginalis
, a bacterium associated with bacterial vaginosis. Our results demonstrate that the vaginal microbiota, including specific species of
Lactobacillus
, can alter the diffusional barrier properties of CVM against HIV and likely other sexually transmitted viruses and that these microbiota-associated changes may account in part for the elevated risks of HIV acquisition linked to bacterial vaginosis or intermediate vaginal microbiota.

IMPORTANCE
Variations in the vaginal microbiota, especially shifts away from
Lactobacillus
-dominant microbiota, are associated with differential risks of acquiring HIV or other sexually transmitted infections. However, emerging evidence suggests that
Lactobacillus iners
frequently colonizes women with recurring bacterial vaginosis, raising the possibility that
L. iners
may not be as protective as other
Lactobacillus
species. Our study was designed to improve understanding of how the cervicovaginal mucus barrier against HIV may vary between women along with the vaginal microbiota and led to the finding that the vaginal microbiota, including specific species of
Lactobacillus
, can directly alter the diffusional barrier properties of cervicovaginal mucus. This work advances our understanding of the complex barrier properties of mucus and highlights the differential protective ability of different species of
Lactobacillus
, with
Lactobacillus crispatus
and possibly other species playing a key role in protection against HIV and other sexually transmitted infections. These findings could lead to the development of novel strategies to protect women against HIV.
Identification of a Natural Viral RNA Motif That Optimizes Sensing of Viral RNA by RIG-I
Authors: Xu Jie , Mercado-López Xiomara , Grier Jennifer T. , Kim Won-keun , Chun Lauren F. , Irvine Edward B. , Del Toro Duany Yoandris , Kell Alison , Hur Sun , Gale Michael , Raj Arjun , López Carolina B.
Published: October 2015

Stimulation of the antiviral response depends on the sensing of viral pathogen-associated molecular patterns (PAMPs) by specialized cellular proteins. During infection with RNA viruses, 5′-di- or -triphosphates accompanying specific single or double-stranded RNA motifs trigger signaling of intracellular RIG-I-like receptors (RLRs) and initiate the antiviral response. Although these molecular signatures are present during the replication of many viruses, it is unknown whether they are sufficient for strong activation of RLRs during infection. Immunostimulatory defective viral genomes (iDVGs) from Sendai virus (SeV) are among the most potent natural viral triggers of antiviral immunity. Here we describe an RNA motif (DVG
70-114
) that is essential for the potent immunostimulatory activity of 5′-triphosphate-containing SeV iDVGs. DVG
70-114
enhances viral sensing by the host cell independently of the long stretches of complementary RNA flanking the iDVGs, and it retains its stimulatory potential when transferred to otherwise inert viral RNA.
In vitro
analysis showed that DVG
70-114
augments the binding of RIG-I to viral RNA and promotes enhanced RIG-I polymerization, thereby facilitating the onset of the antiviral response. Together, our results define a new natural viral PAMP enhancer motif that promotes viral recognition by RLRs and confers potent immunostimulatory activity to viral RNA.

IMPORTANCE
A discrete group of molecular motifs, including 5′-triphosphates associated with double-stranded RNA, have been identified as essential for the triggering of antiviral immunity. Most RNA viruses expose these motifs during their replication; however, successful viruses normally evade immune recognition and replicate to high levels before detection, indicating that unknown factors drive antiviral immunity. DVGs from SeV are among the most potent natural viral stimuli of the antiviral response known to date. These studies define a new natural viral motif present in DVGs that maximizes viral recognition by the intracellular sensor RIG-I, allowing fast and strong antiviral responses even in the presence of viral-encoded immune antagonists. This motif can be harnessed to increase the immunostimulatory potential of otherwise inert viral RNAs and represents a novel immunostimulatory enhancer that could be used in the development of vaccine adjuvants and antivirals.
Trading Capsule for Increased Cytotoxin Production: Contribution to Virulence of a Newly Emerged Clade of
emm89
Streptococcus pyogenes
Authors: Zhu Luchang , Olsen Randall J. , Nasser Waleed , de la Riva Morales Ivan , Musser James M.
Published: October 2015

Strains of
emm89
Streptococcus pyogenes
have become one of the major causes of invasive infections worldwide in the last 10 years. We recently sequenced the genome of 1,125
emm89
strains and identified three major phylogenetic groups, designated clade 1, clade 2, and the epidemic clade 3. Epidemic clade 3 strains, which now cause the great majority of infections, have two distinct genetic features compared to clade 1 and clade 2 strains. First, all clade 3 organisms have a variant 3
nga
promoter region pattern, which is associated with increased production of secreted cytolytic toxins SPN (
S. pyogenes
NADase) and SLO (streptolysin O). Second, all clade 3 strains lack the
hasABC
locus mediating hyaluronic acid capsule synthesis, whereas this locus is intact in clade 1 and clade 2 strains. We constructed isogenic mutant strains that produce different levels of SPN and SLO toxins and capsule (none, low, or high). Here we report that
emm89
strains with elevated toxin production are significantly more virulent than low-toxin producers. Importantly, we also show that capsule production is dispensable for virulence in strains that already produce high levels of SPN and SLO. Our results provide new understanding about the molecular mechanisms contributing to the rapid emergence and molecular pathogenesis of epidemic clade 3
emm89
S. pyogenes
.

IMPORTANCE
S. pyogenes
(group A streptococcus [GAS]) causes pharyngitis (“strep throat”), necrotizing fasciitis, and other human infections. Serious infections caused by
emm89
S. pyogenes
strains have recently increased in frequency in many countries. Based on whole-genome sequence analysis of 1,125 strains recovered from patients on two continents, we discovered that a new
emm89
clone, termed clade 3, has two distinct genetic features compared to its predecessors: (i) absence of the genes encoding antiphagocytic hyaluronic acid capsule virulence factor and (ii) increased production of the secreted cytolytic toxins SPN and SLO.
emm89
S. pyogenes
strains with the clade 3 phenotype (absence of capsule and high expression of SPN and SLO) are highly virulent in mice. These findings provide new understanding of how new virulent clones emerge and cause severe infections worldwide. This newfound knowledge of
S. pyogenes
virulence can be used to help understand future epidemics and conduct new translational research.
Plasmodium falciparum-Infected Erythrocyte Knob Density Is Linked to the PfEMP1 Variant Expressed
Authors: Subramani Ramesh , Quadt Katharina , Jeppesen Anine E. , Hempel Casper , Petersen Jens Emil Vang , Hassenkam Tue , Hviid Lars , Barfod Lea
Published: October 2015

Members of the clonally variant
Plasmodium falciparum
erythrocyte membrane protein 1 (PfEMP1) family mediate adhesion of infected erythrocytes (IEs) to vascular receptors. PfEMP1 expression is normally confined to nanoscale knob protrusions on the IE surface membrane. To investigate the relationship between the densities of these IE surface knobs and the PfEMP1 variant expressed, we used specific antibody panning to generate three sublines of the
P. falciparum
clone IT4, which expresses the PfEMP1 variants IT4VAR04, IT4VAR32b, and IT4VAR60. The knob density in each subline was then determined by atomic force microscopy (AFM) and scanning electron microscopy (SEM) and compared to PfEMP1 and knob-associated histidine-rich protein (KAHRP) expression. Selection for uniform expression of IT4VAR04 produced little change in knob density, compared to unselected IEs. In contrast, selection for IT4VAR32b expression increased knob density approximately 3-fold, whereas IEs selected for IT4VAR60 expression were essentially knobless. When IT4VAR60
+
IEs were subsequently selected to express IT4VAR04 or IT4VAR32b, they again displayed low and high knob densities, respectively. All sublines expressed KAHRP regardless of the PfEMP1 expressed. Our study documents for the first time that knob density is related to the PfEMP1 variant expressed. This may reflect topological requirements to ensure optimal adhesive properties of the IEs.

IMPORTANCE
Infections with
Plasmodium falciparum
malaria parasites are still responsible for many deaths, especially among children and pregnant women. New interventions are needed to reduce severe illness and deaths caused by this malaria parasite. Thus, a better understanding of the mechanisms behind the pathogenesis is essential. A main reason why
Plasmodium falciparum
malaria is more severe than disease caused by other malaria species is its ability to express variant antigens on the infected erythrocyte surface. These antigens are presented on membrane protrusions known as knobs. This study set out to investigate the interplay between different variant antigens on the surface of
P. falciparum
-infected erythrocytes and the density of the knobs on which the antigens are expressed. Such a direct analysis of this relationship has not been reported before but adds to the important understanding of the complexity of malaria antigen presentation.
Comparison of the Effects of Pretreatment with Repeated Electroacupuncture at Gv20 and St36 on Fatigue in Rats
Authors: Guo Kai , Zhu Jinyu , Quan Xin , Zhang Dawei , Chen Xiaoyong , Yang Chongfei , Li Xiaojie , Shi Jun , Hu Wendong , Zhu Qingsheng
Published: October 2015

Objective

To investigate and compare the effects of electroacupuncture (EA) pretreatment at GV20 and ST36 on fatigue in rats.

Methods

Rats were randomly allocated into 4 groups: control, fatigue, fatigue+GV20 and fatigue+ST36. The last two groups received EA pretreatment at GV20 or ST36 for 5 days before being maintained in cages filled with water to a height of 1.5 cm to establish an animal model of fatigue. We used the weight-loaded forced swimming test and open-field test and measured 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratios and serum levels of blood urea nitrogen (BUN), lactic dehydrogenase (LDH) and testosterone as behavioural and biochemical markers of fatigue in the rats.

Results

Compared with controls, rats in the (untreated) fatigue group exhibited reduced weight-loaded swimming times and total movement/distance in the open-field test, plus higher BUN/LDH and lower testosterone levels. Both EA pretreatment at GV20 and ST36 increased swimming times, and reduced serum BUN/LDH. EA pretreatment at GV20 (but not ST36) increased serum testosterone. The 5-HIAA/5-HT ratios in four brain regions were decreased in the fatigue+GV20 group compared with the fatigue group (p<0.05). By contrast, 5-HIAA/5-HT ratios in striatum and hypothalamus (but not hippocampus or midbrain) were decreased in the fatigue+ST36 group compared with the fatigue group (p<0.05). Furthermore, only pretreatment at GV20 affected the results of the open-field test.

Conclusions

These results suggest that EA pretreatment had a positive effect on the prevention of fatigue. Pretreatment at GV20 had a greater anti-fatigue effect than pretreatment at ST36.
Primary breast lymphoma presenting as non-healing axillary abscess
Authors: Anele Chukwuemeka , Phan Yih Chyn , Wong Suanne , Poddar Anil
Published: October 2015

A 67-year-old woman with non-insulin dependent diabetes mellitus with a history consistent with a right axillary abscess, presented to her general practitioner (GP). A diagnosis of folliculitis was made and the GP started a course of flucloxacillin. Despite antibiotics, the patient's symptoms worsened and the abscess increased in size. This prompted her GP to perform an incision and drainage procedure of the abscess. The practice nurse subsequently oversaw the follow-up care of the wound. Two months after the incision and drainage, and after regular wound dressing, the patient was referred to the acute surgical team with a complicated, non-healing right axillary abscess cavity and associated generalised right breast cellulitis. There was no history of breast symptoms prior to the onset of the axillary abscess. The patient underwent wound debridement, washout and application of negative pressure vacuum therapy. Biopsies revealed primary breast lymphoma (B-cell). She underwent radical chemotherapy and is currently in remission.
Accuracy and readability of cardiovascular entries on Wikipedia: are they reliable learning resources for medical students?
Authors: Azer Samy A , AlSwaidan Nourah M , Alshwairikh Lama A , AlShammari Jumana M
Published: October 2015

Objective

To evaluate accuracy of content and readability level of English Wikipedia articles on cardiovascular diseases, using quality and readability tools.

Methods

Wikipedia was searched on the 6 October 2013 for articles on cardiovascular diseases. Using a modified DISCERN (DISCERN is an instrument widely used in assessing online resources), articles were independently scored by three assessors. The readability was calculated using Flesch-Kincaid Grade Level. The inter-rater agreement between evaluators was calculated using the Fleiss κ scale.

Results

This study was based on 47 English Wikipedia entries on cardiovascular diseases. The DISCERN scores had a median=33 (IQR=6). Four articles (8.5%) were of good quality (DISCERN score 40–50), 39 (83%) moderate (DISCERN 30–39) and 4 (8.5%) were poor (DISCERN 10–29). Although the entries covered the aetiology and the clinical picture, there were deficiencies in the pathophysiology of diseases, signs and symptoms, diagnostic approaches and treatment. The number of references varied from 1 to 127 references; 25.9±29.4 (mean±SD). Several problems were identified in the list of references and citations made in the articles. The readability of articles was 14.3±1.7 (mean±SD); consistent with the readability level for college students. In comparison, Harrison’s Principles of Internal Medicine 18th edition had more tables, less references and no significant difference in number of graphs, images, illustrations or readability level. The overall agreement between the evaluators was good (Fleiss κ 0.718 (95% CI 0.57 to 0.83).

Conclusions

The Wikipedia entries are not aimed at a medical audience and should not be used as a substitute to recommended medical resources. Course designers and students should be aware that Wikipedia entries on cardiovascular diseases lack accuracy, predominantly due to errors of omission. Further improvement of the Wikipedia content of cardiovascular entries would be needed before they could be considered a supplementary resource.
Engaging youth in communities: a framework for promoting adolescent and community health
Authors: Ballard Parissa J , Syme S Leonard
Published: October 2015

Health researchers and practitioners increasingly recognise the important role communities play in shaping individual health. Health researchers recognise the role of community factors ascauses or determinantsof health problems; use community-basedmethodsfor understanding complex health issues; and design community-level healthsolutions. In this commentary, we propose a fourth way to think about the role of communities in individual health by arguing that the community engagement process itself has implications for individual health and strong communities. This topic is especially important during adolescence, a developmental window of opportunity during which individuals need meaningful opportunities to contribute to the world around them.
Educational recommendations for the conduct, content and format of EULAR musculoskeletal ultrasound Teaching the Teachers Courses
Authors: Iagnocco A , Terslev L , Backhaus M , Balint P , Bruyn G A W , Damjanov N , Filippucci E , Hammer H B , Jousse-Joulin S , Kane D , Koski J M , Mandl P , Möller I , Peetrons P , Schmidt W , Szkudlarek M , Vojinovic J , Wakefield R J , Hofer M , D'Agostino M A , Naredo E
Published: October 2015

Objective

To produce educational guidelines for the conduct, content and format of theoretical and practical teaching at EULAR musculoskeletal ultrasound (MSUS) Teaching the Teachers (TTT) Courses.

Methods

A Delphi-based procedure with 24 recommendations covering five main areas (Duration and place of the course; Faculty members; Content of the course; Evaluation of the teaching skills; TTT competency assessment) was distributed among a group of experts involved in MSUS teaching, in addition to an advisory educational expert being present. Consensus for each recommendation was considered achieved when the percentage of agreement was >75%.

Results

21 of 24 invited participants responded to the first Delphi questionnaire (88% response rate). All 21 participants also responded to the second round. Agreement on 19 statements was obtained after two rounds.

Conclusions

This project has led to the development of guidelines for the conduct, content and format of teaching at the EULAR MSUS TTT Courses that are organised annually, with the aim of training future teachers of EULAR MSUS Courses, EULAR Endorsed MSUS Courses, as well as national and local MSUS Courses. The presented work gives indications on how to homogenise the teaching at the MSUS TTT Courses, thus resolving current discrepancies in the field.