bluuebunny/crossref_metadata_2025 huggingface dataset:
The US3 Protein of Pseudorabies Virus Drives Viral Passage across the Basement Membrane in Porcine Respiratory Mucosa Explants
Authors: Lamote Jochen A. S. , Glorieux Sarah , Nauwynck Hans J. , Favoreel Herman W.
Published: September 2016

Passage of the basement membrane (BM), which forms a barrier between the epithelium and the underlying lamina propria, represents an important step in the early pathogenesis of different alphaherpesviruses. Rho GTPase signaling plays an important role in transmigration of cells across the BM during physiological and pathological processes. We reported earlier that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) interferes with Rho GTPase signaling and causes a reorganization of the host cell cytoskeleton, which as a consequence, enhances viral cell-to-cell spread in epithelial cell cultures. Here, using an
ex vivo
system of porcine nasal respiratory mucosa explants that allows to study PRV invasion through the BM, we found that a PRV strain that lacks US3 expression (ΔUS3 PRV) showed a reduced spread in mucosal epithelium and was virtually unable to breach the BM, in contrast to isogenic wild-type (WT) or US3 rescue PRV strains. Interestingly, addition of IPA3, an inhibitor of p21-activated kinases that blocks the effects of US3 on the cytoskeleton, suppressed the ability of WT PRV to spread across the BM. In addition, artificial suppression of RhoA signaling using CPC3 (cell-permeable C3 transferase) to mimic the effects of US3 on Rho GTPase signaling, significantly increased passage of ΔUS3 PRV through the BM, whereas it did not significantly affect BM passage of WT or US3 rescue PRV. In conclusion, these data indicate that US3 plays an important role in PRV mucosal invasion across the BM, which involves its interference with Rho GTPase signaling. This is the first report describing an alphaherpesvirus protein that drives viral BM passage.

IMPORTANCE
Many viruses, including alphaherpesviruses, primarily replicate in epithelial cells of surface mucosae, such as the respiratory mucosa. Some of these viruses breach the basement membrane underlying these epithelial cells to reach underlying connective tissue and blood vessels and invade the host. Hence, epithelial spread and basement membrane passage represent crucial but still poorly understood early steps in (alphaherpes)virus pathogenesis. Here, using
ex vivo
porcine respiratory mucosa explants, we show that the conserved US3 protein of the porcine alphaherpesvirus pseudorabies virus (PRV) is critical for passage of PRV across the basement membrane and contributes to efficient viral epithelial spread. In addition, we show that US3-mediated viral epithelial spread and passage across the basement membrane depend at least in part on the ability of this viral protein to modulate cellular Rho GTPase signaling. This is the first report that identifies an alphaherpesvirus protein that drives viral basement membrane passage.
Structure of Aichi Virus 1 and Its Empty Particle: Clues to Kobuvirus Genome Release Mechanism
Authors: Sabin Charles , Füzik Tibor , Škubník Karel , Pálková Lenka , Lindberg A. Michael , Plevka Pavel
Published: September 2016

Aichi virus 1
(AiV-1) is a human pathogen from the
Kobuvirus
genus of the
Picornaviridae
family. Worldwide, 80 to 95% of adults have antibodies against the virus. AiV-1 infections are associated with nausea, gastroenteritis, and fever. Unlike most picornaviruses, kobuvirus capsids are composed of only three types of subunits: VP0, VP1, and VP3. We present here the structure of the AiV-1 virion determined to a resolution of 2.1 Å using X-ray crystallography. The surface loop puff of VP0 and knob of VP3 in AiV-1 are shorter than those in other picornaviruses. Instead, the 42-residue BC loop of VP0 forms the most prominent surface feature of the AiV-1 virion. We determined the structure of AiV-1 empty particle to a resolution of 4.2 Å using cryo-electron microscopy. The empty capsids are expanded relative to the native virus. The N-terminal arms of capsid proteins VP0, which mediate contacts between the pentamers of capsid protein protomers in the native AiV-1 virion, are disordered in the empty capsid. Nevertheless, the empty particles are stable, at least
in vitro
, and do not contain pores that might serve as channels for genome release. Therefore, extensive and probably reversible local reorganization of AiV-1 capsid is required for its genome release.

IMPORTANCE
Aichi virus 1 (AiV-1) is a human pathogen that can cause diarrhea, abdominal pain, nausea, vomiting, and fever. AiV-1 is identified in environmental screening studies with higher frequency and greater abundance than other human enteric viruses. Accordingly, 80 to 95% of adults worldwide have suffered from AiV-1 infections. We determined the structure of the AiV-1 virion. Based on the structure, we show that antiviral compounds that were developed against related enteroviruses are unlikely to be effective against AiV-1. The surface of the AiV-1 virion has a unique topology distinct from other related viruses from the
Picornaviridae
family. We also determined that AiV-1 capsids form compact shells even after genome release. Therefore, AiV-1 genome release requires large localized and probably reversible reorganization of the capsid.
Herpes Simplex Virus 1 Tegument Protein UL41 Counteracts IFIT3 Antiviral Innate Immunity
Authors: Jiang Zhangtao , Su Chenhe , Zheng Chunfu
Published: September 2016

The interferon-induced protein with tetratricopeptide repeat 3 (IFIT3 or ISG60) is a host-intrinsic antiviral factor that restricts many instances of DNA and RNA virus replication. Herpes simplex virus 1 (HSV-1), a DNA virus bearing a large genome, can encode many viral proteins to counteract the host immune responses. However, whether IFIT3 plays a role upon HSV-1 infection is little known. In this study, we show for the first time that HSV-1 tegument protein UL41, a viral endoribonuclease, plays an important role in inhibiting the antiviral activity of IFIT3. Here, we demonstrated that ectopically expressed IFIT3 could restrict the replication of vesicular stomatitis virus (VSV) but had little effect on the replication of wild-type (WT) HSV-1. Further study showed that WT HSV-1 infection downregulated the expression of IFIT3, and ectopic expression of UL41, but not the immediate-early protein ICP0, notably reduced the expression of IFIT3. The underlying molecular mechanism was that UL41 diminished the accumulation of IFIT3 mRNA to abrogate its antiviral activity. In addition, our results illustrated that ectopic expression of IFIT3 inhibited the replication of UL41-null mutant virus (R2621), and stable knockdown of IFIT3 facilitated its replication. Taking these findings together, HSV-1 was shown for the first time to evade the antiviral function of IFIT3 via UL41.

IMPORTANCE
The tegument protein UL41 of HSV-1 is an endoribonuclease with the substrate specificity of RNase A, which plays an important role in viral infection. Upon HSV-1 infection, interferons are critical cytokines that regulate immune responses against viral infection. Host antiviral responses are significantly boosted or crippled in the presence or absence of IFIT3; however, whether IFIT3 plays a role during HSV-1 infection is still unknown. Our data show for the first time that IFIT3 has little effect on HSV-1 replication, as UL41 decreases the accumulation of IFIT3 mRNA and subverts its antiviral activity. This study identifies IFIT3 as a novel target of the tegument protein UL41 and provides new insight into HSV-1-mediated immune evasion.
The Coat Protein and NIa Protease of Two Potyviridae Family Members Independently Confer Superinfection Exclusion
Authors: Tatineni Satyanarayana , French Roy
Published: September 2016

Superinfection exclusion (SIE) is an antagonistic virus-virus interaction whereby initial infection by one virus prevents subsequent infection by closely related viruses. Although SIE has been described in diverse viruses infecting plants, humans, and animals, its mechanisms, including involvement of specific viral determinants, are just beginning to be elucidated. In this study, SIE determinants encoded by two economically important wheat viruses,
Wheat streak mosaic virus
(WSMV; genus
Tritimovirus
, family
Potyviridae
) and
Triticum mosaic virus
(TriMV; genus
Poacevirus
, family
Potyviridae
), were identified in gain-of-function experiments that used heterologous viruses to express individual virus-encoded proteins in wheat. Wheat plants infected with TriMV expressing WSMV P1, HC-Pro, P3, 6K1, CI, 6K2, NIa-VPg, or NIb cistrons permitted efficient superinfection by WSMV expressing green fluorescent protein (WSMV-GFP). In contrast, wheat infected with TriMV expressing WSMV NIa-Pro or coat protein (CP) substantially excluded superinfection by WSMV-GFP, suggesting that both of these cistrons are SIE effectors encoded by WSMV. Importantly, SIE is due to functional WSMV NIa-Pro or CP rather than their encoding RNAs, as altering the coded protein products by minimally changing RNA sequences led to abolishment of SIE. Deletion mutagenesis further revealed that elicitation of SIE by NIa-Pro requires the entire protein while CP requires only a 200-amino-acid (aa) middle fragment (aa 101 to 300) of the 349 aa. Strikingly, reciprocal experiments with WSMV-mediated expression of TriMV proteins showed that TriMV CP, and TriMV NIa-Pro to a lesser extent, likewise excluded superinfection by TriMV-GFP. Collectively, these data demonstrate that WSMV- and TriMV-encoded CP and NIa-Pro proteins are effectors of SIE and that these two proteins trigger SIE independently of each other.

IMPORTANCE
Superinfection exclusion (SIE) is an antagonistic virus-virus interaction that prevents secondary invasions by identical or closely related viruses in the same host cells. Although known to occur in diverse viruses, SIE remains an enigma in terms of key molecular determinants and action mechanisms. In this study, we found that
Wheat streak mosaic virus
(WSMV) and
Triticum mosaic virus
(TriMV) encode two independently functioning cistrons that serve as effectors of SIE at the protein but not the RNA level. The coat protein and NIa-Pro encoded by these two viruses, when expressed from a heterologous virus, exerted SIE to the cognate viruses. The identification of virus-encoded effectors of SIE and their transgenic expression could potentially facilitate the development of virus-resistant crop plants. Additionally, functional conservation of SIE in diverse virus groups suggests that a better understanding of the underlying mechanisms of SIE could facilitate the development of novel antiviral therapies against viral diseases.
Reovirus μ1 Protein Affects Infectivity by Altering Virus-Receptor Interactions
Authors: Thete Deepti , Snyder Anthony J. , Mainou Bernardo A. , Danthi Pranav
Published: September 2016

Proteins that form the reovirus outer capsid play an active role in the entry of reovirus into host cells. Among these, the σ1 protein mediates attachment of reovirus particles to host cells via interaction with cell surface glycans or the proteinaceous receptor junctional adhesion molecule A (JAM-A). The μ1 protein functions to penetrate the host cell membrane to allow delivery of the genome-containing viral core particle into the cytoplasm to initiate viral replication. We demonstrate that a reassortant virus that expresses the M2 gene-encoded μ1 protein derived from prototype strain T3D in an otherwise prototype T1L background (T1L/T3DM2) infects cells more efficiently than parental T1L. Unexpectedly, the enhancement in infectivity of T1L/T3DM2 is due to its capacity to attach to cells more efficiently. We present genetic data implicating the central region of μ1 in altering the cell attachment property of reovirus. Our data indicate that the T3D μ1-mediated enhancement in infectivity of T1L is dependent on the function of σ1 and requires the expression of JAM-A. We also demonstrate that T1L/T3DM2 utilizes JAM-A more efficiently than T1L. These studies revealed a previously unknown relationship between two nonadjacent reovirus outer capsid proteins, σ1 and μ1.

IMPORTANCEHow reovirus attaches to host cells has been extensively characterized. Attachment of reovirus to host cells is mediated by the σ1 protein, and properties of σ1 influence the capacity of reovirus to target specific host tissues and produce disease. Here, we present new evidence indicating that the cell attachment properties of σ1 are influenced by the nature of μ1, a capsid protein that does not physically interact with σ1. These studies could explain the previously described role for μ1 in influencing reovirus pathogenesis. These studies are also of broader significance because they highlight an example of how genetic reassortment between virus strains could produce phenotypes that are distinct from those of either parent.
Genome Diversity, Recombination, and Virulence across the Major Lineages of
Paracoccidioides
Authors: Muñoz José F. , Farrer Rhys A. , Desjardins Christopher A. , Gallo Juan E. , Sykes Sean , Sakthikumar Sharadha , Misas Elizabeth , Whiston Emily A. , Bagagli Eduardo , Soares Celia M. A. , Teixeira Marcus de M. , Taylor John W. , Clay Oliver K. , McEwen Juan G. , Cuomo Christina A.
Published: September 2016

Characterization of genetic differences between lineages of the dimorphic human-pathogenic fungus
Paracoccidioides
can identify changes linked to important phenotypes and guide the development of new diagnostics and treatments. In this article, we compared genomes of 31 diverse isolates representing the major lineages of
Paracoccidioides
spp. and completed the first annotated genome sequences for the PS3 and PS4 lineages. We analyzed the population structure and characterized the genetic diversity among the lineages of
Paracoccidioides
, including a deep split of S1 into two lineages (S1a and S1b), and differentiated S1b, associated with most clinical cases, as the more highly recombining and diverse lineage. In addition, we found patterns of positive selection in surface proteins and secreted enzymes among the lineages, suggesting diversifying mechanisms of pathogenicity and adaptation across this species complex. These genetic differences suggest associations with the geographic range, pathogenicity, and ecological niches of
Paracoccidioides
lineages.
Different Regulations of
ROM2
and
LRG1
Expression by Ccr4, Pop2, and Dhh1 in the Saccharomyces cerevisiae Cell Wall Integrity Pathway
Authors: Li Xia , Ohmori Tetsuro , Irie Kaoru , Kimura Yuichi , Suda Yasuyuki , Mizuno Tomoaki , Irie Kenji
Published: September 2016

We find here that Ccr4, Pop2, and Dhh1 modulate the levels of mRNAs for specific Rho1 regulators, Rom2 and Lrg1. In budding yeast, Rho1 activity is tightly regulated both temporally and spatially. It is anticipated that Ccr4, Pop2, and Dhh1 may contribute to the precise spatiotemporal control of Rho1 activity by regulating expression of its regulators temporally and spatially. Our finding on the roles of the components of the Ccr4-Not complex in yeast would give important information for understanding the roles of the evolutionary conserved Ccr4-Not complex.
Physicochemical equivalence of generic antihypertensive medicines (EQUIMEDS): protocol for a quality of medicines assessment
Authors: Redfern Julie , Adedoyin Rufus Adesoji , Ofori Sandra , Anchala Raghupathy , Ajay Vamadevan S , De Andrade Luciano , Zelaya Jose , Kaur Harparkash , Balabanova Dina , Sani Mahmoud U
Published: September 2016

Background

Prevention and optimal management of hypertension in the general population is paramount to the achievement of the World Heart Federation (WHF) goal of reducing premature cardiovascular disease (CVD) mortality by 25% by the year 2025 and widespread access to good quality antihypertensive medicines is a critical component for achieving the goal. Despite research and evidence relating to other medicines such as antimalarials and antibiotics, there is very little known about the quality of generic antihypertensive medicines in low-income and middle-income countries. The aim of this study was to determine the physicochemical equivalence (percentage of active pharmaceutical ingredient, API) of generic antihypertensive medicines available in the retail market of a developing country.

Methods

An observational design will be adopted, which includes literature search, landscape assessment, collection and analysis of medicine samples. To determine physicochemical equivalence, a multistage sampling process will be used, including (1) identification of the 2 most commonly prescribed classes of antihypertensive medicines prescribed in Nigeria; (2) identification of a random sample of 10 generics from within each of the 2 most commonly prescribed classes; (3) a geographical representative sampling process to identify a random sample of 24 retail outlets in Nigeria; (4) representative sample purchasing, processing to assess the quality of medicines, storage and transport; and (5) assessment of the physical and chemical equivalence of the collected samples compared to the API in the relevant class. In total, 20 samples from each of 24 pharmacies will be tested (total of 480 samples).

Discussion

Availability of and access to quality antihypertensive medicines globally is therefore a vital strategy needed to achieve the WHF 25×25 targets. However, there is currently a scarcity of knowledge about the quality of antihypertensive medicines available in developing countries. Such information is important for enforcing and for ensuring the quality of antihypertensive medicines.
The National Early Warning Score (NEWS) for outcome prediction in emergency department patients with community-acquired pneumonia: results from a 6-year prospective cohort study
Authors: Sbiti-Rohr Diana , Kutz Alexander , Christ-Crain Mirjam , Thomann Robert , Zimmerli Werner , Hoess Claus , Henzen Christoph , Mueller Beat , Schuetz Philipp
Published: September 2016

Objective

To investigate the accuracy of the National Early Warning Score (NEWS) to predict mortality and adverse clinical outcomes for patients with community-acquired pneumonia (CAP) compared to standard risk scores such as the pneumonia severity index (PSI) and CURB-65.

Design

Secondary analysis of patients included in a previous randomised-controlled trial with a median follow-up of 6.1 years.

Settings

Patients with CAP included on admission to the emergency departments (ED) of 6 tertiary care hospitals in Switzerland.

Participants

A total of 925 patients with confirmed CAP were included. NEWS, PSI and CURB-65 scores were calculated on admission to the ED based on admission data.

Main outcome measure

Our primary outcome was all-cause mortality within 6 years of follow-up. Secondary outcomes were adverse clinical outcome defined as intensive care unit (ICU) admission, empyema and unplanned hospital readmission all occurring within 30 days after admission. We used regression models to study associations of baseline risk scores and outcomes with the area under the receiver operating curve (AUC) as a measure of discrimination.

Results

6-year overall mortality was 45.1% (n=417) with a stepwise increase with higher NEWS categories. For 30 day and 6-year mortality prediction, NEWS showed only low discrimination (AUC 0.65 and 0.60) inferior compared to PSI and CURB-65. For prediction of ICU admission, NEWS showed moderate discrimination (AUC 0.73) and improved the prognostic accuracy of a regression model, including PSI (AUC from 0.66 to 0.74, p=0.001) and CURB-65 (AUC from 0.64 to 0.73, p=0.015). NEWS was also superior to PSI and CURB-65 for prediction of empyema, but did not well predict rehospitalisation.

Conclusions

NEWS provides additional prognostic information with regard to risk of ICU admission and complications and thereby improves traditional clinical-risk scores in the management of patients with CAP in the ED setting.

Trial registration number

ISRCTN95122877; Post-results.
Herbal medicine (Gyejibongneyong-hwan) for treating primary dysmenorrhoea: a protocol for a systematic review of randomised controlled trials
Authors: Lee Ju Ah , Park Sunju , Jung Jeeyoun , Jun Ji Hee , Choi Jiae , Lee Myeong Soo
Published: September 2016

Introduction

Gyejibongneyong-hwan (GBH), also known as Guizhi Fuling formula, and is widely used for uterine fibroids in East Asian countries. Many clinical trials assessing the efficacy and safety of GBH formula for the treatment of dysmenorrhoea have been reported. This review will assess the clinical evidence for and against the use of GBH formula as a treatment for dysmenorrhoea. It will also discuss the proposed mechanism(s) that could link herbal medicine to improvements in dysmenorrhoea.

Methods and analysis

Fourteen databases will be searched until September 2016. We will include randomised controlled trials (RCTs) examining GBH decoctions for any type of dysmenorrhoea. All RCTs of decoctions or modified decoctions will be included. The methodological qualities of the RCTs will be assessed using the Cochrane Collaboration tool for assessing risk of bias.

Ethics and dissemination

This systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print. It will be updated to inform and guide healthcare practices.

Trial registration number

CRD42015023419.
Effects of universally offered parenting interventions for parents with infants: a systematic review
Authors: Pontoppidan Maiken , Klest Sihu K , Patras Joshua , Rayce Signe Boe
Published: September 2016

Objectives

From a developmental perspective, infancy is a critical stage of life. Early childhood interventions aim to support caretakers, but the effects of universal interventions for parents with infants are unknown. The objective is to determine the effects of universal parenting interventions offered to parents with infants 0–12 months on measures of child development and parent–child relationship.

Design

A systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We extracted publications from 10 databases in June 2013, January 2015 and June 2016 and supplemented with grey and hand search. Risk of bias was assessed, and effect sizes were calculated.

Participants

Inclusion criteria are: (1) randomised controlled trials of structured, psychosocial interventions offered to a universal population of parents with infants 0–12 months old in western OECD countries, (2) interventions that include a minimum of 3 sessions with at least half of the sessions delivered postnatally and (3) programme outcomes reported for child development or parent–child relationship.

Results

14 papers representing 7 studies are included. There were no statistically significant effects of the intervention for the majority of the primary outcomes across the studies.

Conclusions

The findings of this review are mixed. No clear conclusions can be drawn regarding the effects of universally offered parenting interventions on child development and parent–child relationship for this age group.
Decisional support for young people who self-harm: protocol for a feasibility trial
Authors: Rowe Sarah L , French Rebecca S , Henderson Claire , Ougrin Dennis , Slade Mike , Moran Paul
Published: September 2016

Introduction

Self-harm is common in adolescents, and it is the strongest predictor of suicide. Young people who self-harm are often unsure of how and where to get help. Decision aids (DAs) have been shown to help with decisional conflict where there is uncertainty around different options. We have developed an online DA to support young people in help-seeking for self-harm. A feasibility trial will examine the acceptability of the online intervention and the ability to recruit and follow-up participants within a school setting.

Methods and analysis

In this parallel arm, single-blind feasibility trial, 60 participants aged 12–18 years who have self-harmed in the past 12 months, will be randomised to either (1) a group receiving the online DA or (2) a control group receiving general information about feelings and emotions. Both groups will complete measures assessing decision-making and help-seeking behaviour. The school counsellor will be notified of any participants who have been randomised to ensure safeguarding for the young person. Participants in both groups will be followed up at 4 weeks, and the measures will be repeated. Qualitative interviews will be conducted with a subset of participants to explore their views and experiences of the DA and of participation in the study.

Ethics and dissemination

Ethical approval was granted by King's College London (KCL) College Research Ethics Committee. Results of this study will help to clarify if we can recruit and administer an online decisional support intervention within a school setting for young people who self-harm. The study will inform the design and implementation of a larger randomised controlled trial to test the effectiveness of the DA. Dissemination of the study findings will target publication in peer-reviewed journals of general and special interest. The funder will be sent a report outlining the major findings of the study.

Trial registration number

ISRCTN11230559.
Adherence to the Tobacco Control Act, 2007: presence of a workplace policy on tobacco use in bars and restaurants in Nairobi, Kenya
Authors: Karimi K J , Ayah R , Olewe T
Published: September 2016

Introduction

Despite extensive knowledge about effective tobacco control interventions, the prevalence of tobacco use in many middle- and low-income countries continues to rise. In these countries, public appreciation of levels of protection provided by laws and regulations on tobacco use and exposure to tobacco smoke is limited. After ratification of the Framework Convention on Tobacco Control, Kenya enacted the Tobacco Control Act, 2007, banning smoking in public places except in designated smoking areas.

Objective

To assess adherence to the Tobacco Control Act, 2007 by determining the presence of a workplace policy on tobacco use in bars and restaurants.

Methods

A survey of 176 liquor licensed bars and restaurants in Nairobi County was carried out. Their managers were asked about the presence of a workplace policy governing smoking of tobacco, and observations made on provisions that determine adherence to the Tobacco Control Act, 2007.

Results

Smoking took place in almost all bars and restaurants (150 (85%)). Half the establishments (86 (49%)) had a workplace policy governing tobacco use among employees, although a difference between bars (11 (23%)) and restaurants (75 (58%)) was recorded (p<0.001). Establishments at which managers had lower levels of education were less likely to have a workplace policy (p<0.001) and less likely to have ‘no smoking’ signs and designated smoking areas (p<0.005).

Conclusions and recommendations

Kenya's implementation of the Tobacco Control Act, 2007 does not provide sufficient protection of patrons and workers in bars and restaurants. It is important to sensitise hospitality workers to the dangers of tobacco smoke. Bar and restaurants managers should have a minimum post-secondary education level. The Tobacco Control Act, 2007 requires strengthening to ensure that bars and restaurants have a smoke-free environment.
Impacts of the 2011 Fukushima nuclear accident on emergency medical service times in Soma District, Japan: a retrospective observational study
Authors: Morita Tomohiro , Tsubokura Masaharu , Furutani Tomoyuki , Nomura Shuhei , Ochi Sae , Leppold Claire , Takahara Kazuhiro , Shimada Yuki , Fujioka Sho , Kami Masahiro , Kato Shigeaki , Oikawa Tomoyoshi
Published: September 2016

Objective

To assess the influence of the 3.11 triple disaster (earthquake, tsunami and nuclear accident) on the emergency medical service (EMS) system in Fukushima.

Methods

Total EMS time (from EMS call to arrival at a hospital) was assessed in the EMS system of Soma district, located 10–40 km north of the nuclear plant, from 11 March to 31 December 2011. We defined the affected period as when total EMS time was significantly extended after the disasters compared with the historical control data from 1 January 2009 to 10 March 2011. To identify risk factors associated with the extension of total EMS time after the disasters, we investigated trends in 3 time segments of total EMS time; response time, defined as time from an EMS call to arrival at the location, on-scene time, defined as time from arrival at the location to departure, and transport time, defined as time from departure from the location to arrival at a hospital.

Results

For the affected period from week 0 to week 11, the median total EMS time was 36 (IQR 27–52) minutes, while that in the predisaster control period was 31 (IQR 24–40) min. The percentage of transports exceeding 60 min in total EMS time increased from 8.2% (584/7087) in the control period to 22.2% (151/679) in the affected period. Among the 3 time segments, there was the most change in transport time (standardised mean difference: 0.41 vs 0.13–0.17).

Conclusions

EMS transport was significantly delayed for ∼3 months, from week 1 to 11 after the 3.11 triple disaster. This delay may be attributed to malfunctioning emergency hospitals after the triple disaster.
Improving Emergency Department flow through optimized bed utilization
Authors: Chartier Lucas Brien , Simoes Licinia , Kuipers Meredith , McGovern Barb
Published: September 2016

Over the last decade, patient volumes in the emergency department (ED) have grown disproportionately compared to the increase in staffing and resources at the Toronto Western Hospital, an academic tertiary care centre in Toronto, Canada. The resultant congestion has spilled over to the ED waiting room, where medically undifferentiated and potentially unstable patients must wait until a bed becomes available. The aim of this quality improvement project was to decrease the 90th percentile of wait time between triage and bed assignment (time-to-bed) by half, from 120 to 60 minutes, for our highest acuity patients. We engaged key stakeholders to identify barriers and potential strategies to achieve optimal flow of patients into the ED. We first identified multiple flow-interrupting challenges, including operational bottlenecks and cultural issues. We then generated change ideas to address two main underlying causes of ED congestion: unnecessary patient utilization of ED beds and communication breakdown causing bed turnaround delays. We subsequently performed seven tests of change through sequential plan-do-study-act (PDSA) cycles. The most significant gains were made by improving communication strategies: small gains were achieved through the optimization of in-house digital information management systems, while significant improvements were achieved through the implementation of a low-tech direct contact mechanism (a two-way radio or walkie-talkie). In the post-intervention phase, time-to-bed for the 90th percentile of high-acuity patients decreased from 120 minutes to 66 minutes, with special cause variation showing a significant shift in the weekly measurements.
Pediatric Intensive Care Unit rounding improvements
Authors: Beck Kirsten , Albert Elaine , Johnsen Andrew , Newhouse Courtney , McGuire John
Published: September 2016

Medical rounds in the Pediatric Intensive Care Unit (PICU) took about four hours each day to complete. The length of rounds was affecting the advancement of care of the patients, the engagement of sub-specialty providers who needed to be present on other rounds, and the engagement of the PICU faculty and staff due to overburdening waste created by the long duration of rounds.

Specific interventions were identified aimed at reducing the duration of rounds each day, increasing engagement of the rounding team and satisfying the needs of the patients and families. Post-improvement results were that rounding times were reduced to two hours each day and were pre-scheduled for families, the burden of excess work was lifted for attending physicians, and the presentation expectations during rounds were specified by role. Quality and safety were improved through standard work and auditing.
A request for euthanasia: advising a colleague
Authors: Knight Andrew
Published: September 2016

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.

In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘A request for euthanasia: advising a colleague’, was submitted and is discussed by Andrew Knight. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue. Discussion of the dilemma ‘Too hot to handle?’, which was published in the September issue of In Practice, appears on page 470.

The series is being coordinated by Steven McCulloch, a practising vet with a PhD in the ethics of veterinary policy. It is hoped it will provide a framework that will help practitioners find solutions when facing similar dilemmas.
Adherence to recommended UK sampling protocols for detecting mast cell mediator release in perioperative anaphylaxis
Authors: Egner William
Published: September 2016

Background

Sheffield National Adverse Reactions Consultancy Service (NARCOS) investigates and triages suspected perioperative anaesthetic reactions to allergy clinics, using serial tryptase samples, urinary methylhistamine and clinical information on a pro forma request.

Objective

To determine if current UK guidelines on serial tryptase samples are achieved and describe the patterns of tryptase release.

Method

A retrospective review of 3455 NARCOS cases. Tryptase and clinical details were analysed. 1746 had sufficient clinical information to grade the reactions according to the Ring and Messmer scale.

Results

98% provided two or more acute samples, but only 60% supplied clinical information. 308 patients never dropped within the reference range over three samples.

Conclusions

Good compliance with UK guidelines for tryptase measurements is achievable in this long-term cohort, but obtaining clinical details at referral remains a challenge. Sample sequence labelling and apparent timing may be misleading. Baseline tryptase may frequently need to be rechecked in allergy clinics to estimate true peak-to-trough changes.
Selling conscience short: a response to Schuklenk and Smalling on conscientious objections by medical professionals
Authors: Maclure Jocelyn , Dumont Isabelle
Published: September 2016

In a thought-provoking paper, Schuklenk and Smalling argue that no right to conscientious objection should be granted to medical professionals. First, they hold that it is impossible to assess either the truth of conscience-based claims or the sincerity of the objectors. Second, even a fettered right to conscientious refusal inevitably has adverse effects on the rights of patients. We argue that the main problem with their position is that it is not derived from a broader reflection on the meaning and implications of freedom of conscience and reasonable accommodation. We point out that they collapse two related but distinct questions, that is, the subjective conception of freedom of conscience and the sincerity test. We note that they do not successfully show that the standard norm according to which exemption claims should not impose undue hardship on others is unworkable. We suggest that the main reason why arguments such as no one is forced to be a medical professional are flawed is that public norms should not constrain citizens to choose between two of their basic rights unless it is necessary. In fine, Schuklenk and Smalling, who see conscience claims as arbitrary dislikes, sell freedom of conscience short and forego any attempts at balancing the competing rights involved. We maintain the authors neglect that most of legal reasoning is contextual and that the blanket restriction of healthcare professionals' freedom of conscience is disproportionate.
Remote aspiration thrombectomy in large vessel acute ischemic stroke
Authors: Haussen Diogo C , Bouslama Mehdi , Grossberg Jonathan A , Nogueira Raul G
Published: September 2016

The use of balloon guide catheters in acute ischemic stroke intervention has been associated with improved reperfusion rates and clinical outcomes. This technique acts by promoting flow arrest and subsequent reversal to capture the thrombus debris that may be generated during the clot retrieval process. However, to the best of our knowledge, the use of BGC to remotely aspirate and remove intracranial thrombus has not been previously described. We report a three case series of patients with acute ischemic stroke from supraclinoidal internal carotid artery occlusions treated with remote aspiration thrombectomy through a BGC placed at the cervical internal carotid artery, leading to complete reperfusion without the need for intracranial catheterization. Remote thrombectomy in the setting of intracranial internal carotid artery occlusion may constitute a relatively fast and inexpensive initial thrombectomy maneuver. Further investigation is warranted.
Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial
Authors: Strand Vibeke , Lee Eun Bong , Fleischmann Roy , Alten Rieke E , Koncz Tamas , Zwillich Samuel H , Gruben David , Wilkinson Bethanie , Krishnaswami Sriram , Wallenstein Gene
Published: September 2016

Objectives

To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX.

Methods

In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]).

Results

PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F.

Conclusions

Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier.

Trial registration number

NCT01039688.
Cancer immunotherapy-induced rheumatic diseases emerge as new clinical entities
Authors: Cappelli Laura C , Shah Ami A , Bingham Clifton O
Published: September 2016

Immune checkpoint inhibitors (ICIs) are newly approved treatments for advanced malignancies that are increasing survival. The mechanism of these drugs, non-specifically activating T cells, also leads to immune-mediated damage of tissue or immune-related adverse events (IRAE). IRAEs with rheumatic phenotypes are increasingly being recognised. Inflammatory arthritis, sicca syndrome, inflammatory myopathy, vasculitis and lupus nephritis have been described as a result of ICIs. Use of ICIs will be expanding in the coming years for several reasons. ICIs will be used in earlier stage cancer, for more indications, and additional drugs will be approved. The rheumatologist plays a critical role in evaluating and treating these patients. The expertise of rheumatologists in evaluating rheumatic signs and symptoms and treating patients with immunosuppression are critical in ensuring the optimal outcomes for patients with rheumatic IRAE. Collaboration between oncology and rheumatology for clinical care and research will enhance understanding of these new disease entities.
The Palaeogene Armathwaite–Cleveland Dyke in upper Teesdale, northern England: magnetic characteristics and relationship to mineralization
Authors: Searle Roger C. , Young Brian , Mwandoe Elijah
Published: September 2016

A magnetometer survey, conducted with the initial aim of delineating the extent of a magnetite-rich orebody within the Teesdale Fault in the Harwood Valley of Upper Teesdale, unexpectedly revealed a Palaeogene remanent magnetization. This is interpreted as reflecting the presence at depth of a hitherto unrecorded section of the Armathwaite–Cleveland Dyke, a member of the Palaeogene Mull Swarm of intrusions. The dyke has now been continuously mapped magnetically from the easternmost outcrop of its Armathwaite section in the South Tyne Valley, near Garrigill, to the westernmost outcrop of the Cleveland section in Ettersgill, Teesdale, where it follows the Teesdale Fault and undergoes a small dextral
en-échelon
offset. We retain the originally proposed mechanism for the formation of the orebody, by the interaction between Northern Pennine mineralizing fluids and the still hot, recently intruded Permo-Carboniferous Whin Sill and its contact rocks. We find no evidence of a wider distribution of ore, or of Permian magnetization. We conclude that the orebody was emplaced along the Teesdale fault and that its magnetic signature was thermally re-set during the Palaeogene intrusion.
Stratigraphy, sedimentology and structure of the Jurassic (Callovian to Lower Oxfordian) succession at Castle Hill, Scarborough, North Yorkshire, UK
Authors: Powell John H. , Riding James B.
Published: September 2016

Site investigation borehole cores and temporary shaft exposures at the Toll House Pumping Station shaft site, Castle Hill, Scarborough, North Yorkshire, have revealed new data on the Callovian to Lower Oxfordian (Jurassic) succession. The condensed transgressive marine unit, the Lower Callovian Cornbrash Formation, rich in berthierine ooids and abundant shelly fossils, and the attenuated Cayton Clay Formation represent the Early Callovian marine transgression that flooded the low-gradient alluvial plain, which is represented by the underlying Scalby Formation. The Callovian Osgodby Formation (Red Cliff Rock and Langdale members) is an extensively bioturbated, silty sandstone with abundant berthierine–pyrite ooids in the lower part. It was deposited in lower- to upper-shoreface settings. Slow sedimentation rates, with long sediment residence time, resulted in a diverse ichnofauna and a high bioturbation index. Framboidal pyrite ooids in the lower Osgodby Formation sandstones are interpreted as being formed in anoxic lagoons in the nearshore zone; ooids were subsequently swept offshore during storm surge-ebb events. Cold water dinoflagellate cysts of Boreal affinity such as
Gonyaulacysta dentata
in the lower part of the Oxford Clay Formation indicate an Early Oxfordian age. This is confirmed by the presence of the zonal ammonite species
Quenstedoceras mariae
and is consistent with a relatively cold, but warming, palaeoclimate at this time. Shaft excavations revealed a new major fault, the Toll House Fault, which is interpreted to be a splay fault bifurcating off the main Castle Hill Fault. Together, the Toll House and Castle Hill faults form the western bounding faults of the Peak Trough, a graben-like structure that extends northwards, offshore.

Supplementary material:
Supplementary data 1 (Macrofossil identifications from the Toll House shaft) and Supplementary data 2 (List of macropalaeontological specimens from the Toll House Boreholes) are available at
https://dx.doi.org/10.6084/m9.figshare.c.3469968
Petrogenesis of mafic magmatic enclaves of the Bundelkhand granitoids near Orchha, Central Indian shield: evidence for rapid crystallization
Authors: Ramiz Mir Md , Mondal M. E. A.
Published: September 2016

An attempt has been made to understand the origin and emplacement of the widespread mafic magmatic enclaves (MMEs) in the Neoarchean–Palaeoproterozoic Bundelkhand granitoids in the central Indian shield. These MMEs are very fine grained in texture, elliptical and ovoidal in shape and have a very sharp contact with the host granitoids. The MMEs exhibit sub-ophitic texture, acicular apatite and overgrowth of orthopyroxene over olivine crystals pointing towards a rapid crystallization of the MMEs magma in the granitoid magma. The host granitoids are calc-alkaline while the MMEs are tholeiitic, indicating contrasting geochemical composition. Low concentration of Rb, Sr, Ba and K in MMEs points away from the magma mixing with the granitoid magma. Both MMEs and host granitoids are metaluminous and are formed in a subduction zone environment. Although both MMEs and the granitoids were formed at the same time as the mafic magma was injected into the granitoid magma which was still crystallizing (semimolten stage), negligible to no mixing took place between the two contrasting magmas. We propose that the MMEs in the Bundelkhand granitoids are the result of rapid crystallization of the mafic magma in the cooler felsic one.
EarSketch
Authors: Magerko Brian , Freeman Jason , Mcklin Tom , Reilly Mike , Livingston Elise , Mccoid Scott , Crews-Brown Andrea
Published: September 2016

This article presents EarSketch, a learning environment that combines computer programming with sample-based music production to create a computational remixing environment for learning introductory computing concepts. EarSketch has been employed in both formal and informal settings, yielding significant positive results in student content knowledge and attitudes toward computing as a discipline, especially in ethnic and gender populations that are currently underrepresented in computing fields. This article describes the rationale and components of EarSketch, the evaluation design, and lessons learned to apply to future environment design and development.
Mining At Most Top-K% Spatiotemporal Co-occurrence Patterns in Datasets with Extended Spatial Representations
Authors: Pillai Karthik Ganesan , Angryk Rafal A. , Banda Juan M. , Kempton Dustin , Aydin Berkay , Martens Petrus C.
Published: September 2016

Spatiotemporal co-occurrence patterns (STCOPs) in datasets with extended spatial representations are two or more different event types, represented as polygons evolving in time, whose instances often occur together in both space and time. Finding STCOPs is an important problem in domains such as weather monitoring, wildlife migration, and solar physics. Nevertheless, in real life, it is difficult to find a suitable prevalence threshold without prior domain-specific knowledge. In this article, we focus our work on the problem of mining at most top-K% of STCOPs from continuously evolving spatiotemporal events that have polygon-like representations, without using a user-specified prevalence threshold.