bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal patterns of desiccation tolerance in natural populations ofDrosophila melanogaster
Authors: Rajpurohit Subhash , Gefen Eran , Bergland Alan , Petrov Dmitri , Gibbs Allen G , Schmidt Paul S
Published: October 2016

Water availability is a major environmental challenge to a variety of terrestrial organisms. In insects, desiccation tolerance varies predictably over various spatial and temporal scales and is an important physiological basis of fitness variation among natural populations. Here, we examine the dynamics of desiccation tolerance in North American populations ofDrosophila melanogasterusing: 1) natural populations sampled across latitudes and seasons in the eastern USA; 2) experimental evolution in the field in response to changing seasonal environments; 3) a sequenced panel of inbred lines (DGRP) to perform genome wide associations and examine whether SNPs/genes associated with variation in desiccation tolerance exhibit patterns of clinal and/or seasonal enrichment in pooled sequencing of populations. In natural populations we observed a shallow cline in desiccation tolerance, for which tolerance exhibited a positive association with latitude; the steepness of this cline increased with decreasing culture temperature, demonstrating a significant degree of thermal plasticity. No differences in desiccation tolerance were observed between spring and autumn collections from three mid-to-northern latitude populations, or as a function of experimental evolution to seasonality. Similarly, water loss rates did not vary significantly among latitudinal, seasonal or experimental evolution populations. However, changes in metabolic rates during prolonged exposure to dry conditions indicate increased tolerance in higher latitude populations. Genome wide association studies identified thirty-six SNPs in twenty-eight genes associated with sex-averaged drought tolerance. Among North American populations, genes associated with drought tolerance do not show increased signatures of spatially varying selection relative to the rest of the genome, whereas among Australian populations they do.
Accurate contact predictions for thousands of protein families using PconsC3
Authors: Skwark Marcin J. , Michel Mirco , Menéndez Hurtado David , Ekeberg Magnus , Elofsson Arne
Published: October 2016

Protein structure prediction was for decades one of the grand unsolved challenges in bioinformatics. A few years ago it was shown that by using a maximum entropy approach to describe couplings between columns in a multiple sequence alignment it was possible to significantly increase the accuracy of residue contact predictions. For very large protein families with more than 1000 effective sequences the accuracy is sufficient to produce accurate models of proteins as well as complexes. Today, for about half of all Pfam domain families no structure is known, but unfortunately most of these families have at most a few hundred members, i.e. are too small for existing contact prediction methods. To extend accurate contact predictions to the thousands of smaller protein families we present PconsC3, an improved method for protein contact predictions that can be used for families with as little as 100 effective sequence members. We estimate that PconsC3 provides accurate contact predictions for up to 4646 Pfam domain families. In addition, PconsC3 outperforms previous methods significantly independent on family size, secondary structure content, contact range, or the number of selected contacts. This improvement translates into improved de-novo prediction of three-dimensional structures. PconsC3 is available as a web server and downloadable version athttp://c3.pcons.net. The downloadable version is free for all to use and licensed under the GNU General Public License, version 2.
Behavior ofCaenorhabditis elegansin a nicotine gradient modulated by food
Authors: Sobkowiak Robert , Kaczmarek Piotr , Kowalski Mateusz , Kabaciński Rafał , Lesicki Andrzej
Published: October 2016

Nicotine decreases food intake, and smokers often report that they smoke to control their weight. To see whether similar phenomena could be observed in the model organismCaenorhabditis elegans, we challenged drug-naïve nematodes with a chronic low (0.01 mM) and high (1 mM) nicotine concentration for 55 h (from hatching to adulthood). After that, we recorded changes in their behavior in a nicotine gradient, where they could choose a desired nicotine concentration. By using a combination of behavioral and morphometric methods, we found that both nicotine and food modulate worm behavior. In the presence of food the nematodes adapted to the low nicotine concentration, when placed in the gradient, chose a similar nicotine concentration likeC. elegansadapted to the high nicotine concentration. However, in the absence of food, the nematodes adapted to the low nicotine concentration, when placed in the gradient of this alkaloid, chose a similar nicotine concentration like naïve worms. The nematodes growing up in the presence of high concentrations of nicotine had a statistically smaller body size, compared to the control condition, and the presence of food did not cause any enhanced slowing movement. These results provide a platform for more detailed molecular and cellular studies of nicotine addiction and food intake in this model organism.
Collider Scope: When selection bias can substantially influence observed associations
Authors: Munafò Marcus R. , Tilling Kate , Taylor Amy E. , Evans David M. , Davey Smith George
Published: October 2016

Large-scale cross-sectional and cohort studies have transformed our understanding of the genetic and environmental determinants of health outcomes. However, the representativeness of these samples may be limited – either through selection into studies, or by attrition from studies over time. Here we explore the potential impact of this selection bias on results obtained from these studies, from the perspective that this amounts to conditioning on a collider (i.e., a form of collider bias). While it is acknowledged that selection bias will have a strong effect on representativeness and prevalence estimates, it is often assumed that it should not have a strong impact on estimates of associations. We argue that because selection can induce collider bias (which occurs when two variables independently influence a third variable, and that third variable is conditioned upon), selection can lead to substantially biased estimates of associations. In particular, selection related to phenotypes can bias associations with genetic variants associated with those phenotypes. In simulations, we show that even modest influences on selection into, or attrition from, a study can generate biased and potentially misleading estimates of both phenotypic and genotypic associations. Our results highlight the value of knowing which population your study sample is representative of. If the factors influencing selection and attrition are known, they can be adjusted for. For example, having DNA available on most participants in a birth cohort study offers the possibility of investigating the extent to which polygenic scores predict subsequent participation, which in turn would enable sensitivity analyses of the extent to which bias might distort estimates.

Key Messages

Selection bias (including selective attrition) may limit the representativeness of large-scale cross-sectional and cohort studies.

This selection bias may induce collider bias (which occurs when two variables independently influence a third variable, and that variable is conditioned upon).

This may lead to substantially biased estimates of associations, including of genetic associations, even when selection / attrition is relatively modest.
PoGo: Jumping from Peptides to Genomic Loci
Authors: Schlaffner Christoph N. , Pirklbauer Georg , Bender Andreas , Choudhary Jyoti S.
Published: October 2016

Current tools for visualization and integration of proteomics with other omics datasets are inadequate for large-scale studies and capture only basic sequence identity information. We developed PoGo for mapping peptides identified through mass spectrometry to a reference genome to overcome these limitations. PoGo exhibited superior performance over other tools on benchmarking with large-scale human tissue and cancer phosphoproteome datasets. Additionally, extended functionality enables representation of single nucleotide variants, post-translational modifications and quantitative features.
Types of Migration: The Motivations, Composition, and Early Integration Patterns of “New Migrants” in Europe
Authors: Luthra Renee , Platt Lucinda , Salamońska Justyna
Published: October 2016

Applying latent class analysis to a unique data source of 3,500 Polish migrants in Western Europe, we develop a new typology of Polish migrants under “free movement” following the 2004 expansion of the European Union. We characterize these diverse migrant types in terms of their premigration characteristics and link them to varied early social and economic integration outcomes. We show that alongside traditional circular and temporary labor migration, European Union expansion has given rise to new migrant types who are driven by experiential concerns, resulting in a more complex relationship between their economic and social integration in destination countries.
The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer
Authors: Law Emily K. , Sieuwerts Anieta M. , LaPara Kelly , Leonard Brandon , Starrett Gabriel J. , Molan Amy M. , Temiz Nuri A. , Vogel Rachel Isaksson , Meijer-van Gelder Marion E. , Sweep Fred C. G. J. , Span Paul N. , Foekens John A. , Martens John W. M. , Yee Douglas , Harris Reuben S.
Published: October 2016

An antiviral enzyme promotes drug resistance in breast cancer.
Genomic Comparison of Campylobacter spp. and Their Potential for Zoonotic Transmission between Birds, Primates, and Livestock
Authors: Weis Allison M. , Storey Dylan B. , Taff Conor C. , Townsend Andrea K. , Huang Bihua C. , Kong Nguyet T. , Clothier Kristin A. , Spinner Abigail , Byrne Barbara A. , Weimer Bart C.
Published: October 2016

Campylobacter
is the leading cause of human gastroenteritis worldwide. Wild birds, including American crows, are abundant in urban, suburban, and agricultural settings and are likely zoonotic vectors of
Campylobacter
. Their proximity to humans and livestock increases the potential spreading of
Campylobacter
via crows between the environment, livestock, and humans. However, no studies have definitively demonstrated that crows are a vector for pathogenic
Campylobacter
. We used genomics to evaluate the zoonotic and pathogenic potential of
Campylobacter
from crows to other animals with 184 isolates obtained from crows, chickens, cows, sheep, goats, humans, and nonhuman primates. Whole-genome analysis uncovered two distinct clades of
Campylobacter jejuni
genotypes; the first contained genotypes found only in crows, while a second genotype contained “generalist” genomes that were isolated from multiple host species, including isolates implicated in human disease, primate gastroenteritis, and livestock abortion. Two major β-lactamase genes were observed frequently in these genomes (
oxa-184
, 55%, and
oxa-61
, 29%), where
oxa-184
was associated only with crows and
oxa-61
was associated with generalists. Mutations in
gyrA
, indicative of fluoroquinolone resistance, were observed in 14% of the isolates. Tetracycline resistance (
tetO
) was present in 22% of the isolates, yet it occurred in 91% of the abortion isolates. Virulence genes were distributed throughout the genomes; however,
cdtC
alleles recapitulated the crow-only and generalist clades. A specific
cdtC
allele was associated with abortion in livestock and was concomitant with
tetO
. These findings indicate that crows harboring a generalist
C. jejuni
genotype may act as a vector for the zoonotic transmission of
Campylobacter
.

IMPORTANCE
This study examined the link between public health and the genomic variation of
Campylobacter
in relation to disease in humans, primates, and livestock. Use of large-scale whole-genome sequencing enabled population-level assessment to find new genes that are linked to livestock disease. With 184
Campylobacter
genomes, we assessed virulence traits, antibiotic resistance susceptibility, and the potential for zoonotic transfer to observe that there is a “generalist” genotype that may move between host species.
Genetic Diversity and Origins of the Homoploid-Type Hybrid
Phytophthora ×alni
Authors: Aguayo Jaime , Halkett Fabien , Husson Claude , Nagy Zoltán Á. , Szigethy András , Bakonyi József , Frey Pascal , Marçais Benoit
Published: October 2016

Assessing the process that gives rise to hybrid pathogens is central to understanding the evolution of emerging plant diseases.
Phytophthora ×alni
, a pathogen of alder, results from the homoploid hybridization of two related species,
Phytophthora uniformis
and
Phytophthora
×
multiformis
. Describing the genetic characteristics of
P
. ×
alni
should help us understand how reproductive mechanisms and historical processes shaped the population structure of this emerging hybrid pathogen. The population genetic structure of
P
. ×
alni
and the relationship with its parental species were investigated using 12 microsatellites and one mitochondrial DNA (mtDNA) marker on a European collection of 379 isolates. Populations of
P
. ×
alni
were dominated by one multilocus genotype (MLG). The frequency of this dominant MLG increased after the disease emergence together with a decline in diversity, suggesting that it was favored by a genetic mechanism such as drift or selection. Combined microsatellite and mtDNA results confirmed that
P
. ×
alni
originated from multiple hybridization events that involved different genotypes of the progenitors. Our detailed analyses point to a geographic structure that mirrors that observed for
P. uniformis
in Europe. The study provides more insights on the contribution of
P. uniformis
, an invasive species in Europe, to the emergence of
Phytophthora
-induced alder decline.

IMPORTANCE
Our study describes an original approach to assess the population genetics of polyploid organisms using microsatellite markers. By studying the parental subgenomes present in the interspecific hybrid
P. ×alni
, we were able to assess the geographical and temporal structure of European populations of the hybrid, shedding new light on the evolution of an emerging plant pathogen. In turn, the study of the parental subgenomes permitted us to assess some genetic characteristics of the parental species of
P. ×alni
,
P. uniformis
, and
P
. ×
multiformis
, which are seldom sampled in nature. The subgenomes found in
P. ×alni
represent a picture of the “fossilized” diversity of the parental species.
The Surface-Associated Exopolysaccharide of Bifidobacterium longum 35624 Plays an Essential Role in Dampening Host Proinflammatory Responses and Repressing Local T
H
17 Responses
Authors: Schiavi Elisa , Gleinser Marita , Molloy Evelyn , Groeger David , Frei Remo , Ferstl Ruth , Rodriguez-Perez Noelia , Ziegler Mario , Grant Ray , Moriarty Thomas Fintan , Plattner Stephan , Healy Selena , O'Connell Motherway Mary , Akdis Cezmi A. , Roper Jennifer , Altmann Friedrich , van Sinderen Douwe , O'Mahony Liam
Published: October 2016

The immune-modulating properties of certain bifidobacterial strains, such as
Bifidobacterium longum
subsp.
longum
35624 (
B. longum
35624), have been well described, although the strain-specific molecular characteristics associated with such immune-regulatory activity are not well defined. It has previously been demonstrated that
B. longum
35624 produces a cell surface exopolysaccharide (sEPS), and in this study, we investigated the role played by this exopolysaccharide in influencing the host immune response.
B. longum
35624 induced relatively low levels of cytokine secretion from human dendritic cells, whereas an isogenic exopolysaccharide-negative mutant derivative (termed sEPS
neg
) induced vastly more cytokines, including interleukin-17 (IL-17), and this response was reversed when exopolysaccharide production was restored in sEPS
neg
by genetic complementation. Administration of
B. longum
35624 to mice of the T cell transfer colitis model prevented disease symptoms, whereas sEPS
neg
did not protect against the development of colitis, with associated enhanced recruitment of IL-17
+
lymphocytes to the gut. Moreover, intranasal administration of sEPS
neg
also resulted in enhanced recruitment of IL-17
+
lymphocytes to the murine lung. These data demonstrate that the particular exopolysaccharide produced by
B. longum
35624 plays an essential role in dampening proinflammatory host responses to the strain and that loss of exopolysaccharide production results in the induction of local T
H
17 responses.

IMPORTANCE
Particular gut commensals, such as
B. longum
35624, are known to contribute positively to the development of mucosal immune cells, resulting in protection from inflammatory diseases. However, the molecular basis and mechanisms for these commensal-host interactions are poorly described. In this report, an exopolysaccharide was shown to be decisive in influencing the immune response to the bacterium. We generated an isogenic mutant unable to produce exopolysaccharide and observed that this mutation caused a dramatic change in the response of human immune cells
in vitro
. In addition, the use of mouse models confirmed that lack of exopolysaccharide production induces inflammatory responses to the bacterium. These results implicate the surface-associated exopolysaccharide of the
B. longum
35624 cell envelope in the prevention of aberrant inflammatory responses.
Sulfur-oxidizing bacteria prior to the Great Oxidation Event from the 2.52 Ga Gamohaan Formation of South Africa
Authors: Czaja Andrew D. , Beukes Nicolas J. , Osterhout Jeffrey T.
Published: October 2016

The first 2 b.y. of Earth’s history was an important time for life when microbes evolved and diversified into essentially all of the metabolic forms that now exist. Because of feedbacks between biology and the surface environment, understanding Earth’s biological history can help us understand the evolution of Earth itself. The morphological and geochemical evidence for this ancient biological history is sparse but is increasing. Here we report evidence for 2.52 Ga exceptionally large, organic, smooth-walled, coccoidal microfossils preserved in a deep-water black chert in the Gamohaan Formation of the Kaapvaal craton of South Africa. These fossils occur mainly as compressed solitary coccoids that range in size from 20 to 265 µm but occasionally occur in short chains of cells. Morphologically these fossils are similar to Proterozoic and Phanerozoic acritarchs and to certain Archean fossils interpreted as possible cyanobacteria. However, their exceptionally large size, simple cell wall microstructure, and paleoecological setting, as well as multiple sulfur isotope systematics of pyrite within the unit, suggest that the Gamohaan Formation fossils were sulfur-oxidizing bacteria similar to those of the modern genus Thiomargarita, organisms that live in anoxic and sulfidic deep-water settings. These are the oldest reported fossil sulfur bacteria and reveal a diversity of life and ecosystems, previously only interpreted from geochemical proxies, just prior to the Great Oxidation Event, a time of major atmospheric evolution.
Luxatio erecta humeri with neurovascular compromise: inferior glenohumeral dislocation illustrating associated injuries
Authors: Owen David , Nambiar Mithun , Moore Peter , Thomas Malcolm
Published: October 2016

Luxatio erecta humeri (LEH) is a rare type of shoulder dislocation in which the humeral head becomes trapped beneath the glenoid. Patients present with the arm in a fixed hyperabducted position. LEH is estimated to occur in 0.5% of all shoulder dislocations, most often caused by trauma and has a significant association with local bone, ligament and less frequently neurovascular injury. We present a case with initial neurovascular compromise and sustained neurological impairment at long-term follow-up. Urgent closed reduction is advocated and subsequent treatment is dependent on associated injuries.
Dimensions of tinnitus-related complaints reported by patients and their significant others: protocol for a systematic review
Authors: Haider Haúla , Fackrell Kathryn , Kennedy Veronica , Hall Deborah A
Published: October 2016

Introduction

Over 70 million people in Europe and >50 million people in the USA are reported to experience tinnitus (the sensation of noise in the absence of any corresponding sound source). Tinnitus is a multidimensional concept. Individual patients may report different profiles of tinnitus-related symptoms which may each require a tailored management approach and an appropriate measure of therapeutic benefit. This systematic review concerns the patient perspective and has the purpose to find what symptoms are reported by people who experience tinnitus and by their significant others.

Methods and analysis

This protocol lays out the methodology to define what dimensions of tinnitus-related symptoms patients and their significant others report as being a problem. Methods are defined according to the Preferred Reporting Items for Systematic reviews and Meta-analyses for Protocols (PRISMA-P) 2015 and data will be collated in a narrative synthesis. Findings will contribute to the eventual establishment of a Core Domain Set for clinical trials of tinnitus.

Ethics and dissemination

No ethical issues are foreseen. Findings will be reported at national and international ENT and audiology conferences and in a peer-reviewed journal.

Trial registration number

CRD42015020629.
Community-randomised controlled trial embedded in the Anishinaabek Cervical Cancer Screening Study: human papillomavirus self-sampling versus Papanicolaou cytology
Authors: Zehbe Ingeborg , Jackson Robert , Wood Brianne , Weaver Bruce , Escott Nicholas , Severini Alberto , Krajden Mel , Bishop Lisa , Morrisseau Kyla , Ogilvie Gina , Burchell Ann N , Little Julian
Published: October 2016

Objectives

The incidence of cervical cancer is up to 20-fold higher among First Nations women in Canada than the general population, probably due to lower participation in screening. Offering human papillomavirus (HPV) self-sampling in place of Papanicolaou (Pap) testing may eventually increase screening participation and reduce cervical cancer rates in this population.

Design

A community-randomised controlled screening trial.

Setting

First Nations communities in Northwest Ontario, Canada.

Participants

Women aged between 25 and 69, living in Robinson Superior Treaty First Nations. The community was the unit of randomisation.

Interventions

Women were asked to complete a questionnaire and have screening by HPV self-sampling (arm A) or Pap testing (arm B).

Primary outcome measures

The number of women who participated in cervical screening.

Randomisation

Community clusters were randomised to include approximately equivalent numbers of women in each arm.

Results

6 communities were randomised to arm A and 5 to arm B. One community withdrew, leaving 5 communities in each group (834 eligible women). Participation was <25%. Using clustered intention-to-treat (ITT) analysis, initial and cumulative averaged uptakes in arm A were 1.4-fold (20% vs 14.3%, p=0.628) and 1.3-fold (20.6% vs 16%, p=0.694) higher compared to arm B, respectively. Corresponding per protocol (PP) analysis indicates 2.2-fold (22.9% vs 10.6%, p=0.305) and 1.6-fold (22.9% vs 14.1%, p=0.448) higher uptakes in arm A compared to arm B. Screening uptake varied between communities (range 0–62.1%). Among women who completed a questionnaire (18.3% in arm A, 21.7% in arm B), the screening uptake was 1.8-fold (ITT; p=0.1132) or 3-fold (PP; p<0.01) higher in arm A versus arm B.

Conclusions

Pap and HPV self-sampling were compared in a marginalised, Canadian population. Results indicated a preference for self-sampling. More research on how to reach underscreened Indigenous women is necessary.

Trial registration number

ISRCTN84617261.
Age and sex differences in hospitalisation of nursing home residents: a systematic review
Authors: Hoffmann Falk , Allers Katharina
Published: October 2016

Objectives

Nursing home residents (NHRs) are frequently suffering from multimorbidity, functional and cognitive impairment, often leading to hospital admissions. Studies have found that male NHRs are more often hospitalised. The influence of age is inconclusive. We aimed to investigate the epidemiology of hospitalisations in NHRs, particularly focusing on age-specific and sex-specific differences.

Design

A systematic review was performed in PubMed, CINAHL and Scopus. Quality of studies was assessed.

Setting

Studies conducted in nursing homes were included.

Participants

Nursing home residents.

Primary and secondary outcomes

Outcome measures were the prevalence, incidence or duration of all-cause hospitalisation by age or sex.

Results

We identified 21 studies, 13 were conducted in the USA. The proportion of residents being hospitalised ranged across studies from 6.8% to 45.7% for various time periods of follow-up. A total of 20 studies assessed the influence of sex and found that hospitalisations are more often in male NHRs. A total of 16 studies conducted multivariate analyses and the OR of hospitalisation for males was between 1.22 and 1.67. Overall, 18 studies assessed the influence of age. Some studies showed an increasing proportion of admissions with increasing age, but several studies also found decreasing hospitalisations above the age of about 80–85 years. 8 of 13 studies conducting multivariate analyses included age as a continuous variable. Only 1 study reported stratified analyses by age and sex. 2 studies investigating primary causes of hospitalisation stratified by sex found some differences in main diagnoses.

Discussion

Male NHRs are more often hospitalised than females, but reasons for that are not well investigated. The influence of age is less clear, but there seems to be no clear linear relationship between age and the proportion being hospitalised. Further studies should investigate age and sex differences in frequencies and reasons for hospitalisation in NHRs.
Increasing the uptake of long-acting reversible contraception in general practice: the Australian Contraceptive ChOice pRoject (ACCORd) cluster randomised controlled trial protocol
Authors: Mazza Danielle , Black Kirsten , Taft Angela , Lucke Jayne , McGeechan Kevin , Haas Marion , McKay Heather , Peipert Jeffery F
Published: October 2016

Introduction

The increased use of long-acting reversible contraceptives (LARCs), such as intrauterine devices and hormonal implants, has the potential to reduce unintended pregnancy and abortion rates. However, use of LARCs in Australia is very low, despite clinical practice guidance and statements by national and international peak bodies advocating their increased use. This protocol paper describes the Australian Contraceptive ChOice pRojet (ACCORd), a cluster randomised control trial that aims to test whether an educational intervention targeting general practitioners (GPs) and establishing a rapid referral service are a cost-effective means of increasing LARC uptake.

Methods and analysis

The ACCORd intervention is adapted from the successful US Contraceptive CHOICE study and involves training GPs to provide ‘LARC First’ structured contraceptive counselling to women seeking contraception, and implementing rapid referral pathways for LARC insertion. Letters of invitation will be sent to 600 GPs in South-Eastern Melbourne. Using randomisation stratified by whether the GP inserts LARCs or not, a total of 54 groups will be allocated to the intervention (online ‘LARC First’ training and rapid referral pathways) or control arm (usual care). We aim to recruit 729 women from each arm. The primary outcome will be the number of LARCs inserted; secondary outcomes include the women's choice of contraceptive method and quality of life (Short Form Health Survey, SF-36). The costs and outcomes of the intervention and control will be compared in a cost-effectiveness analysis.

Ethics and dissemination

The ACCORd study has been approved by the Monash University Human Research Ethics Committee: CF14/3990-2014002066 and CF16/188-2016000080. Any protocol modifications will be communicated to Ethics Committee and Trial Registration registry. The authors plan to disseminate trial outcomes through formal academic pathways comprising journal articles, nation and international conferences and reports, as well as using more ‘popular’ strategies including seminars, workshops and media engagements.

Trial registration number

ACTRN12615001346561.
Detection of HPV subtypes by mass spectrometry in FFPE tissue specimens: a reliable tool for routine diagnostics
Authors: Kriegsmann Mark , Wandernoth Petra , Lisenko Katharina , Casadonte Rita , Longuespée Rémi , Arens Norbert , Kriegsmann Jörg
Published: October 2016

Aims

Human papilloma virus (HPV) infection is a causative agent for approximately 5% of all new cancer cases in humans. The virus is detected in cervical, anal, vaginal, penile, vulvar and head and neck cancers and has prognostic implications. Thus, test systems are required to detect high-risk but also low-risk HPV subtypes with high specificity and sensitivity in a time-effective and cost-effective manner. In the present study we developed a new mass spectrometry (MS)-based test system for the detection of HPV infections in formalin-fixed paraffin-embedded (FFPE) tissue samples.

Methods

A high-throughput matrix-assisted laser desorption ionisation time of flight MS-based assay was applied to genotype 19 HPV types in FFPE tissue specimens (n=46). The results from the MS assay were compared with the results obtained from two hybridisation-based test systems: the HPV 3.5 LCD-array kit and the EuroArrayHPV system.

Results

In 36 out of 46 (78%) tissue samples, a HPV infection could be detected by the MS-based HPV assay. In 16 samples (44%) only one and in 20 samples (56%) two to six HPV subtypes were identified. The overall agreement of all three assays was almost perfect (Cohen's k value: 0.83).

Conclusions

The MS-based assay is highly sensitive, reliable as well as cost-effective and represents a suitable technology for the detection of HPV infections in FFPE tissue material.
Unintentional injury in England: an analysis of the emergency care data set pilot in Oxfordshire from 2012 to 2014
Authors: Kirkwood Graham , Hughes Thomas C , Pollock Allyson M
Published: October 2016

Background

A pilot injury data collection exercise at the emergency departments (EDs) of Oxford University Hospitals National Health Service (NHS) Foundation Trust (OUH) ran from 2012 to 2014 to inform the current development of the new NHS England emergency care data set.

Methods

Data collected at the EDs of OUH 1 January 2012 to 30 March 2014 analysed for Oxford City and Cherwell District Council areas. Data completeness and quality checked against Hospital Episode Statistic (HES) returns.

Results

Of the 63 877 injury attendances recorded at the 2 sites, 26 536 were unintentional with a home postcode within Oxford City or Cherwell District Council areas. The most frequent location, mechanism, activity and diagnosis were home (39.1% of all unintentional injuries (UIs)), low-level falls (47.1%), leisure (31.1%) and ‘injuries to unspecified part of trunk, limb or body region’ (20.5%), respectively. The most deprived quintile of the population (Index of Multiple Deprivation (IMD) 1) had the highest European Age Standardised Rate (EASR) for all UIs and IMD 5 had the lowest, 54.4 (95% CI 52.3 to 56.5) and 32.2 (31.4 to 33.0) per 1000 person-years, respectively. There was a significant association between increasing levels of deprivation and an increasing incidence rate ratio (IRR) for all UIs, for those in the home, for low-level fall UIs and for non-sport leisure UIs with a particularly sharp increase in the IRR for IMD 1 compared with IMD 5. Sport-related injuries were inversely related to deprivation apart from football.

Conclusions

This pilot has demonstrated both the feasibility and importance of prioritising the collection of a national injury data set.
Republished: A rare case of absent left common carotid artery with bovine origin of the left external carotid artery
Authors: Goyal Sumit , Sinha Ajit Kumar
Published: October 2016

A 22-year-old man had cerebral venous sinus thrombosis and his angiogram incidentally revealed an absent left common carotid artery with bovine origin of the left external carotid artery. There was also an associated low bifurcation of the right common carotid artery and basilar artery fenestration. The absence of a common carotid artery is a very rare angiographic finding, and an association with a bovine origin of the left external carotid artery has not been reported previously in the literature. Here we provide a description of the case along with a review of the literature and embryology.
Common toxidromes in movement disorder neurology
Authors: Malek N , Baker M R
Published: October 2016

Background

Physicians can come across patients who are exposed to certain prescription drugs or toxins that can result in adverse effects and complications which have high rates of morbidity and mortality.

Objective

To summarise the key clinical features and management of the common movement disorder toxidromes relevant to physicians (with an interest in neurology).

Methods

We searched PUBMED from 1946 to 2016 for papers relating to movement toxidromes and their treatment. The findings from those studies were then summarised and are presented here.

Results

The key features of 6 of the common movement disorder toxidromes and their treatment are tabulated and highlighted. The management of toxidromes with the highest mortality like neuroleptic malignant syndrome and serotonin syndrome are discussed in detail.

Conclusion

There are several toxidromes that have the potential to become a serious life-threatening emergency if there is a delay in recognition of key clinical features and instituting the appropriate treatment at the earliest is crucial.
Taking care of volunteers in a stroke trial: a new assisted-management strategy
Authors: Stuart Amber C , Sico Jason J , Viscoli Catherine M , Tayal Ashis H , Inzucchi Silvio E , Ford Gary A , Furie Karen L , Cote Robert , Spence J David , Tanne David , Kernan Walter N
Published: October 2016

Background and purpose

Providing participants with evidence-based care for secondary prevention is an ethical and scientific priority for trials in stroke therapy. The optimal strategy, however, is uncertain. We report the performance of a new approach for delivering preventive care to trial participants.

Methods

Participants were enrolled in the Insulin Resistance Intervention after Stroke trial, which examined the insulin sensitiser, pioglitazone versus placebo for prevention of stroke and myocardial infarction after ischaemic stroke or transient ischaemic attack. Preventive care was the responsibility of the participants’ personal healthcare providers, but investigators monitored care and provided feedback annually. We studied achievement of 8 prevention goals at baseline and 3 annual visits, with a focus on 3 priority goals: blood pressure <140/90 mm Hg, low-density lipoprotein (LDL) cholesterol <2.59 mmol/L and antithrombotic therapy.

Results

The proportion of participants achieving the priority goals was highest for antithrombotic use (96–99% in each year) and similar for blood pressure (66–72% in each year) and LDL (68–70% in each year). All 3 priority goals were achieved by 47–52% of participants in any given year. However, only 22% of participants achieved all 3 goals in each year.

Conclusions

A strategy of monitoring care and providing feedback was associated with high average yearly achievement of 3 priority secondary prevention goals, but the majority of trial participants did not persist in being at goal over time.

Trial registration number

NCT00091949.
Spontaneous initiation of premature ventricular complexes and arrhythmias in type 2 long QT syndrome
Authors: Huang Xiaodong , Kim Tae Yun , Koren Gideon , Choi Bum-Rak , Qu Zhilin
Published: October 2016

The occurrence of early afterdepolarizations (EADs) and increased dispersion of repolarization are two known factors for arrhythmogenesis in long QT syndrome. However, increased dispersion of repolarization tends to suppress EADs due to the source-sink effect, and thus how the two competing factors cause initiation of arrhythmias remains incompletely understood. Here we used optical mapping and computer simulation to investigate the mechanisms underlying spontaneous initiation of arrhythmias in type 2 long QT (LQT2) syndrome. In optical mapping experiments of transgenic LQT2 rabbit hearts under isoproterenol, premature ventricular complexes (PVCs) were observed to originate from the steep spatial repolarization gradient (RG) regions and propagated unidirectionally. The same PVC behaviors were demonstrated in computer simulations of tissue models of rabbits. Depending on the heterogeneities, these PVCs could lead to either repetitive focal excitations or reentry without requiring an additional vulnerable substrate. Systematic simulations showed that cellular phase 2 EADs were either suppressed or confined to the long action potential region due to the source-sink effect. Tissue-scale phase 3 EADs and PVCs occurred due to tissue-scale dynamical instabilities caused by RG and enhanced L-type calcium current ( ICa,L), occurring under both large and small RG. Presence of cellular EADs was not required but potentiated PVCs when RG was small. We also investigated how other factors affect the dynamical instabilities causing PVCs. Our main conclusion is that tissue-scale dynamical instabilities caused by RG and enhanced ICa,Lgive rise to both the trigger and the vulnerable substrate simultaneously for spontaneous initiation of arrhythmias in LQT2 syndrome.
MicroRNA-29c regulates apoptosis sensitivity via modulation of the cell-surface death receptor, Fas, in lung fibroblasts
Authors: Matsushima Shingo , Ishiyama Junichi
Published: October 2016

MicroRNAs play an important role in the development and progression of various diseases, such as idiopathic pulmonary fibrosis (IPF). Although the accumulation of aberrant fibroblasts resistant to apoptosis is a hallmark in IPF lungs, the mechanism regulating apoptosis susceptibility is not fully understood. Here, we investigated the role of miR-29, which is the most downregulated microRNA in IPF lungs and is also known as a regulator of extracellular matrix (ECM), in the mechanism of apoptosis resistance. We found that functional inhibition of miR-29c caused resistance to Fas-mediated apoptosis in lung fibroblasts. Furthermore, experiments using miR-29c inhibitor and miR-29c mimic revealed that miR-29c regulated expression of the death receptor, Fas, and formation of death-inducing signaling complex leading to extrinsic apoptosis. The representative profibrotic transforming growth factor (TGF)-β downregulated the expression of miR-29c as well as Fas receptor and conferred resistance to apoptosis. We also found that introduction of miR-29c mimic abrogated these TGF-β-induced phenotypes of Fas repression and apoptosis resistance. The results presented here suggest that downregulation of miR-29 observed in IPF lungs may be associated with the apoptosis-resistant phenotype of IPF lung fibroblasts via downregulation of Fas receptor. Therefore, restoration of miR-29 expression in IPF lungs could not only inhibit the accumulation of ECM but also normalize the sensitivity to apoptosis in lung fibroblasts, which may be an effective strategy for treatment of IPF.
The effect of endothelin A and B receptor blockade on cutaneous vascular and sweating responses in young men during and following exercise in the heat
Authors: Fujii Naoto , Singh Maya S. , Halili Lyra , Louie Jeffrey C. , Kenny Glen P.
Published: October 2016

During exercise, cutaneous vasodilation and sweating responses occur, whereas these responses rapidly decrease during postexercise recovery. We hypothesized that the activation of endothelin A (ETA) receptors, but not endothelin B (ETB) receptors, attenuate cutaneous vasodilation during high-intensity exercise and contribute to the subsequent postexercise suppression of cutaneous vasodilation. We also hypothesized that both receptors increase sweating during and following high-intensity exercise. Eleven men (24 ± 4 yr) performed an intermittent cycling protocol consisting of two 30-min bouts of moderate- (40% V̇o2peak) and high-intensity (75% V̇o2peak) exercise in the heat (35°C), each separated by a 20- and 40-min recovery period, respectively. Cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal microdialysis skin sites: 1) lactated Ringer (control), 2) 500 nM BQ123 (a selective ETA receptor blocker), 3) 300 nM BQ788 (a selective ETB receptor blocker), or 4) a combination of BQ123 + BQ788. There were no between-site differences in CVC during each exercise bout (all P > 0.05); however, CVC following high-intensity exercise was greater at BQ123 (56 ± 9%max) and BQ123 + BQ788 (55 ± 14%max) sites relative to the control site (43 ± 12%max) (all P ≤ 0.05). Sweat rate did not differ between sites throughout the protocol (all P > 0.05). We show that neither ETA nor ETB receptors modulate cutaneous vasodilation and sweating responses during and following moderate- and high-intensity exercise in the heat, with the exception that ETA receptors may partly contribute to the suppression of cutaneous vasodilation following high-intensity exercise.
Peptide affinity analysis of proteins that bind to an unstructured region containing the transactivating domain of the osmoprotective transcription factor NFAT5
Authors: Dumond Jenna F. , Zhang Xue , Izumi Yuichiro , Ramkissoon Kevin , Wang Guanghui , Gucek Marjan , Wang Xujing , Burg Maurice B. , Ferraris Joan D.
Published: October 2016

NFAT5 is a transcription factor originally identified because it is activated by hypertonicity and that activation increases expression of genes that protect against the adverse effects of the hypertonicity. However, its targets also include genes not obviously related to tonicity. The transactivating domain of NFAT5 is contained in its COOH-terminal region, which is predicted to be unstructured. Unstructured regions are common in transcription factors particularly in transactivating domains where they can bind co-regulatory proteins essential to their function. To identify potential binding partners of NFAT5 from either cytoplasmic or nuclear HEK293 cell extracts, we used peptide affinity chromatography followed by mass spectrometry. Peptide aptamer-baits consisted of overlapping 20 amino acid peptides within the predicted COOH-terminal unstructured region of NFAT5. We identify a total of 351 unique protein preys that associate with at least one COOH-terminal peptide bait from NFAT5 in either cytoplasmic or nuclear extracts from cells incubated at various tonicities (NaCl varied). In addition to finding many proteins already known to associate with NFAT5, we found many new ones whose function suggest novel aspects of NFAT5 regulation, interaction, and function. Relatively few of the proteins pulled down by peptide baits from NFAT5 are generally involved in transcription, and most, therefore, are likely to be specifically related to the regulation of NFAT5 or its function. The novel associated proteins are involved with cancer, effects of hypertonicity on chromatin, development, splicing of mRNA, transcription, and vesicle trafficking.
Stent Thrombosis Patients with Hyporesponsiveness to Clopidogrel, Prasugrel, and Ticagrelor: A Case Series Using Short Thromboelastography
Authors: Olechowski Bartosz , Ashby Alexander , Sambu Nalyaka , Mahmoudi Michael , Curzen Nick
Published: October 2016

Patients after percutaneous coronary intervention (PCI) with stent implantation and functional hyporesponsiveness to P2Y12inhibitors are at higher risk of ischaemic events, particularly stent thrombosis (ST). It is currently not routine practice to assess the functional response to these agents. However, concern over functional hyporesponsiveness to clopidogrel has led to widespread uptake of prasugrel and ticagrelor as the default P2Y12inhibitor after stent implantation in patients with acute coronary syndrome. Here we report, for the first time, 3 cases in which patients who have had ST exhibit hyporesponsiveness to clopidogrel, prasugrel, and ticagrelor.
Clinical Characteristics and Short-Term Outcomes of HIV Patients Admitted to an African Intensive Care Unit
Authors: Kwizera Arthur , Nabukenya Mary , Peter Agaba , Semogerere Lameck , Ayebale Emmanuel , Katabira Catherine , Kizito Samuel , Nantume Cecilia , Clarke Ian , Nakibuuka Jane
Published: October 2016

Purpose. In high-income countries, improved survival has been documented among intensive care unit (ICU) patients infected with human immune deficiency virus (HIV). There are no data from low-income country ICUs. We sought to identify clinical characteristics and survival outcomes among HIV patients in a low-income country ICU.Materials and Methods. A retrospective cohort study of HIV infected patients admitted to a university teaching hospital ICU in Uganda. Medical records were reviewed. Primary outcome was survival to hospital discharge. Statistical significance was predetermined in reference toP<0.05.Results. There were 101 HIV patients. Average length of ICU stay was 4 days and ICU mortality was 57%. Mortality in non-HIV patients was 28%. Commonest admission diagnoses were Acute Respiratory Distress Syndrome (ARDS) (58.4%), multiorgan failure (20.8%), and sepsis (20.8%). The mean Acute Physiologic and Chronic Health Evaluation (APACHE II) score was 24. At multivariate analysis, APACHE II (OR 1.24 (95% CI: 1.1–1.4,P=0.01)), mechanical ventilation (OR 1.14 (95% CI: 0.09–0.76,P=0.01)), and ARDS (OR 4.5 (95% CI: 1.07–16.7,P=0.04)) had a statistically significant association with mortality.Conclusion. ICU mortality of HIV patients is higher than in higher income settings and the non-HIV population. ARDS, APACHE II, and need for mechanical ventilation are significantly associated with mortality.
Molecular Cues Guiding Matrix Stiffness in Liver Fibrosis
Authors: Saneyasu Takaoki , Akhtar Riaz , Sakai Takao
Published: October 2016

Tissue and matrix stiffness affect cell properties during morphogenesis, cell growth, differentiation, and migration and are altered in the tissue remodeling following injury and the pathological progression. However, detailed molecular mechanisms underlying alterations of stiffnessin vivoare still poorly understood. Recent engineering technologies have developed powerful techniques to characterize the mechanical properties of cell and matrix at nanoscale levels. Extracellular matrix (ECM) influences mechanical tension and activation of pathogenic signaling during the development of chronic fibrotic diseases. In this short review, we will focus on the present knowledge of the mechanisms of how ECM stiffness is regulated during the development of liver fibrosis and the molecules involved in ECM stiffness as a potential therapeutic target for liver fibrosis.