bluuebunny/crossref_metadata_2025 huggingface dataset:
Hybrid Shiga Toxin-Producing and Enterotoxigenic Escherichia sp. Cryptic Lineage 1 Strain 7v Harbors a Hybrid Plasmid
Authors: Leonard Susan R. , Mammel Mark K. , Rasko David A. , Lacher David W.
Published: May 2016

Hybrid isolates of Shiga toxin-producing
Escherichia coli
(STEC) and enterotoxigenic
E. coli
(ETEC) encoding heat-stable enterotoxin (ST) are being reported with increasing frequency from a variety of sources. However, information regarding the plasmids that these strains harbor is scarce. In this study, we sequence and characterize a plasmid, p7v, from the STEC/ETEC hybrid strain 7v. Whole-genome phylogenetic analyses of STEC/ETEC hybrid strains and prototype
E. coli
isolates of other pathotypes placed 7v in the
Escherichia
sp. cryptic lineage 1 (CL1) clade. The complete plasmid, p7v, was determined to be 229,275 bp and encodes putative virulence factors that are typically carried on STEC plasmids as well as those often carried on ETEC plasmids, indicating that the hybrid nature of the strain extends beyond merely encoding the two toxins. Plasmid p7v carries two copies of
sta
with identical sequences, which were discovered to be divergent from the
sta
sequences found in the prototype human ETEC strains. Using a nomenclature scheme based on a phylogeny constructed from
sta
and
stb
sequences, the
sta
encoded on p7v is designated STa4.
In silico
analysis determined that p7v also encodes the K88 fimbria, a colonization factor usually associated with porcine ETEC plasmids. The p7v sequence and the presence of plasmid-encoded virulence factors are compared to those of other STEC/ETEC CL1 hybrid genomes and reveal gene acquisition/loss at the strain level. In addition, the interrogation of 24 STEC/ETEC hybrid genomes for identification of plasmid replicons, colonization factors, Stx and ST subtypes, and other plasmid-encoded virulence genes highlights the diversity of these hybrid strains.

IMPORTANCE
Hybrid Shiga toxin-producing
Escherichia coli
/enterotoxigenic
Escherichia coli
(STEC/ETEC) strains, which have been isolated from environmental, animal, and human clinical samples, may represent an emerging threat as food-borne pathogens. Characterization of these strains is important for assessing virulence potential, aiding in the development of pathogen detection methods, and understanding how the hybrid strains evolve to potentially have a greater impact on public health. This study represents, to our knowledge, both the first characterization of a closed plasmid sequence from a STEC/ETEC hybrid strain and the most comprehensive phylogenetic analysis of available STEC/ETEC hybrid genomes to date. The results demonstrate how the mobility of plasmid-associated virulence genes has resulted in the creation of a diverse plasmid repertoire within the STEC/ETEC hybrid strains.
Athletic groin pain: a systematic review of surgical diagnoses, investigations and treatment
Authors: de SA Darren , Hölmich Per , Phillips Mark , Heaven Sebastian , Simunovic Nicole , Philippon Marc J , Ayeni Olufemi R
Published: May 2016

Introduction

Athletic groin pain requiring surgery remains a diagnostic and therapeutic challenge. This systematic review aims to identify the most common causes of groin pain in athletes requiring surgery. Additionally, it aims to further characterise their susceptible athlete profiles, common physical examination and imaging techniques, and surgical procedures performed. This will enable the orthopaedic sports medicine clinician/surgeon to best treat these patients.

Materials and methods

The electronic databases MEDLINE, PubMed and EMBASE were searched from database inception to 13 August 2014 for studies in the English language that addressed athletic groin pain necessitating surgery. The search was updated on 4 August 2015 to find any articles published after the original search. The studies were systematically screened and data were abstracted in duplicate, with descriptive data presented.

Results

A total of 73 articles were included within our study, with data from 4655 patients abstracted. Overall, intra-articular and extra-articular causes of groin pain in athletes requiring surgery were equal. The top five causes for pain were: femoroacetabular impingement (FAI) (32%), athletic pubalgia (24%), adductor-related pathology (12%), inguinal pathology (10%) and labral pathology (5%), with 35% of this labral pathology specifically attributed to FAI.

Conclusions

Given the complex anatomy, equal intra-articular and extra-articular contribution, and potential for overlap of clinical entities causing groin pain leading to surgery in athletes, further studies are required to ascertain the finer details regarding specific exam manoeuvres, imaging views and surgical outcomes to best treat this patient population.
What is the association between sedentary behaviour and cognitive function? A systematic review
Authors: Falck Ryan S , Davis Jennifer C , Liu-Ambrose Teresa
Published: May 2016

Aim

The increasing rate of all-cause dementia worldwide and the lack of effective pharmaceutical treatments emphasise the value of lifestyle approaches as prevention strategies. Emerging evidence suggests sedentary behaviour is associated with impaired cognitive function. A better understanding of this association would significantly add to our knowledge of how to best promote healthy cognitive ageing. Thus, we conducted a systematic review ascertaining the contribution of sedentary behaviour towards associated changes in cognitive function over the adult lifespan.

Study design

Systematic review of peer-reviewed literature examining the association of sedentary behaviour with cognition.

Data sources

We searched PubMed, PsycINFO, EBSCO and Web of Science, and reference lists of relevant reviews on sedentary behaviour. Two independent reviewers extracted (1) study characteristics and (2) information regarding measurement of sedentary behaviour and cognitive function. We also assessed study quality using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.

Eligibility criteria

We limited search results to adults ≥40 years, observational studies published in English since 1990 and studies investigating associations between sedentary behaviour and cognitive function.

Results

8 studies examined the association of sedentary behaviour with cognitive function. 6 studies reported significant negative associations between sedentary behaviour and cognitive function. 8 different measures of sedentary behaviour and 13 different measures of cognitive function were used across all eight studies.

Sedentary behaviour is associated with lower cognitive performance, although the attributable risk of sedentary time to all-cause dementia incidence is unclear. Our systematic review provides evidence that limiting sedentary time and concomitantly engaging in regular moderate-to-vigorous physical activity may best promote healthy cognitive ageing.
Prediction of protective sensory loss, neuropathy and foot ulceration in type 2 diabetes
Authors: Paisey R B , Darby T , George A M , Waterson M , Hewson P , Paisey C F , Thomson M P
Published: May 2016

Objectives

To prospectively determine clinical and biochemical characteristics associated with the development of peripheral neuropathy, loss of protective sensation, and foot ulceration in persons with type 2 diabetes mellitus (DM) over 7 years.

Research design and methods

Graded monofilament (MF) testing, vibration perception threshold, and neuropathy symptom questionnaires were undertaken in 206 participants with type 2 DM without peripheral vascular disease or history of foot ulceration and 71 healthy participants without DM at baseline and after 7 years. 6 monthly glycosylated hemoglobin (HbA1c) levels and annual serum lipid profiles were measured during follow-up of those with DM. Incident foot ulceration was recorded at follow-up.

Results

Taller stature and higher quartiles of serum triglyceride and HbA1c levels were associated with neuropathy at follow-up (p=0.008). Remission of baseline neuropathy was observed in 7 participants at follow-up. 9 participants with type 2 DM developed foot ulcers by the end of the study, only 1 at low risk. Mean HbA1c levels were higher in those who developed foot ulceration (p<0.0001). 1 participant with neuropathy throughout developed a Charcot foot. Failure to perceive 2 or more 2, 4 and 6 g MF stimuli at baseline predicted loss of protective sensation at follow-up.

Conclusions

Tall stature and worse metabolic control were associated with progression to neuropathy. Mean HbA1c levels were higher in those who developed foot ulcers. Graded MF testing may enrich recruitment to clinical trials and assignation of high risk for foot ulceration.
City mouse, country mouse: a mixed-methods evaluation of perceived communication barriers between rural family physicians and urban consultants in Newfoundland and Labrador, Canada
Authors: Renouf Tia , Alani Sabrina , Whalen Desmond , Harty Chris , Pollard Megan , Morrison Megan , Coombs-Thorne Heidi , Dubrowski Adam
Published: May 2016

Objectives

To examine perceived communication barriers between urban consultants and rural family physicians practising routine and emergency care in remote subarctic Newfoundland and Labrador (NL).

Design

This study used a mixed-methods design. Quantitative and qualitative data were collected through exploratory surveys, comprised of closed and open-ended questions. The quantitative data was analysed using comparative statistical analyses, and a thematic analysis was applied to the qualitative data.

Participants

52 self-identified rural family physicians and 23 urban consultants were recruited via email. Rural participants were also recruited at the Family Medicine Rural Preceptor meetings in St John's, NL.

Setting

Rural family physicians and urban consultants in NL completed a survey assessing perceived barriers to effective communication.

Results

Data confirmed that both groups perceived communication difficulties with one another; with 23.1% rural and 27.8% urban, rating the difficulties as frequent (p=0.935); 71.2% rural and 72.2% urban as sometimes (p=0.825); 5.8% rural and 0% urban acknowledged never perceiving difficulties (p=0.714). Overall, 87.1% of participants indicated that perceived communication difficulties impacted patient care. Primary trends that emerged as perceived barriers for rural physicians were time constraints and misunderstanding of site limitations. Urban consultants' perceived barriers were inadequate patient information and lack of native language skills.

Conclusions

Barriers to effective communication are perceived between rural family physicians and urban consultants in NL.
Positive lifestyle changes around the time of pregnancy: a cross-sectional study
Authors: O'Keeffe Linda M , Dahly Darren L , Murphy Marion , Greene Richard A , Harrington Janas M , Corcoran Paul , Kearney Patricia M
Published: May 2016

Objectives

To examine the prevalence of positive lifestyle behaviours before and during pregnancy in Ireland.

Design

Cross-sectional study.

Setting

Population-based study in Ireland.

Participants

A total of 718 women of predominantly Caucasian origin from the Pregnancy Risk Assessment Monitoring System (PRAMS), Ireland, were included.

Primary and secondary outcome measures

Positive lifestyle behaviour changes before and during pregnancy in Ireland on alcohol consumption, smoking, folate use and nutrition.

Results

Of 1212 women surveyed, 718 (59%) responded. 26% were adherent to all three recommendations on alcohol consumption, smoking and folate use before pregnancy. This increased to 39% for the same three behaviours during pregnancy, with greater increases in adherence observed among women with the lowest adherence before pregnancy. Age, education and ethnicity gaps in adherence before pregnancy appeared to narrow during pregnancy. Adherence to all seven food pyramid guidelines was less than 1% overall, and less than 1% of participants met all four micronutrient guidelines on vitamin D, folate, calcium and iron intake around the time of pregnancy.

Conclusions

Low levels of healthy lifestyle behaviours before pregnancy and low levels of positive lifestyle behaviours during pregnancy demonstrate an urgent need for increased clinical and public health efforts to target deleterious health behaviours before, during and after pregnancy.
How different are baby-led weaning and conventional complementary feeding? A cross-sectional study of infants aged 6–8 months
Authors: Morison Brittany J , Taylor Rachael W , Haszard Jillian J , Schramm Claire J , Williams Erickson Liz , Fangupo Louise J , Fleming Elizabeth A , Luciano Ashley , Heath Anne-Louise M
Published: May 2016

Objectives

To compare the food, nutrient and ‘family meal’ intakes of infants following baby-led weaning (BLW) with those of infants following a more traditional spoon-feeding (TSF) approach to complementary feeding.

Study design and participants

Cross-sectional study of dietary intake and feeding behaviours in 51 age-matched and sex-matched infants (n=25 BLW, 26 TSF) 6–8 months of age.

Methods

Parents completed a questionnaire, and weighed diet records (WDRs) on 1–3 non-consecutive days, to investigate food and nutrient intakes, the extent to which infants were self-fed or parent-fed, and infant involvement in ‘family meals’.

Results

BLW infants were more likely than TSF infants to have fed themselves all or most of their food when starting complementary feeding (67% vs 8%, p<0.001). Although there was no statistically significant difference in the large number of infants consuming foods thought to pose a choking risk during the WDR (78% vs 58%, p=0.172), the CI was wide, so we cannot rule out increased odds with BLW (OR, 95% CI: 2.57, 0.63 to 10.44). No difference was observed in energy intake, but BLW infants appeared to consume more total (48% vs 42% energy, p<0.001) and saturated (22% vs 18% energy, p<0.001) fat, and less iron (1.6 vs 3.6 mg, p<0.001), zinc (3.0 vs 3.7 mg, p=0.001) and vitamin B12(0.2 vs 0.5 μg, p<0.001) than TSF infants. BLW infants were more likely to eat with their family at lunch and at the evening meal (both p≤0.020).

Conclusions

Infants following BLW had similar energy intakes to those following TSF and were eating family meals more regularly, but appeared to have higher intakes of fat and saturated fat, and lower intakes of iron, zinc and vitamin B12. A high proportion of both groups were offered foods thought to pose a choking risk.
Algorithms for detecting and predicting influenza outbreaks: metanarrative review of prospective evaluations
Authors: Spreco A , Timpka T
Published: May 2016

Objectives

Reliable monitoring of influenza seasons and pandemic outbreaks is essential for response planning, but compilations of reports on detection and prediction algorithm performance in influenza control practice are largely missing. The aim of this study is to perform a metanarrative review of prospective evaluations of influenza outbreak detection and prediction algorithms restricted settings where authentic surveillance data have been used.

Design

The study was performed as a metanarrative review. An electronic literature search was performed, papers selected and qualitative and semiquantitative content analyses were conducted. For data extraction and interpretations, researcher triangulation was used for quality assurance.

Results

Eight prospective evaluations were found that used authentic surveillance data: three studies evaluating detection and five studies evaluating prediction. The methodological perspectives and experiences from the evaluations were found to have been reported in narrative formats representing biodefence informatics and health policy research, respectively. The biodefence informatics narrative having an emphasis on verification of technically and mathematically sound algorithms constituted a large part of the reporting. Four evaluations were reported as health policy research narratives, thus formulated in a manner that allows the results to qualify as policy evidence.

Conclusions

Awareness of the narrative format in which results are reported is essential when interpreting algorithm evaluations from an infectious disease control practice perspective.
Too much information? A document analysis of sport safety resources from key organisations
Authors: Bekker Sheree , Finch Caroline F
Published: May 2016

Objectives

The field of sport injury prevention has seen a marked increase in published research in recent years, with concomitant proliferation of lay sport safety resources, such as policies, fact sheets and posters. The aim of this study was to catalogue and categorise the number, type and topic focus of sport safety resources from a representative set of key organisations.

Design

Cataloguing and qualitative document analysis of resources available from the websites of six stakeholder organisations in Australia.

Setting

This study was part of a larger investigation, the National Guidance for Australian Football Partnerships and Safety (NoGAPS) project.

Participants

The NoGAPS study provided the context for a purposive sampling of six organisations involved in the promotion of safety in Australian football. These partners are recognised as being highly representative of organisations at national and state level that reflect similarly in their goals around sport safety promotion in Australia.

Results

The catalogue comprised 284 resources. More of the practical and less prescriptive types of resources, such as fact sheets, than formal policies were found. Resources for the prevention of physical injuries were the predominant sport safety issue addressed, with risk management, environmental issues and social behaviours comprising other categories. Duplication of resources for specific safety issues, within and across organisations, was found.

Conclusions

People working within sport settings have access to a proliferation of resources, which creates a potential rivalry for sourcing of injury prevention information. Important issues that are likely to influence the uptake of safety advice by the general sporting public include the sheer number of resources available, and the overlap and duplication of resources addressing the same issues. The existence of a large number of resources from reputable organisations does not mean that they are necessarily evidence based, fully up to date or even effective in supporting sport safety behaviour change.
Economic evaluations on centralisation of specialised healthcare services: a systematic review of methods
Authors: Bhattarai Nawaraj , McMeekin Peter , Price Christopher , Vale Luke
Published: May 2016

Objective

To systematically review and appraise the quality of economic evaluations assessing centralisation of specialised healthcare services.

Methods

A systematic review to identify economic evaluations on centralisation of any specialised healthcare service. Full economic evaluations comparing costs and consequences of centralisation of any specialised healthcare service were eligible for inclusion. Methodological characteristics of included studies were appraised using checklists adapted from recommended guidelines.

Results

A total of 64 full-text articles met the inclusion criteria. Two studies were conducted in the UK. Most of the studies used volume of activity as a proxy measure of centralisation. The methods used to assess centralisation were heterogeneous. Studies differed in terms of study design used and aspect of centralisation they considered. There were major limitations in studies. Only 12 studies reported the study perspective. Charges which are not true representation of costs were used by 17 studies to assess cost outcomes. Only 10 reported the detailed breakdown of the cost components used in their analysis. Discounting was necessary in 14 studies but was reported only in 7 studies. Sensitivity analyses were included by less than one-third of the studies. The applicability of the identified studies to a setting other than the one they were conducted in is questionable, given variations in the organisation of services and healthcare costs. Centralisation as a concept has also been variably and narrowly defined as activity of specific services which may not reflect the wider aspects of centralisation.

Conclusions

Confounded and biased information coming from studies without standardised methods may mislead decision-makers towards making wrong decisions on centralisation. It is important to improve the methodology and reporting of economic evaluations in order to provide more robust and transferable evidence. Wider aspects of healthcare centralisation should be considered in the estimates of costs and health outcomes.
Improving analgesia in fractured neck of femur with a standardised fascia iliaca block protocol
Authors: Watson Paul , Keenan Robert , Rugonfalvi-Kiss Szabolcs
Published: May 2016

Fractured neck of femur (NOF) causes significant morbidity and pain for patients; adequate analgesia is an essential component of patient centred care. Patients experiencing greater pain during treatment for fractured NOF are slower to mobilise and have poorer health-related quality of life. NICE guidance suggests considering adding nerve blocks if paracetamol and opioids do not provide sufficient preoperative pain relief. We set out to audit pain levels in this group of patients in a small District General Hospital and to develop a protocol to improve analgesia provision if required. We identified that patients waiting a long time for fixation of fractured NOF could benefit from safe, effective analgesia by way of fascia iliaca compartment block (FICB). We drew up a protocol and held training sessions bringing about a culture change to provide an excellent standard of analgesia for these patients. Most patients reported much better levels of analgesia post-block and junior doctors felt more empowered. Further developments considered are training of senior ED nurses to administer FICB (in keeping with the AAGBI position statement) and a fascia iliaca catheter placement service.
T-cell abnormalities in common variable immunodeficiency: the hidden defect
Authors: Wong Gabriel K , Huissoon Aarnoud P
Published: May 2016

This review discusses how the T-cell compartment in common variable immunodeficiency is marked by the premature arrest in thymic output, leading to T-cell exhaustion and immune dysregulation. Although B cells have been the main focus of the disorder, ample experimental data suggest that T-cell abnormalities can be seen in a large proportion of Freiburg Group 1a patients and those suffering from inflammatory complications. The reductions in T-cell receptor excision circles, naïve T cells, invariant NKT cells and regulatory T cells suggest a diminished thymic output, while CD8 T cells are driven towards exhaustion either via an antigen-dependent or an antigen-independent manner. The theoretical risk of anti-T-cell therapies is discussed, highlighting the need for an international effort in generating longitudinal data in addition to better-defined underlying molecular characterisation.
Myocardial infarction induces atrial inflammation that can be prevented by C1-esterase inhibitor
Authors: Begieneman Mark PV , Emmens Reindert W , Rijvers Liza , Woudstra Linde , Paulus Walter J , Kubat Bela , Vonk Alexander BA , van Rossum Albert C , Wouters Diana , Zeerleder Sacha , van Ham Marieke , Schalkwijk Casper G , Niessen Hans WM , Krijnen Paul AJ
Published: May 2016

Aims

Inflammation plays an important role in the pathogenesis of myocardial infarction (MI). Whether MI induces atrial inflammation is unknown however. Here, we analysed atrial inflammation in patients with MI and in rats with experimentally induced MI. The effect of the anti-inflammatory agent C1-esterase inhibitor (C1inh) on atrial inflammation in rats was also analysed.

Methods

In the hearts of patients who died at different time points after MI (total n=24, mean age=60), neutrophils (myeloperoxidase-positive cells), lymphocytes (CD45-positive cells) and macrophages (CD68-positive cells) were quantified in the myocardium of the left and right atria and the infarcted left and non-infarcted right ventricles and compared with control patients (n=5, mean age=59). For the left and right atria, inflammatory cells were also quantified in the atrial adipose tissue. MI was induced in 17 rats, of which 10 were subsequently treated with C1inh for 6 days. Forty-two days post-MI, lymphocytes, macrophages and the endothelial inflammation marker Nε-(carboxymethyl)lysine (CML) were analysed in the myocardium of both the atria and ventricles.

Results

In all investigated areas of the human hearts increased lymphocytes and macrophages were observed to a varying extent, especially between 6 h and 5 days following MI. Similarly, in rats MI resulted in an increase of inflammatory cells and CML in the atria. C1inh treatment decreased atrial inflammation.

Conclusions

MI induces atrial inflammation in patients and in rats. C1inh treatment could counteract this MI-induced atrial inflammation in rats.
Molecular status ofPI3KCA,KRASandBRAFin ovarian clear cell carcinoma: an analysis of 63 patients
Authors: Zannoni Gian Franco , Improta Giuseppina , Pettinato Angela , Brunelli Chiara , Troncone Giancarlo , Scambia Giovanni , Fraggetta Filippo
Published: May 2016

Aims

To evaluate the incidence ofPI3KCA,KRASandBRAFmutations in primary ovarian clear cell carcinoma (OCCC).

Methods

63 consecutive patients, with a proven diagnosis of OCCC, according to WHO criteria, were included into the study. Pyrosequencing analysis of all three genes hotspot regions were performed on 2.5 µm sections of formalin-fixed paraffin-embedded tissue from primary OCCC.

Results

PI3KCAmutations were found in 20/63 (32%) cases;KRASmutations were found in 8/63 (13%); noBRAFV600 mutations were found. In particular, 12/20 mutations (60%) ofPI3KCAwere found in the exon 20, whereas the remaining eight cases presented mutations in exon 9 (8/20; 40%).KRASpyrosequencing analysis revealed higher incidence of codon 12 mutations (7/8; 90%) than codon 13 mutations (1/8; 10%). In five cases (5/66; 8%), synchronous mutations, affectingPI3KCAandKRASgenes, were found. No differences were found in the distribution of hotspot mutations, according to the stage.

Conclusions

The high frequency ofPI3KCAmutations, the low rate of mutations inKRASand the absence of mutations in BRAF, indicate a molecular signature of OCCCs different from other ovarian carcinomas. Detection of driver mutations, such as PI3KCA and KRAS, may be the basis for a targeted therapy, although the clinical and therapeutic implications of these findings have to be supported by further studies.
Angiostrongylus‐associated pneumonia in a red panda (Ailurus fulgens)
Authors: Kubiak Marie , Stidworthy Mark Frederick , Sharpe Sam
Published: May 2016

A red panda (Ailurus fulgens) within a zoological collection was noted by keepers to be acutely dyspnoeic with no apparent premonitory signs and died before intervention. Postmortem examination demonstrated severe verminous pneumonia with concurrent pulmonary thromboarteritis and splenic infarction, attributed to Angiostrongylus vasorum infection.
Diurnal? Calling activity patterns reveal nocturnal habits in the aposematic toadMelanophryniscusrubriventris
Authors: Pereyra L.C. , Akmentins M.S. , Sanabria E.A. , Vaira M.
Published: May 2016

In diurnal species with short breeding seasons, an extension of diel activity to the night hours could be favoured to maximize mating opportunities, but individuals must deal with physiological and behavioural constraints. We tested this hypothesis in the Yungas Red-belly Toad (Melanophryniscus rubriventris (Vellard, 1947)). We registered the diel pattern of male calling activity in two localities using automated recording systems, and related it to abiotic factors such as temperature, relative air humidity, and precipitation. The diel pattern of vocalization was mainly diurnal. Interestingly though, nocturnal calling activity was a common feature, representing between 40% and 43% of call records in both localities. Vocal activity was significantly influenced by time of the day and presence of rainfall. Calling males showed high plasticity, with activity in the entire environmental range of relative air humidity and temperature. Nocturnal calling seems to play an important role in the mating strategy of males, and it is probably more frequent in the genus Melanophryniscus than currently assumed. We discuss the implications of our findings in relation to different aspects of ecology of the species and suggest that bright colouration in M. rubriventris might result from a compromise between several nonconflicting functions (e.g., aposematism and thermoregulation).
Discordant signaling and autophagy response to fasting in hearts of obese mice: Implications for ischemia tolerance
Authors: Andres Allen M. , Kooren Joel A. , Parker Sarah J. , Tucker Kyle C. , Ravindran Nandini , Ito Bruce R. , Huang Chengqun , Venkatraman Vidya , Van Eyk Jennifer E. , Gottlieb Roberta A. , Mentzer Robert M.
Published: May 2016

Autophagy is regulated by nutrient and energy status and plays an adaptive role during nutrient deprivation and ischemic stress. Metabolic syndrome (MetS) is a hypernutritive state characterized by obesity, dyslipidemia, elevated fasting blood glucose levels, and insulin resistance. It has also been associated with impaired autophagic flux and larger-sized infarcts. We hypothesized that diet-induced obesity (DIO) affects nutrient sensing, explaining the observed cardiac impaired autophagy. We subjected male friend virus B NIH (FVBN) mice to a high-fat diet, which resulted in increased weight gain, fat deposition, hyperglycemia, insulin resistance, and larger infarcts after myocardial ischemia-reperfusion. Autophagic flux was impaired after 4 wk on a high-fat diet. To interrogate nutrient-sensing pathways, DIO mice were subjected to overnight fasting, and hearts were processed for biochemical and proteomic analysis. Obese mice failed to upregulate LC3-II or to clear p62/SQSTM1 after fasting, although mRNA for LC3B and p62/SQSTM1 were appropriately upregulated in both groups, demonstrating an intact transcriptional response to fasting. Energy- and nutrient-sensing signal transduction pathways [AMPK and mammalian target of rapamycin (mTOR)] also responded appropriately to fasting, although mTOR was more profoundly suppressed in obese mice. Proteomic quantitative analysis of the hearts under fed and fasted conditions revealed broad changes in protein networks involved in oxidative phosphorylation, autophagy, oxidative stress, protein homeostasis, and contractile machinery. In many instances, the fasting response was quite discordant between lean and DIO mice. Network analysis implicated the peroxisome proliferator-activated receptor and mTOR regulatory nodes. Hearts of obese mice exhibited impaired autophagy, altered proteome, and discordant response to nutrient deprivation.
Minireview: Role of genetic changes of faciogenital dysplasia protein 1 in human disease
Authors: Pedigo Nancy G. , Van Delden Danielle , Walters Laura , Farrell Christopher L.
Published: May 2016

The FGD1 gene encodes for a guanine exchange factor (GEF) protein that specifically activates the Rho GTPase Cdc42. For cellular migration, Cdc42 is a key molecular switch that regulates cytoskeleton restructuring, gene transcription, cellular morphology, extension, and cell adhesion. In the past decade, germline mutations in the FGD1 gene have been associated with a rare X-linked disorder known as faciogenital dysplasia (FGDY). Malformations are consistent with a loss of cellular migration during embryonic development. Insertion and deletion mutations in FGD1 result in a frameshift causing inactivation of fgd1 protein. Since Cdc42 is a key molecular switch in cytoskeletal restructuring and cell adhesion, the loss of fgd1 is postulated to attenuate Cdc42-mediated cellular migration in embryonic development. In metastatic tumors, Cdc42 modulates migration and invasiveness. Fgd1 overexpression has been found in infiltrating and poorly differentiated breast and invasive prostate tumors. Amplification at Xp11.21, the FGD1 gene locus, has been reported in several cancers. Sequencing analyses in numerous types of cancer have found missense mutations in the FGD1 gene in metastatic tumors. FGDY and cancer studies suggest that the germline and somatic changes downregulate or upregulate the FGD1 gene playing a key role in the development of diseases.
Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment
Authors: Masson-Lecomte Alexandra , López de Maturana Evangelina , Goddard Michael E. , Picornell Antoni , Rava Marta , González-Neira Anna , Márquez Mirari , Carrato Alfredo , Tardon Adonina , Lloreta Josep , Garcia-Closas Montserrat , Silverman Debra , Rothman Nathaniel , Kogevinas Manolis , Allory Yves , Chanock Stephen J. , Real Francisco X. , Malats Núria
Published: May 2016

Background: Increasing evidence points to the role of tumor immunologic environment on urothelial bladder cancer prognosis. This effect might be partly dependent on the host genetic context. We evaluated the association of SNPs in inflammation-related genes with non–muscle-invasive bladder cancer (NMIBC) risk-of-recurrence and risk-of-progression.

Methods: We considered 822 NMIBC included in the SBC/EPICURO Study followed-up >10 years. We selected 1,679 SNPs belonging to 251 inflammatory genes. The association of SNPs with risk-of-recurrence and risk-of-progression was assessed using Cox regression single-marker (SMM) and multimarker methods (MMM) Bayes A and Bayesian LASSO. Discriminative abilities of the models were calculated using the c index and validated with bootstrap cross-validation procedures.

Results: While no SNP was found to be associated with risk-of-recurrence using SMM, three SNPs in TNIP1, CD5, and JAK3 showed very strong association with posterior probabilities >90% using MMM. Regarding risk-of-progression, one SNP in CD3G was significantly associated using SMM (HR, 2.69; P = 1.55 × 10−5) and two SNPs in MASP1 and AIRE, showed a posterior probability ≥80% with MMM. Validated discriminative abilities of the models without and with the SNPs were 58.4% versus 60.5% and 72.1% versus 72.8% for risk-of-recurrence and risk-of-progression, respectively.

Conclusions: Using innovative analytic approaches, we demonstrated that SNPs in inflammatory-related genes were associated with NMIBC prognosis and that they improve the discriminative ability of prognostic clinical models for NMIBC.

Impact: This study provides proof of concept for the joint effect of genetic variants in improving the discriminative ability of clinical prognostic models. The approach may be extended to other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1144–50. ©2016 AACR.
Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials
Authors: Coleman C. Norman , Higgins Geoff S. , Brown J. Martin , Baumann Michael , Kirsch David G. , Willers Henning , Prasanna Pataje G.S. , Dewhirst Mark W. , Bernhard Eric J. , Ahmed Mansoor M.
Published: May 2016

There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. Clin Cancer Res; 22(13); 3138–47. ©2016 AACR.
Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer
Authors: Kitai Hidenori , Ebi Hiromichi , Tomida Shuta , Floros Konstantinos V. , Kotani Hiroshi , Adachi Yuta , Oizumi Satoshi , Nishimura Masaharu , Faber Anthony C. , Yano Seiji
Published: May 2016

KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo. These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.

Significance: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non–small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754–69. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 681
Unexpectedly High Incidence of Stroke and Left Atrial Appendage Thrombus Formation After Electrical Isolation of the Left Atrial Appendage for the Treatment of Atrial Tachyarrhythmias
Authors: Rillig Andreas , Tilz Roland R. , Lin Tina , Fink Thomas , Heeger Christian-H. , Arya Anita , Metzner Andreas , Mathew Shibu , Wissner Erik , Makimoto Hisaki , Wohlmuth Peter , Kuck Karl-Heinz , Ouyang Feifan
Published: May 2016

Background—

Electric left atrial appendage (LAA) isolation (LAAI) may occur during catheter ablation of atrial tachyarrhythmias. Data regarding the risk of thromboembolic events and stroke after LAAI are sparse. This study evaluated the incidence of LAA thrombus formation and thromboembolic events after LAAI.

Methods and Results—

Fifty patients had LAAI (age=71 years; female=56%; CHA
2
DS
2
-VASc score before ablation =3 [2;3]). LAAI patients were compared with matched patients with comparable baseline characteristics who underwent atrial fibrillation ablation without LAAI (n=50). Ablation strategies in the LAAI group included pulmonary vein isolation in 50 (100%), left atrial isthmus line in 47 (94%), anterior line in 45 (90%), complex atrial fractionated potentials in 24 (48%), and roofline in 14 (28%) patients. Transesophageal echocardiography was performed during follow-up in 47/50 (94%) patients in the LAAI group and in all patients of the control group. Oral anticoagulation (OAC) independent of CHA
2
DS
2
-VASc score was strongly recommended in all patients. During a median follow-up of 6.5 (4–12) months, stroke occurred in 2 patients on OAC and transient ischemic attack in one without OAC in the LAAI group. In the remaining 47 patients, LAA thrombus was identified on transesophageal echocardiography in 10 (21%) patients (OAC=9; no OAC=1). In the control group, no LAA thrombus was detected and no stroke occurred (
P
<0.001). Stable sinus rhythm was maintained in 32 patients (64%) of the LAAI group after a median follow-up of 6.5 months (4–12), including 17/32 patients on antiarrhythmic drugs.

Conclusions—

After LAAI, an unexpectedly high incidence of LAA thrombus formation and stroke was observed despite OAC therapy.
Relevance of Conduction Disorders in Bachmann’s Bundle During Sinus Rhythm in Humans
Authors: Teuwen Christophe P. , Yaksh Ameeta , Lanters Eva A.H. , Kik Charles , van der Does Lisette J.M.E. , Knops Paul , Taverne Yannick J.H.J. , van de Woestijne Pieter C. , Oei Frans B.S. , Bekkers Jos A. , Bogers Ad J.J.C. , Allessie Maurits A. , de Groot Natasja M.S.
Published: May 2016

Background—

Bachmann’s bundle (BB) is considered to be the main route of interatrial conduction and to play a role in development of atrial fibrillation (AF). The goals of this study are to characterize the presence of conduction disorders in BB during sinus rhythm and to study their relation with AF.

Methods and Results—

High-resolution epicardial mapping (192 unipolar electrodes, interelectrode distance: 2 mm) of sinus rhythm was performed in 185 patients during coronary artery bypass surgery of whom 13 had a history of paroxysmal AF. Continuous rhythm monitoring was used to detect postoperative AF during the first 5 postoperative days. In 67% of the patients, BB was activated from right to left; in the remaining patients from right and middle (21%), right, central, and left (8%), or central (4%) site. Mean effective conduction velocity was 89 cm/s. Conduction block was present in most patients (75%; median 1.1%, range 0–12.8) and was higher in patients with paroxysmal AF compared with patients without a history of AF (3.2% versus 0.9%;
P
=0.03). A high amount of conduction block (>4%) was associated with de novo postoperative AF (
P
=0.02). Longitudinal lines of conduction block >10 mm were also associated with postoperative AF (
P
=0.04).

Conclusions—

BB may be activated through multiple directions, but the predominant route of conduction is from right to left. Conduction velocity across BB is around 90 cm/s. Conduction is blocked in both longitudinal and transverse direction in the majority of patients. Conduction disorders, particularly long lines of longitudinal conduction block, are more pronounced in patients with AF episodes.
Transcatheter Aortic Valve Implantation Compared With Surgical Aortic Valve Replacement in Low-Risk Patients
Authors: Rosato Stefano , Santini Francesco , Barbanti Marco , Biancari Fausto , D’Errigo Paola , Onorati Francesco , Tamburino Corrado , Ranucci Marco , Covello Remo Daniel , Santoro Gennaro , Grossi Claudio , Ventura Martina , Fusco Danilo , Seccareccia Fulvia
Published: May 2016

Background—

The proven efficacy of transcatheter aortic valve implantation (TAVI) in high-risk patients is leading to the expansion of its indications toward lower-risk patients. However, this shift is not supported by meaningful evidence of its benefit over surgical aortic valve replacement (SAVR). This analysis aims to describe outcomes of TAVI versus SAVR in low-risk patients.

Methods and Results—

We compared the outcome after TAVI and SAVR of low-risk patients (European System for Cardiac Operative Risk Evaluation II [EuroSCORE II] <4%) included in the Observational Study of Effectiveness of SAVR–TAVI Procedures for Severe Aortic Stenosis Treatment (OBSERVANT) study. The primary outcome was 3-year survival. Secondary outcomes were early events and major adverse cardiac and cerebrovascular events at 3 years. Propensity score matching resulted in 355 pairs of patients with similar baseline characteristics. Thirty-day survival was 97.1% after SAVR and 97.4% after TAVI (
P
=0.82). Cardiac tamponade, permanent pacemaker implantation, major vascular damage, and moderate-to-severe paravalvular regurgitation were significantly more frequent after TAVI compared with SAVR. Stroke rates were equal in the study groups. SAVR was associated with higher risk of cardiogenic shock, severe bleeding, and acute kidney injury. At 3 years, survival was 83.4% after SAVR and 72.0% after TAVI (
P
=0.0015), whereas freedom from major adverse cardiac and cerebrovascular events was 80.9% after SAVR and 67.3% after TAVI (
P
<0.001).

Conclusions—

In patients with low operative risk, significantly better 3-year survival and freedom from major adverse cardiac and cerebrovascular events were observed after SAVR compared with TAVI. Further studies on new-generation valve prostheses are necessary before expanding indications of TAVI toward lower-risk patients.
Integrating Two Theoretical Models to Understand and Prevent Military and Veteran Suicide
Authors: Wolfe-Clark Andrea L. , Bryan Craig J.
Published: May 2016

Despite increasing prevention efforts, military suicide rates have surpassed those of the general population. This trend may reflect a deficit in our understanding of suicide, historically atheoretical and based on decreasing risk factors of suicide. The interpersonal–psychological theory of suicide (IPTS) provides a theoretical foundation to understand suicide but only assesses three risk factors of suicide and is primarily aimed at explaining who may die by suicide, but not when. The fluid vulnerability theory (FVT) provides a broad theoretical framework to understand and organize risk and protective factors of suicide in order to understand the process of suicide risk over time. Overlaying the IPTS’s constructs of thwarted belongingness, perceived burdensomeness, and the acquired capability for suicide within the FVT framework provides a robust model to understand not only who is at risk for suicide but also when suicide risk is likely to emerge.
Safety distance control for multi-car lifts
Authors: Gerstenmeyer Stefan , Peters Richard
Published: May 2016

The efficient use of lift shafts has becoming increasingly important because of the trend towards building taller buildings. In traditional lift systems only one lift car travels up and down a shaft. Systems with two independent cars in one shaft exist. If multiple cars are moving together in one or multiple vertical shafts certified safety systems ensure a minimum distance between cars at any time. The lift control system needs to control the distance between cars during normal and unexpected operation. This paper considers the stopping distance for a certified safety system and describes the theory and mathematics needed to determine controlled stopping positions and safety distances for lift control in a multi-car lift system. The minimum distance possible between two cars while levelling and standing at floors as well as the possible distance between cars while travelling during normal operation is calculated.

Practical application: In lift systems with multiple cars travelling in one or multiple shafts, control strategies need to consider safety distance constraints. The lift control also needs to stop cars in unexpected situations with a controlled deceleration before the certified safety systems are forced to stop the cars in an uncontrolled manner to avoid collision. To monitor this critical distance and to ensure operation without unexpected deceleration the equations derived in this paper are necessary and can be applied to lift control systems.