bluuebunny/crossref_metadata_2025 huggingface dataset:
CRISPR-Cas: biology, mechanisms and relevance
Authors: Hille Frank , Charpentier Emmanuelle
Published: September 2016

Prokaryotes have evolved several defence mechanisms to protect themselves from viral predators. Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) display a prokaryotic adaptive immune system that memorizes previous infections by integrating short sequences of invading genomes—termed spacers—into the CRISPR locus. The spacers interspaced with repeats are expressed as small guide CRISPR RNAs (crRNAs) that are employed by Cas proteins to target invaders sequence-specifically upon a reoccurring infection. The ability of the minimal CRISPR-Cas9 system to target DNA sequences using programmable RNAs has opened new avenues in genome editing in a broad range of cells and organisms with high potential in therapeutical applications. While numerous scientific studies have shed light on the biochemical processes behind CRISPR-Cas systems, several aspects of the immunity steps, however, still lack sufficient understanding. This review summarizes major discoveries in the CRISPR-Cas field, discusses the role of CRISPR-Cas in prokaryotic immunity and other physiological properties, and describes applications of the system as a DNA editing technology and antimicrobial agent.

This article is part of the themed issue ‘The new bacteriology’.
Old concepts, new molecules and current approaches applied to the bacterial nucleotide signalling field
Authors: Gründling Angelika , Lee Vincent T.
Published: September 2016

Signalling nucleotides are key molecules that help bacteria to rapidly coordinate cellular pathways and adapt to changes in their environment. During the past 10 years, the nucleotide signalling field has seen much excitement, as several new signalling nucleotides have been discovered in both eukaryotic and bacterial cells. The fields have since advanced quickly, aided by the development of important tools such as the synthesis of modified nucleotides, which, combined with sensitive mass spectrometry methods, allowed for the rapid identification of specific receptor proteins along with other novel genome-wide screening methods. In this review, we describe the principle concepts of nucleotide signalling networks and summarize the recent work that led to the discovery of the novel signalling nucleotides. We also highlight current approaches applied to the research in the field as well as resources and methodological advances aiding in a rapid identification of nucleotide-specific receptor proteins.

This article is part of the themed issue ‘The new bacteriology’.
Streptococcus pneumoniae bacteraemia due to parotitis in a patient with systemic sclerosis and secondary Sjögren’s syndrome
Authors: Yii Irene Yuen Lin , Tan Jamie Bee Xian , Fong Warren Weng Seng
Published: September 2016

Introduction:

Invasive pneumococcal disease is an uncommon and notifiable disease in Singapore. It is often associated with significant morbidity and mortality. We report a rare case of invasive pneumococcal bacteraemia due to parotitis in a patient with systemic sclerosis and secondary Sjögren’s syndrome. We also present a retrospective review of Streptococcus pneumoniae bacteraemia cases in Singapore General Hospital from January 2011 to April 2016.

Case presentation:

A 59-year-old Malay lady with a history of systemic sclerosis with secondary Sjögren’s syndrome presented with fever and left parotid gland swelling. Clinical examination revealed poor salivary pooling and left parotid swelling without fluctuance. Ultrasound of the left parotid gland confirmed acute parotitis without evidence of abscess or sialolithiasis. Blood cultures were positive for S. pneumoniae. She was diagnosed to have invasive pneumococcal bacteraemia secondary to acute parotitis, and treated with intravenous benzylpenicillin with clearance of bacteraemia after 3 days. Upon discharge, her antibiotics were changed to intravenous ceftriaxone to facilitate outpatient parenteral antibiotic therapy for another 2 weeks. She responded favourably to antibiotics at follow-up, with no complications from the bacteraemia. A review of the microbiological records of the Singapore General Hospital revealed 116 cases of pneumococcal bacteraemia, most (80.3 %) of which were due to pneumonia. None were due to parotitis.

Conclusion:

S. pneumoniae parotitis and subsequent bacteraemia is rare. Prompt recognition of the disease and appropriate use of antibiotics are important. This case highlights that close communication between healthcare workers (microbiologist, rheumatologist and infectious disease specialist) is essential in ensuring good clinical outcomes in patients with a potentially fatal disease.
Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset
Authors: Shirts Michael R. , Klein Christoph , Swails Jason M. , Yin Jian , Gilson Michael K. , Mobley David L. , Case David A. , Zhong Ellen D.
Published: September 2016

We describe our efforts to prepare common starting structures and models for the SAMPL5 blind prediction challenge. We generated the starting input files and single configuration potential energies for the host-guest in the SAMPL5 blind prediction challenge for the GROMACS, AMBER, LAMMPS, DESMOND and CHARMM molecular simulation programs. All conversions were fully automated from the originally prepared AMBER input files using a combination of the ParmEd and InterMol conversion programs.

We find that the energy calculations for all molecular dynamics engines for this molecular set agree to a better than 0.1% relative absolute energy for all energy components, and in most cases an order of magnitude better, when reasonable choices are made for different cutoff parameters. However, there are some surprising sources of statistically significant differences. Most importantly, different choices of Coulomb’s constant between programs are one of the largest sources of discrepancies in energies. We discuss the measures required to get good agreement in the energies for equivalent starting configurations between the simulation programs, and the energy differences that occur when simulations are run with program-specific default simulation parameter values. Finally, we discuss what was required to automate this conversion and comparison.
Brain oscillations and connectivity in autism spectrum disorders (ASD): new approaches to methodology, measurement and modelling
Authors: Kessler K. , Seymour R. A. , Rippon G.
Published: September 2016

Although atypical social behaviour remains a key characterisation of ASD, the presence of sensory and perceptual abnormalities has been given a more central role in recent classification changes. An understanding of the origins of such aberrations could thus prove a fruitful focus for ASD research. Early neurocognitive models of ASD suggested that the study of high frequency activity in the brain as a measure of cortical connectivity might provide the key to understanding the neural correlates of sensory and perceptual deviations in ASD. As our review shows, the findings from subsequent research have been inconsistent, with a lack of agreement about the nature of any high frequency disturbances in ASD brains. Based on the application of new techniques using more sophisticated measures of brain synchronisation, direction of information flow, and invoking the coupling between high and low frequency bands, we propose a framework which could reconcile apparently conflicting findings in this area and would be consistent both with emerging neurocognitive models of autism and with the heterogeneity of the condition.

Highlights

Sensory and perceptual aberrations are becoming a core feature of the ASD symptom prolife.

Brain oscillations and functional connectivity are consistently affected in ASD.

Relationships (coupling) between high and low frequencies are also deficient.

Novel framework proposes the ASD brain is marked by local dysregulation and reduced top-down connectivity

The ASD brain’s ability to predict stimuli and events in the environment may be affected

This may underlie perceptual sensitives and cascade into social processing deficits in ASD
Mechanisms for Stable Bump Activity, Winner-Take-All and Group Selection in Neuronal Spiking Networks
Authors: Chen Yanqing
Published: September 2016

A major function of central nervous systems is to discriminate different categories or types of sensory input. Neuronal networks accomplish such tasks by learning different sensory maps at several stages of neural hierarchy, such that different neurons fire selectively to reflect different internal or external patterns and states. The exact mechanisms of such map formation processes in the brain are not totally understood. Here we study the mechanism by which a simple recurrent/reentrant neuronal network accomplish group selection and discrimination to different inputs in order to generate sensory maps. We describe the conditions and mechanism of transition from a rhythmic epileptic state (in which all neurons fire synchronized and indiscriminately to any input) to a winner-take-all state in which only a subset of neurons fire for a specific input. We prove an analytic condition under which a stable bump solution and a soft winner-take-all state can emerge from the local recurrent excitation-inhibition interactions in a three-layer spiking network with distinct excitatory and inhibitory populations, and demonstrate the importance of surround inhibitory connection topology on the stability of dynamic patterns in spiking neural network.
Variational Bayesian parameter estimation techniques for the general linear model
Authors: Starke Ludger , Ostwald Dirk
Published: September 2016

Variational Bayes (VB), variational maximum likelihood (VML), restricted maximum likelihood (ReML), and maximum likelihood (ML) are cornerstone parametric statistical estimation techniques in the analysis of functional neuroimaging data. However, the theoretical underpinnings of these model parameter estimation techniques are rarely covered in introductory statistical texts. Because of the widespread practical use of VB, VML, ReML, and ML in the neuroimaging community, we reasoned that. a theoretical treatment of their relationships and their application in a basic modelling scenario may be helpful for both neuroimaging novices and practitioners alike. In this technical study, we thus revisit the conceptual and formal underpinnings of VB, VML, ReML, and ML and provide a detailed account of their mathematical relationships and implementational details. We further apply VB, VML, ReML, and ML to the general linear model (GLM) with non-spherical error covariance as commonly encountered in the first-level analysis of fMRI data. To this end, we explicitly derive the corresponding free energy objective functions and ensuing iterative algorithms. Finally, in the applied part of our study, we evaluate the parameter and model recovery properties of VB, VML, ReML, and ML, first in an exemplary setting and then in the analysis of experimental fMRI data acquired from a single participant under visual stimulation.
ImSig: A resource for the identification and quantification of immune signatures in blood and tissue transcriptomics data
Authors: Nirmal Ajit Johnson , Regan Tim , Shih Barbara Bo-Ju , Hume David Arthur , Sims Andrew Harvey , Freeman Tom Charles
Published: September 2016

The outcome of many diseases is commonly correlated with the immune response at the site of pathology. The ability to monitor the status of the immune system in situ provides a mechanistic understanding of disease progression, a prognostic assessment and a guide for therapeutic intervention. Global transcriptomic data can be deconvoluted to provide an indication of the cell types present and their activation state, but the gene signatures proposed to date are either disease-specific or have been derived from data generated from isolated cell populations. Here we describe an improved set of immune gene signatures,ImSig, derived based on their co-expression in blood and tissue datasets.ImSigincludes validated lists of marker genes for the main immune cell types and a number of core pathways. When used in combination with network analysis,ImSigis an accurate and easy to use approach for monitoring immune phenotypes in transcriptomic data derived from clinical samples.
Scrounging by foragers can resolve the paradox of enrichment
Authors: Toyokawa Wataru
Published: September 2016

Theoretical models of predator-prey system predict that sufficient enrichment of prey can generate large amplitude limit cycles, paradoxically causing a high risk of extinction (the paradox of enrichment). While real ecological communities contain many gregarious species whose foraging behaviour should be influenced by socially transmitted information, few theoretical studies have examined the possibility that social foraging might be a resolution of the paradox. I considered a predator population in which individuals play the producer-scrounger foraging game both in a one-prey-one-predator system and a two-prey-one-predator system. I analysed the stability of a coexisting equilibrium point in the former one-prey system and that of non-equilibrium dynamics of the latter two-prey system. The result showed that social foraging can stabilise both systems and thereby resolves the paradox of enrichment when scrounging behaviour is prevalent in predators. This suggests a previously neglected mechanism underlying a powerful effect of group-living animals on sustainability of ecological communities.
An Electrochemistry Study of Cryoelectrolysis in Frozen Physiological Saline
Authors: Manuel Thomas J. , Munnangi Pujita , Rubinsky Boris
Published: September 2016

This is the first quantitative study on the fundamental physical and electrochemical processes that occur during cryoelectrolysis. Cryoelectrolysis is a new minimally invasive tissue ablation surgical technique that combines the processes of electrolysis and solid/liquid phase transformation (freezing). We measured the pH front propagation and the changes in resistance in a tissue simulant made of physiological saline gel with a pH dye as a function of the sample temperature in the high subzero range above the eutectic. Results demonstrate that effective electrolysis can occur in a high subzero freezing milieu and that the propagation of the pH front is only weakly dependent on temperature. These observations are consistent with a mechanism involving ionic movement through the concentrated saline solution channels between ice crystals at subfreezing temperatures above the eutectic. The Joule heating in these microchannel may cause local microscopic melting, the observed weak dependence of pH front propagation on temperature, and the large changes in resistance with time. In addition, we observed that the pH front propagation from the anode is more rapid than from the cathode. The explanation is the electro-osmotic flow from the cathode to the anode. The findings in this paper may be of fundamental value for designing future cryoelectrolytic ablation surgery protocols.
A pyrethroïd-treated bed net increases host attractiveness forAnopheles gambiae s.s.carrying thekdrallele in a dual-choice olfactometer
Authors: Porciani Angélique , Diop Malal , Moiroux Nicolas , Kadoke-Lambi Tatiana , Cohuet Anna , Chandre Fabrice , Dormont Laurent , Pennetier Cédric
Published: September 2016

The use of long lasting insecticide nets (LLINs) treated with pyrethroïd is known for its major contribution in malaria control. However, LLINs are suspected to induce behavioral changes in malaria vectors, which may in turn drastically affect their efficacy againstPlasmodium sp. transmission. In sub Saharan Africa, where malaria imposes the heaviest burden, the main malaria vectors are widely resistant to pyrethroïds, the insecticide family used on LLINs, which also threatens LLIN efficiency. There is therefore a crucial need for deciphering how insecticide-impregnated materials might affect the host-seeking behavior of malaria vectors in regards to insecticide resistance. In this study, we explored the impact of permethrin-impregnated net on the host attractiveness forAnopheles gambiaemosquitoes, either susceptible to insecticides, or carrying the insecticide resistance conferring allelekdr. Groups of female mosquitoes were released in a dual-choice olfactometer and their movements towards an attractive odor source (a rabbit) protected by insecticide-treated (ITN) or untreated nets (UTN) were monitored.Kdrhomozygous mosquitoes, resistant to insecticides, were more attracted by a host behind an ITN than an UTN, while the presence of insecticide on the net did not affect the choice of susceptible mosquitoes. These results suggest that permethrin-impregnated net is detectable by malaria vectors and that thekdrmutation impacts their response to a LLIN protected host. We discuss the implication of these results for malaria vector control.
A statistical framework for mapping risk genes fromde novomutations in whole-genome sequencing studies
Authors: Liu Yuwen , Liang Yanyu , Cicek A. Ercument , Li Zhongshan , Li Jinchen , Muhle Rebecca , Krenzer Martina , Mei Yue , Wang Yan , Knoblauch Nicholas , Morrison Jean , Zhao Siming , Jiang Yi , Geller Evan , Ionita-Laza Iuliana , Wu Jinyu , Xia Kun , Noonan James , Sun Zhong Sheng , He Xin
Published: September 2016

Analysis ofde novomutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWAS) strongly suggests that variants important to human diseases often lie in non-coding regions. Extending DNM-based approaches to non-coding sequences is, however, challenging because the functional significance of non-coding mutations is difficult to predict. We propose a new statistical framework for analyzing DNMs from whole-genome sequencing (WGS) data. This method, TADA-Annotations (TADA-A), is a major advance of the TADA method we developed earlier for DNM analysis in coding regions. TADA-A is able to incorporate many functional annotations such as conservation and enhancer marks, learn from data which annotations are informative of pathogenic mutations and combine both coding and non-coding mutations at the gene level to detect risk genes. It also supports meta-analysis of multiple DNM studies, while adjusting for study-specific technical effects. We applied TADA-A to WGS data of ∼300 autism family trios across five studies, and discovered several new autism risk genes. The software is freely available for all research uses.
tert-Butyl 2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylate
Authors: Jordon Jason A. , Badenock Jeanese C. , Gribble Gordon W. , Kaur Manpreet , Jasinski Jerry P.
Published: September 2016

In the title molecule, C16H19NO2, all the non-hydrogen atoms except two of the C atoms of thetert-butyl group lie on a crystallographic mirror plane. No classical hydrogen bonds are observed. The crystal packing is influenced by weak π–π and C—H...π interactions.
Necrosociality: isolated death and unclaimed cremains in Japan
Authors: Kim Jieun
Published: September 2016

Inquiring into concerns surrounding death and the afterlife in an underclass enclave in Japan, this article proposes that the politics of survival involves engaging with the enduring relationship between the living and the dead, referred to as ‘necrosociality’. Based on fieldwork carried out in Yokohama, it explores how ‘isolated death’ (kodokushi) and ‘disconnected spirits’ (muenbotoke) have become major concerns in homeless activism and support, giving rise to various necrosocial innovations and practices. The emergent necrosociality in Yokohama conjures up an alternative logic of care that connects people based on the general premise of inevitable decay and decline rather than familial ties and intimate memories. This article suggests that the concept of necrosociality provides a useful framework for analysing how social relations are negotiated, reaffirmed, or negated through bodily remains and graves, effectively shaping the modes of being and care among the living.
Natural Antimicrobial Edible Coatings for Microbial Safety and Food Quality Enhancement
Authors: Aloui Hajer , Khwaldia Khaoula
Published: September 2016

Natural antimicrobial agents have been investigated as alternatives to synthetic ones for ensuring food safety and quality. However, the practical use of these preservatives in the food industry is limited due to their negative impact on the odor and taste of food products, as well as the early loss of functionality due to their rapid diffusion and interaction with food components. The incorporation of natural antimicrobial agents into edible coatings has been investigated to control diffusion of active compounds and maintain their concentrations at a critical level on a food surface. Recently, nanoencapsulating and multilayered/nanolaminate delivery systems have emerged as promising tools to enhance the functionality of edible coatings. This review highlights the potential use of polymeric edible coatings for the incorporation of natural antimicrobial agents and the improvement of their controlled release in food systems. The methods used to assess the antimicrobial activity of encapsulated natural antimicrobial agents and the most recent findings regarding the application of nanoencapsulating and multilayered/nanolaminate delivery systems in food products are also discussed.
Diurnal and Nocturnal Flight Activity of Blow Flies (Diptera: Calliphoridae) in a Rainforest Fragment in Brazil: Implications for the Colonization of Homicide Victims
Authors: Soares Thiago F. , Vasconcelos Simao D.
Published: September 2016

Nocturnal flight of blow flies (Diptera: Calliphoridae) is a controversial issue in forensic entomology. We performed two field experiments to investigate the diurnal and nocturnal activity of six blow fly species in a rainforest fragment in Brazil. Initially, nocturnal (17:30–05:30) versus diurnal (05:30–17:30) flight activity was investigated. Only 3.9% of adults were collected at night, mostly the native species Mesembrinella bicolor, and nocturnal oviposition did not occur. In the second experiment, collection of adults took place at the following intervals: 05:30–08:30, 08:30–11:30, 11:30–14:30, and 14:30–17:30. The proportions of adults did not differ significantly among the four diurnal intervals, except for Hemilucilia segmentaria, which was captured more frequently in the early morning. Calliphoridae has predominantly diurnal behavior, not laying eggs in darkness. The association of the native species M. bicolor, Hemilucilia semidiaphana, and H. segmentaria to forested areas reinforces the forensic relevance of data on their flight pattern.
The Impotence of Accountability: The Relationship Between Greater Transparency and Corporate Reform
Authors: Radcliffe Vaughan S. , Spence Crawford , Stein Mitchell
Published: September 2016

This paper explores the role of accounting in the attempted reform of the corporation during the “progressive era” in the United States. Focusing on the activities of three institutional bodies in the early twentieth century, the paper documents how their repeated recourse to “publicity,” which relied crucially on accounting technologies, failed to turn the corporation into an entity more sensitive to the public interest. Specifically, two interrelated contributions are made to existing literature on accounting and corporate governance. Firstly, the paper documents the early historical development of the now taken‐for‐granted phenomenon of accounting and adjudicating at the entity level (Miller and Power 2013). Secondly, the paper offers a rejoinder to present‐day projects of corporate governance which identify better and enhanced accountability as key to the successful reform of the corporation. During the progressive era, accounting expanded and territorialized new spaces, bringing trusts out of a hitherto secretive, private realm and into the view of the public. Yet this was not enough to engender substantive corporate reform.
Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge‐Like and Blunted Chronic Drinking by Mice
Authors: Newman Emily L. , Gunner Georgia , Huynh Polly , Gachette Darrel , Moss Stephen J. , Smart Trevor G. , Rudolph Uwe , DeBold Joseph F. , Miczek Klaus A.
Published: September 2016

Background

Alcohol use disorders are associated with single‐nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor α2‐subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether α2‐containing GABAA receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking.

Methods

Male wild‐type (Wt) C57BL/6J and point‐mutated mice rendered insensitive to GABAergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at α2‐containing GABAA receptors were assessed for their binge‐like, moderate, or escalated chronic drinking using drinking in the dark, continuous access (CA) and intermittent access (IA) to alcohol protocols, respectively. Social approach by mutant and Wt mice in forced alcohol abstinence was compared to approach by EtOH‐naïve controls. Social deficits in forced abstinence were treated with allopregnanolone (0, 3.0, 10.0 mg/kg, intraperitoneal [i.p.]) or midazolam (0, 0.56, 1.0 mg/kg, i.p.).

Results

Mice with BZD‐insensitive α2‐containing GABAA receptors (H101R) escalated their binge‐like drinking. Mutants harboring the Q241M point substitution in Gabra2 showed blunted chronic intake in the CA and IA protocols. S270H/L277A mutants consumed excessive amounts of alcohol but, unlike wild‐types, they did not show forced abstinence‐induced social deficits.

Conclusions

These findings suggest a role for: (i) H101 in species‐typical binge‐like drinking, (ii) Q241 in escalated chronic drinking, and (iii) S270 and/or L277 in the development of forced abstinence‐associated social deficits. Clinical findings report reduced BZD‐binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD‐sensitive α2‐containing receptors. In addition, amino acid residue 241 in Gabra2 is necessary for positive modulation and activation of GABAA receptors by ALLO and THDOC; we postulate that neurosteroid action on α2‐containing receptor may be necessary for escalated chronic EtOH intake.
Alcohol Withdrawal Increases Protein Kinase A Activity in the Rat Inferior Colliculus
Authors: Akinfiresoye Luli R. , Miranda Clive , Lovinger David M. , N'Gouemo Prosper
Published: September 2016

Background

Cyclic AMP‐dependent protein kinase A (PKA) signaling is a key target for the action of alcohol and may therefore play a role in the pathophysiology of alcohol withdrawal seizures (AWSs). Here, we investigated the role of PKA activity with respect to increased seizure susceptibility in rats that were subjected to alcohol withdrawal.

Methods

Adult male Sprague Dawley rats received 3 daily doses of ethanol (EtOH) (or vehicle) for 4 consecutive days. Rats were then tested for susceptibility to acoustically evoked AWSs 3, 24, and 48 hours after the last alcohol dose. In separate experiments, the inferior colliculus (IC) was collected at these same time points from rats subjected to alcohol withdrawal and control rats following alcohol withdrawal. PKA activity, catalytic Cα (PKACα) protein, regulatory RIIα (PKARIIα) protein, and RIIβ (PKARIIβ) protein were measured in the IC. Lastly, in situ pharmacological studies were performed to evaluate whether inhibiting PKA activity in the IC suppressed AWSs.

Results

In the EtOH‐treated group, AWSs were observed at the 24‐hour time point, but not at the 3‐hour or 48‐hour time points. In the IC, PKA activity was significantly higher both 3 hours (i.e., before AWS susceptibility) and 24 hours after the last alcohol dose (when AWS susceptibility peaked) than in control rats. Consistent with these findings, protein levels of the PKACα subunit were significantly increased in the IC both 3 and 24 hours after the last alcohol dose. Lastly, in situ inhibition of PKA activity within the IC suppressed AWSs.

Conclusions

The increase in PKA activity and PKACα protein expression in the IC preceded the occurrence of AWSs, and inhibiting PKA activity within the IC suppressed acoustically evoked AWSs. Together, these findings suggest that altered PKA activity plays a key role in the pathogenesis of AWSs.
Validating a proxy for disease progression in metastatic cancer patients using prescribing and dispensing data
Authors: Joshi Vikram , Adelstein Barbara‐Ann , Schaffer Andrea , Srasuebkul Preeyaporn , Dobbins Timothy , Pearson Sallie‐Anne ,   the Elements of Cancer Care (EoCC) Investigators
Published: September 2016

Background

Routine data collections are used increasingly to examine outcomes of real‐world cancer drug use. These datasets lack clinical details about important endpoints such as disease progression.

Aim

To validate a proxy for disease progression in metastatic cancer patients using prescribing and dispensing claims.

Methods

We used data from a cohort study of patients undergoing chemotherapy who provided informed consent to the collection of cancer‐treatment data from medical records and linkage to pharmaceutical claims. We derived proxy decision rules based on changes to drug treatment in prescription histories (n = 36 patients) and validated the proxy in prescribing data (n = 62 patients). We adapted the decision rules and validated the proxy in dispensing data (n = 109). Our gold standard was disease progression ascertained in patient medical records. Individual progression episodes were the unit of analysis for sensitivity and Positive Predictive Value (PPV) calculations and specificity and Negative Predictive Value (NPV) were calculated at the patient level.

Results

The sensitivity of our proxy in prescribing data was 74.3% (95% Confidence Interval (CI), 55.6–86.6%) and PPV 61.2% (95% CI, 45.0–75.3%); specificity and NPV were 87.8% (95% CI, 73.8–95.9%) and 100% (95% CI, 90.3–100%), respectively. In dispensing data, the sensitivity of our proxy was 64% (95% CI, 55.0–77.0%) and PPV 56.0% (95% CI, 43.0–69.0%); specificity and NPV were 81% (95% CI, 70.05–89.0%) and 91.0% (95% CI, 82.0–97.0%), respectively.

Conclusion

Our proxy overestimated episodes of disease progression. The proxy's performance is likely to improve if the date of prescribing is used instead of date of dispensing in claims data and by incorporating medical service claims (such as imaging prior to drug changes) in the algorithm. Our proxy is not sufficiently robust for use in real world comparative effectiveness research for cancer medicines.
Complement component C1q as potential diagnostic but not predictive marker of preeclampsia
Authors: Agostinis Chiara , Stampalija Tamara , Tannetta Dionne , Loganes Claudia , Vecchi Brumatti Liza , De Seta Francesco , Celeghini Claudio , Radillo Oriano , Sargent Ian , Tedesco Francesco , Bulla Roberta
Published: September 2016

Problem

We have previously found that C1q is constitutively expressed by invading trophoblast and endothelial cells of decidua and contributes to vascular and tissue remodeling. Based on these findings, we sought to determine whether there were changes in the circulating level of C1q that may be used as a diagnostic and predictive marker of preeclampsia.

Method of Study

We measured the levels of C1q, C4, and complement activation products in serum or plasma of normal pregnant women and preeclamptic patients from different cohorts.

Results

We observed a marked decrease in the concentration of C1q associated with a reduced level of C4 in preeclamptic patients as compared to matched healthy pregnant woman but no significant difference in the circulating level of the activating products C5a and the soluble terminal complement complex sC5b‐9. Analysis of serum samples collected at early phase of pregnancy from women who later developed preeclampsia failed to show a decrease in C1q level.

Conclusion

The results of the present investigation demonstrate that low levels of C1q and C4 are associated with preeclampsia but cannot be used as predictive markers.
Survey of horse transportation in Australia: issues and practices
Authors: Padalino B , Raidal SL , Hall E , Knight P , Celi P , Jeffcott L , Muscatello G
Published: September 2016

Objective

To survey amateur and professional participants on equine transportation management, practices and outcomes in Australia.

Methods

An online survey targeting people who organised horse movements at least monthly was made available to a broad cross‐section of amateur and professional equine associations. Respondents were invited to provide demographic details and information relating to their routine transportation management practices and their experiences of issues relating to the transportation of horses.

Results

Of 797 usable responses involving approximately 17,000 horses and 313,000 individual horse transport events, transport‐related behavioural problems were reported by 38% of respondents, particularly at loading. Transport‐related health problems had been experienced during or after transportation by horses in the care of 67% of respondents. The most common problems reported were traumatic injuries (45.0%), diarrhoea (20.0%), muscular problems (13.0%), respiratory problems (12.3%), overheating (10.5%) and colic (10.3%). In the 2 years reviewed in the survey, 9.4% of participants reported at least one case of transport‐associated pneumonia and 35 horses had died, most commonly from fractures, colic or pneumonia. Although respondents identifying as amateurs transported horses less frequently and over shorter distances, the incidence of transport‐related problems was similar between amateurs and professionals. Respondents reported specific precautions before, during and after transportation, although management was often not compliant with the Australian Code of horse transportation.

Conclusions

Responses indicated that there remains a substantial risk of adverse welfare and health outcomes for horses transported in Australia and management practices reported may not be compliant with current recommendations for transportation.
Prothrombin time and activated partial thromboplastin time using a point‐of‐care analyser (Abaxis VSpro®) in Bennett's wallabies (Macropus rufogriseus)
Authors: Nevitt BN , Chinnadurai SK , Watson MK , Langan JN , Adkesson MJ
Published: September 2016

There are few reports of coagulation times in marsupial species. Blood samples collected from 14 Bennett's wallabies (Macropus rufogriseus) under anaesthesia during routine health assessments were analysed for prothrombin time (PT) and activated partial thromboplastin time (aPTT) using a point‐of‐care analyser (POC) (Abaxis VSPro®). The wallabies had an aPTT mean of 78.09 s and median of 78.1 s. The PT for all wallabies was greater than 35 s, exceeding the longest time measured on the POC. Although PT was significantly longer, aPTT was similar to the manufacturer's domestic canine reference range.
Phenotypic and genotypic profiling of antimicrobial resistance in enteric Escherichia coli communities isolated from finisher pigs in Australia
Authors: Smith MG , Jordan D , Gibson JS , Cobbold RN , Chapman TA , Abraham S , Trott DJ
Published: September 2016

Objective

To assess herd‐to‐herd variation in antimicrobial resistance phenotypes and associated antimicrobial resistance genes (ARGs) in faecal commensal Escherichia coli communities isolated from Australian slaughter‐age pigs.

Methods

Hydrophobic grid‐membrane filtration (HGMF) was used to screen populations of E. coli isolated from faecal samples obtained from pigs prior to or at slaughter. Multiplex PCRs were applied to the pooled DNA extracted from the samples to identify specific ARGs.

Methods

Pooled faecal samples from 30 finishers, from 72 different Australian pig farms, produced 5003 isolates for screening. HGMF techniques and image analysis were used to confirm E. coli resistance phenotypes to four antimicrobial agents (ampicillin, gentamicin, florfenicol and ceftiofur) using selective agars. Multiplex PCRs were performed on DNA from pooled samples for 35 ARGs associated with seven chemical classes.

Results

The prevalence of E. coli isolates showing no resistance to any of the drugs was 50.2% (95% confidence interval (CI) 41.8–58.6%). Ceftiofur resistance was very low (1.8%; CI 0.8–3.9%) and no ARGs associated with 3rd‐generation cephalosporin resistance were detected. By contrast, ampicillin (29.4%, CI 22.8–37.0%), florfenicol (24.3%, CI 17.8–32.3%) and gentamicin (CI 17.5%, 10.7–27.2%) resistance prevalence varied greatly between farms and associated ARGs were common. The most common combined resistance phenotype was ampicillin–florfenicol.

Conclusion

The use of registered antimicrobials in Australian pigs leads to the enteric commensal populations acquiring associated ARGs. However, despite a high intensity of sampling, ARGs imparting resistance to the critically important 3rd‐generation cephalosporins were not detected.
Instability and Change in Collective Bargaining: An Analysis of the Effects of Changing Institutional Structures
Authors: Brandl Bernd , Ibsen Christian Lyhne
Published: September 2016

Previous studies on collective bargaining structures and macroeconomic performance have largely ignored the role of stable and instable institutional structures and the effects of institutional change itself. In this article we posit that institutional stability of collective bargaining is of major importance for the moderation of unit labour costs growth. This hypothesis is tested on the basis of data which cover the period 1965–2012 and includes 28 countries. The results show that institutional change impairs the capacity to moderate unit labour cost growth significantly in the subsequent years following the change. This effect also holds for changes in both decentralization and centralization of institutions.
Rapid synthesis of flavone‐based monoamine oxidase (MAO) inhibitors targeting two active sites using click chemistry
Authors: Jia Wei Zhen , Cheng Feng , Zhang Yin Jun , Ge Jin Yan , Yao Shao Q. , Zhu Qing
Published: September 2016

A new library of flavone derivatives targeting two active sites of monoamine oxidases (“aromatic cage” and substrate cavity) were designed and synthesized using click chemistry (CuAAC reaction) between 6‐N3‐2‐phenyl chromones (Az1–Az2) and a series of alkynes (k1–k20). Their inhibitory activities against MAO isoforms (MAO‐A and MAO‐B) are evaluated. Compounds with fluorine, amide bonds, or amino bonds have shown better inhibition. The most potent flavone MAO inhibitor studied is Az2k19 (1.6 μm for MAO‐A, 2.1 μm for MAO‐B), while Az1k15 and Az2k15 displayed better selectivity toward MAO‐B (SI > 10). Docking studies are in accordance with our hypothesis that these inhibitors are most likely located at both the substrate cavity and the “aromatic cage”. Our results show that it is considerable to develop new MAO inhibitors from C6 substitution of flavone derivatives and that these compounds are also potential for the treatment of diseases associated with MAOs.
KLF4 Knockdown Attenuates TBI‐Induced Neuronal Damage through p53 and JAK‐STAT3 Signaling
Authors: Cui Da‐Ming , Zeng Tao , Ren Jie , Wang Ke , Jin Yi , Zhou Lin , Gao Liang
Published: September 2016

Aims

Traumatic brain injury (TBI) is induced by complex primary and secondary mechanisms that give rise to cell death, inflammation, and neurological dysfunction. Understanding the mechanisms that drive neurological damage as well as those that promote repair can guide the development of therapeutic drugs for TBI. Kruppel‐like factor 4 (KLF4) has been reported to negatively regulate axon regeneration of injured retinal ganglion cells (RGCs) through inhibition of JAK‐STAT3 signaling. However, the role of KLF4 in TBI remains unreported. Reactive oxygen species (ROS)‐induced neuronal death is a pathophysiological hallmark of TBI.

Methods

In this study, we used H2O2‐treated RGCs in vitro and the optic nerve crush model in vivo to simulate neuronal damage in TBI. The function of KLF4 in RGC survival and axon regeneration in these models was investigated. In addition, the effects of KLF4 knockdown on neuronal damage after a brain impact that mimics moderate TBI were studied.

Results

The results show that H2O2 induces p53‐dependent apoptosis of RGCs in vitro through upregulation of KLF4. Additionally, KLF4 knockdown in vivo significantly enhances CNTF‐induced axon regeneration of RGCs after optic nerve crush, and more importantly, prevents neuronal damage after a moderate brain impact in rats. Our Western blot analysis and immunoprecipitation assay results indicate that these effects of KLF4 knockdown are mediated by the p53 and JAK‐STAT3 pathways.

Conclusion

These findings provide evidence that KLF4 plays an important role in the pathophysiology of TBI. Blocking KLF4 may be a potential therapeutic strategy for the treatment of TBI, either alone or in combination with agents that target complementary mechanisms.
Postoperative value of serum squamous cell carcinoma antigen as a predictor of recurrence in sinonasal inverted papilloma
Authors: van Zijl F.V.W.J. , Monserez D.A. , Korevaar T.I.M. , Bugter O. , Wieringa M.H. , Baatenburg de Jong R.J. , Hardillo J.A.U.
Published: September 2016

Objectives

Sinonasal inverted papilloma (IP) has several unfavourable characteristics and therefore requires careful monitoring. The goal of this study was to identify whether serum squamous cell carcinoma antigen (SCCa) could predict IP recurrence.

Design

A retrospective cohort study.

Setting

Department of otolaryngology/head and neck surgery, Erasmus Medical Centre, Rotterdam, the Netherlands.

Participants

One hundred and thirty patients with IP treated at our centre with SCCa measurements available were included.

Main outcome measurements

Follow‐up of patients with IP since 2005, recurrence was defined as new disease within primary localisation at least 3 months after adequate surgical removal. We analysed the association between IP recurrence and serum SCCa values measured preoperatively, postoperatively and during follow‐up.

Results

Preoperative SCCa values or values measured during follow‐up were not associated with risk of recurrence. Postoperative SCCa was positively associated with the risk of recurrence (P < 0.001). Postoperative SCCa had a good discriminative ability for the identification of recurrence with an area under the curve of 80.9%.

Conclusion

Postoperative SCCa is strongly associated with risk of recurrence. This might help the surgeon in the postoperative setting by identifying high‐risk patients and planning follow‐up strategy tailored to the individual patient.
Clinicopathological differences between familial colorectal cancer type X and sporadic cancer in an isolated area of spain
Authors: Medina‐Arana V. , Rahy‐Martín A. , Delgado‐Plasencia L. , Martínez‐Riera A. , León‐Ayllón D. , Rodríguez‐Castellano D. , Bravo‐Gutiérrez A. , Fernández‐Peralta A. , González‐Aguilera J. J.
Published: September 2016

Aim

Very few studies have compared the epidemiological characteristics of patients with familial colorectal cancer Type X (FCCTX) with those of sporadic colorectal cancer (S‐CRC). The aim of this study was to compare clinicopathological characteristics and survival between FCCTX and S‐CRC in patients from a historically isolated geographical region.

Method

A retrospective study was carried out of patients with S‐CRC and FCCTX treated in the Canary Islands. Family and personal history of colorectal cancer (CRC) were recorded, together with genetic (microsatellite instability), immunohistochemical and clinical variables.

Results

Forty‐eight (10.6%) of 451 patients were classified as FCCTX and the remaining 403 (89.4%) as S‐CRC. Age at the diagnosis of tumour was significantly lower in FCCTX than in S‐CRC (64.06 ± 12.65 years vs 69.13 ± 10.80 years; P = 0.01; Z = −2.48). Patients with FCCTX had a larger number of synchronous tumours (P = 0.09). Recurrence was significantly higher in FCCTX than in S‐CRC (18.7% vs 8.6%; P = 0.01). Survival correlated significantly with the number of first‐degree and second‐degree relatives with CRC (P = 0.04; OR: 1.368, 95% CI: 1.01–1.84, and P = 0.04; OR: 1.363, 95% CI: 1.08–1.65) and with the total number of cases of CRC in the immediate family (P < 0.01; OR: 1.377, 95% CI: 1.17–1.61). Recurrence‐free time was significantly lower in patients with FCCTX (log‐rank = 0.01).

Conclusion

Significant differences were found in several demographic and clinicopathological variables between patients with FCCTX and patients with S‐CRC. These included increased tumour presentation under the age of 50 years and a higher recurrence rate in patients with FCCTX, suggesting an increased risk of CRC in this group.
A collaborative review of the current concepts and challenges of anastomotic leaks in colorectal surgery
Authors: Vallance A. , Wexner S. , Berho M. , Cahill R. , Coleman M. , Haboubi N. , Heald R. J. , Kennedy R. H. , Moran B. , Mortensen N. , Motson R. W. , Novell R. , O'Connell P. R. , Ris F. , Rockall T. , Senapati A. , Windsor A. , Jayne D. G.
Published: September 2016

The reduction of the incidence, detection and treatment of anastomotic leakage (AL) continues to challenge the colorectal surgical community. AL is not consistently defined and reported in clinical studies, its occurrence is variably reported and its impact on longterm morbidity and health‐care resources has received relatively little attention. Controversy continues regarding the best strategies to reduce the risk. Diagnostic tests lack sensitivity and specificity, resulting in delayed diagnosis and increased morbidity. Intra‐operative fluorescence angiography has recently been introduced as a means of real‐time assessment of anastomotic perfusion and preliminary evidence suggests that it may reduce the rate of AL. In addition, concepts are emerging about the role of the rectal mucosal microbiome in AL and the possible role of new prophylactic therapies. In January 2016 a meeting of expert colorectal surgeons and pathologists was held in London, UK, to identify the ongoing controversies surrounding AL in colorectal surgery. The outcome of the meeting is presented in the form of research challenges that need to be addressed.