bluuebunny/crossref_metadata_2025 huggingface dataset:
Single CA3 pyramidal cells trigger sharp waves in vitro by exciting interneurones
Authors: Bazelot Michaël , Teleńczuk Maria T. , Miles Richard
Published: January 2016

Key points

The CA3 hippocampal region generates sharp waves (SPW), a population activity associated with neuronal representations. The synaptic mechanisms responsible for the generation of these events still require clarification.

Using slices maintained in an interface chamber, we found that the firing of single CA3 pyramidal cells triggers SPW like events at short latencies, similar to those for the induction of firing in interneurons.

Multi‐electrode records from the CA3 stratum pyramidale showed that pyramidal cells triggered events consisting of putative interneuron spikes followed by field IPSPs. SPW fields consisted of a repetition of these events at intervals of 4–8 ms. Although many properties of induced and spontaneous SPWs were similar, the triggered events tended to be initiated close to the stimulated cell.

These data show that the initiation of SPWs in vitro is mediated via pyramidal cell synapses that excite interneurons. They do not indicate why interneuron firing is repeated during a SPW.

Sharp waves (SPWs) are a hippocampal population activity that has been linked to neuronal representations. We show that SPWs in the CA3 region of rat hippocampal slices can be triggered by the firing of single pyramidal cells. Single action potentials in almost one‐third of pyramidal cells initiated SPWs at latencies of 2–5 ms with probabilities of 0.07–0.76. Initiating pyramidal cells evoked field IPSPs (fIPSPs) at similar latencies when SPWs were not initiated. Similar spatial profiles for fIPSPs and middle components of SPWs suggested that SPW fields reflect repeated fIPSPs. Multiple extracellular records showed that the initiated SPWs tended to start near the stimulated pyramidal cell, whereas spontaneous SPWs could emerge at multiple sites. Single pyramidal cells could initiate two to six field IPSPs with distinct amplitude distributions, typically preceeded by a short‐duration extracellular action potential. Comparison of these initiated fields with spontaneously occurring inhibitory field motifs allowed us to identify firing in different interneurones during the spread of SPWs. Propagation away from an initiating pyramidal cell was typically associated with the recruitment of interneurones and field IPSPs that were not activated by the stimulated pyramidal cell. SPW fields initiated by single cells were less variable than spontaneous events, suggesting that more stereotyped neuronal ensembles were activated, although neither the spatial profiles of fields, nor the identities of interneurone firing were identical for initiated events. The effects of single pyramidal cell on network events are thus mediated by different sequences of interneurone firing.
Rosmarinic acid is a homoserine lactone mimic produced by plants that activates a bacterial quorum-sensing regulator
Authors: Corral-Lugo Andrés , Daddaoua Abdelali , Ortega Alvaro , Espinosa-Urgel Manuel , Krell Tino
Published: January 2016

Plants release rosmarinic acid, which mimics bacterial quorum-sensing signals, to interfere with bacterial communication.
Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use
Authors: Sun Jing , Li Ning , Oh Kyu-Seon , Dutta Bhaskar , Vayttaden Sharat J. , Lin Bin , Ebert Thomas S. , De Nardo Dominic , Davis Joie , Bagirzadeh Rustam , Lounsbury Nicolas W. , Pasare Chandrashekhar , Latz Eicke , Hornung Veit , Fraser Iain D. C.
Published: January 2016

Comparative analysis of mouse and human macrophages reveals conserved and species-specific use of Toll-like receptor signaling components.
Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis
Authors: Sergin Ismail , Bhattacharya Somashubhra , Emanuel Roy , Esen Emel , Stokes Carl J. , Evans Trent D. , Arif Batool , Curci John A. , Razani Babak
Published: January 2016

Sequestration of aggregated proteins by p62 prevents macrophages from exacerbating atherosclerosis.
Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis
Authors: Jacobs M. , Grégoire N. , Mégarbane B. , Gobin P. , Balayn D. , Marchand S. , Mimoz O. , Couet W.
Published: January 2016

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [
f
AUC]/MIC of >10 and
f
AUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an
a priori
clear and easy to follow dosing strategy for CMS in ICU-HD patients.
Novel Polyanions Inhibiting Replication of Influenza Viruses
Authors: Ciejka Justyna , Milewska Aleksandra , Wytrwal Magdalena , Wojarski Jacek , Golda Anna , Ochman Marek , Nowakowska Maria , Szczubialka Krzysztof , Pyrc Krzysztof
Published: January 2016

Novel sulfonated derivatives of poly(allylamine hydrochloride) (NSPAHs) and N-sulfonated chitosan (NSCH) have been synthesized, and their activity against influenza A and B viruses has been studied and compared with that of a series of carrageenans, marine polysaccharides of well-documented anti-influenza activity. NSPAHs were found to be nontoxic and very soluble in water, in contrast to gel-forming and thus generally poorly soluble carrageenans.
In vitro
and
ex vivo
studies using susceptible cells (Madin-Darby canine kidney epithelial cells and fully differentiated human airway epithelial cultures) demonstrated the antiviral effectiveness of NSPAHs. The activity of NSPAHs was proportional to the molecular mass of the chain and the degree of substitution of amino groups with sulfonate groups. Mechanistic studies showed that the NSPAHs and carrageenans inhibit influenza A and B virus assembly in the cell.
Complete Sequences of Multidrug Resistance Plasmids Bearing
rmtD1
and
rmtD2
16S rRNA Methyltransferase Genes
Authors: Bueno Maria Fernanda C. , Francisco Gabriela R. , de Oliveira Garcia Doroti , Doi Yohei
Published: January 2016

Complete nucleotide sequences were determined for two plasmids bearing
rmtD
group 16S rRNA methyltransferase genes. pKp64/11 was 78 kb in size, belonged to the IncL/M group, and harbored
bla
TEM-1b
,
sul1
,
qacE
Δ
1
,
dfrA22
, and
rmtD1
across two multidrug resistance regions (MRRs). pKp368/10 was 170 kb in size, belonged to the IncA/C group, and harbored
acrB
,
sul1
,
qacE
Δ
1
,
ant(3″)-Ia
,
aac(6′)-Ib
,
cat
,
rmtD2
, and
bla
CTX-M-8
across three MRRs. The
rmtD
-containing regions shared a conserved motif, suggesting a common origin for the two
rmtD
alleles.
Boronic Acid Transition State Inhibitors Active against KPC and Other Class A β-Lactamases: Structure-Activity Relationships as a Guide to Inhibitor Design
Authors: Rojas Laura J. , Taracila Magdalena A. , Papp-Wallace Krisztina M. , Bethel Christopher R. , Caselli Emilia , Romagnoli Chiara , Winkler Marisa L. , Spellberg Brad , Prati Fabio , Bonomo Robert A.
Published: January 2016

Boronic acid transition state inhibitors (BATSIs) are competitive, reversible β-lactamase inhibitors (BLIs). In this study, a series of BATSIs with selectively modified regions (R1, R2, and amide group) were strategically designed and tested against representative class A β-lactamases of
Klebsiella pneumoniae
, KPC-2 and SHV-1. Firstly, the R1 group of compounds 1a to 1c and 2a to 2e mimicked the side chain of cephalothin, whereas for compounds 3a to 3c, 4a, and 4b, the thiophene ring was replaced by a phenyl, typical of benzylpenicillin. Secondly, variations in the R2 groups which included substituted aryl side chains (compounds 1a, 1b, 1c, 3a, 3b, and 3c) and triazole groups (compounds 2a to 2e) were chosen to mimic the thiazolidine and dihydrothiazine ring of penicillins and cephalosporins, respectively. Thirdly, the amide backbone of the BATSI, which corresponds to the amide at C-6 or C-7 of β-lactams, was also changed to the following bioisosteric groups: urea (compound 3b), thiourea (compound 3c), and sulfonamide (compounds 4a and 4b). Among the compounds that inhibited KPC-2 and SHV-1 β-lactamases, nine possessed 50% inhibitory concentrations (IC
50
s) of ≤600 nM. The most active compounds contained the thiopheneacetyl group at R1 and for the chiral BATSIs, a carboxy- or hydroxy-substituted aryl group at R2. The most active sulfonamido derivative, compound 4b, lacked an R2 group. Compound 2b (S02030) was the most active, with acylation rates (
k
2
/
K
) of 1.2 ± 0.2 × 10
4
M
−1
s
−1
for KPC-2 and 4.7 ± 0.6 × 10
3
M
−1
s
−1
for SHV-1, and demonstrated antimicrobial activity against
Escherichia coli
DH10B carrying
bla
SHV
variants and
bla
KPC-2
or
bla
KPC-3
and against clinical strains of
Klebsiella pneumoniae
and
E. coli
producing different class A β-lactamase genes. At most, MICs decreased from 16 to 0.5 mg/liter.
Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030
Authors: Nguyen Nhu Q. , Krishnan Nikhil P. , Rojas Laura J. , Prati Fabio , Caselli Emilia , Romagnoli Chiara , Bonomo Robert A. , van den Akker Focco
Published: January 2016

Resistance to expanded-spectrum cephalosporins and carbapenems has rendered certain strains of
Klebsiella pneumoniae
the most problematic pathogens infecting patients in the hospital and community. This broad-spectrum resistance to β-lactamases emerges in part via the expression of KPC-2 and SHV-1 β-lactamases and variants thereof. KPC-2 carbapenemase is particularly worrisome, as the genetic determinant encoding this β-lactamase is rapidly spread via plasmids. Moreover, KPC-2, a class A enzyme, is difficult to inhibit with mechanism-based inactivators (e.g., clavulanate). In order to develop new β-lactamase inhibitors (BLIs) to add to the limited available armamentarium that can inhibit KPC-2, we have structurally probed the boronic acid transition state analog S02030 for its inhibition of KPC-2 and SHV-1. S02030 contains a boronic acid, a thiophene, and a carboxyl triazole moiety. We present here the 1.54- and 1.87-Å resolution crystal structures of S02030 bound to SHV-1 and KPC-2 β-lactamases, respectively, as well as a comparative analysis of the S02030 binding modes, including a previously determined S02030 class C ADC-7 β-lactamase complex. S02030 is able to inhibit vastly different serine β-lactamases by interacting with the conserved features of these active sites, which includes (i) forming the bond with catalytic serine via the boron atom, (ii) positioning one of the boronic acid oxygens in the oxyanion hole, and (iii) utilizing its amide moiety to make conserved interactions across the width of the active site. In addition, S02030 is able to overcome more distantly located structural differences between the β-lactamases. This unique feature is achieved by repositioning the more polar carboxyl-triazole moiety, generated by click chemistry, to create polar interactions as well as reorient the more hydrophobic thiophene moiety. The former is aided by the unusual polar nature of the triazole ring, allowing it to potentially form a unique C—H…O 2.9-Å hydrogen bond with S130 in KPC-2.
Trace Metal Acquisition by Marine Heterotrophic Bacterioplankton with Contrasting Trophic Strategies
Authors: Hogle Shane L. , Thrash J. Cameron , Dupont Chris L. , Barbeau Katherine A.
Published: January 2016

Heterotrophic bacteria in the SAR11 and
Roseobacter
lineages shape the marine carbon, nitrogen, phosphorous, and sulfur cycles, yet they do so having adopted divergent ecological strategies. Currently, it is unknown whether these globally significant groups partition into specific niches with respect to micronutrients (e.g., trace metals) and how that may affect marine trace metal cycling. Here, we used comparative genomics to identify diverse iron, cobalt, nickel, copper, and zinc uptake capabilities in SAR11 and
Roseobacter
genomes and uncover surprising unevenness within and between lineages. The strongest predictors for the extent of the metal uptake gene content are the total number of transporters per genome, genome size, total metal transporters, and GC content, but numerous exceptions exist in both groups. Taken together, our results suggest that SAR11 have strongly minimized their trace metal uptake versatility, with high-affinity zinc uptake being a unique exception. The larger
Roseobacter
genomes have greater trace metal uptake versatility on average, but they also appear to have greater plasticity, resulting in phylogenetically similar genomes having largely different capabilities. Ultimately, phylogeny is predictive of the diversity and extent of 20 to 33% of all metal uptake systems, suggesting that specialization in metal utilization mostly occurred independently from overall lineage diversification in both SAR11 and
Roseobacter
. We interpret these results as reflecting relatively recent trace metal niche partitioning in both lineages, suggesting that concentrations and chemical forms of metals in the marine environment are important factors shaping the gene content of marine heterotrophic
Alphaproteobacteria
of the SAR11 and
Roseobacter
lineages.
Dividing the Large Glycoside Hydrolase Family 43 into Subfamilies: a Motivation for Detailed Enzyme Characterization
Authors: Mewis Keith , Lenfant Nicolas , Lombard Vincent , Henrissat Bernard
Published: January 2016

The rapid rise in DNA sequencing has led to an expansion in the number of glycoside hydrolase (GH) families. The GH43 family currently contains α-
l
-arabinofuranosidase, β-
d
-xylosidase, α-
l
-arabinanase, and β-
d
-galactosidase enzymes for the debranching and degradation of hemicellulose and pectin polymers. Many studies have revealed finer details about members of GH43 that necessitate the division of GH43 into subfamilies, as was done previously for the GH5 and GH13 families. The work presented here is a robust subfamily classification that assigns over 91% of all complete GH43 domains into 37 subfamilies that correlate with conserved sequence residues and results of biochemical assays and structural studies. Furthermore, cooccurrence analysis of these subfamilies and other functional modules revealed strong associations between some GH43 subfamilies and CBM6 and CBM13 domains. Cooccurrence analysis also revealed the presence of proteins containing up to three GH43 domains and belonging to different subfamilies, suggesting significant functional differences for each subfamily. Overall, the subfamily analysis suggests that the GH43 enzymes probably display a hitherto underestimated variety of subtle specificity features that are not apparent when the enzymes are assayed with simple synthetic substrates, such as pNP-glycosides.
Ancient Evolution and Recent Evolution Converge for the Biodegradation of Cyanuric Acid and Related Triazines
Authors: Seffernick Jennifer L. , Wackett Lawrence P.
Published: January 2016

Cyanuric acid was likely present on prebiotic Earth, may have been a component of early genetic materials, and is synthesized industrially today on a scale of more than one hundred million pounds per year in the United States. In light of this, it is not surprising that some bacteria and fungi have a metabolic pathway that sequentially hydrolyzes cyanuric acid and its metabolites to release the nitrogen atoms as ammonia to support growth. The initial reaction that opens the
s
-triazine ring is catalyzed by the unusual enzyme cyanuric acid hydrolase. This enzyme is in a rare protein family that consists of only cyanuric acid hydrolase (CAH) and barbiturase, with barbiturase participating in pyrimidine catabolism by some actinobacterial species. The X-ray structures of two cyanuric acid hydrolase proteins show that this family has a unique protein fold. Phylogenetic, bioinformatic, enzymological, and genetic studies are consistent with the idea that CAH has an ancient protein fold that was rare in microbial populations but is currently becoming more widespread in microbial populations in the wake of anthropogenic synthesis of cyanuric acid and other
s
-triazine compounds that are metabolized via a cyanuric acid intermediate. The need for the removal of cyanuric acid from swimming pools and spas, where it is used as a disinfectant stabilizer, can potentially be met using an enzyme filtration system. A stable thermophilic cyanuric acid hydrolase from
Moorella thermoacetica
is being tested for this purpose.
Nicotine Dehydrogenase Complexed with 6-Hydroxypseudooxynicotine Oxidase Involved in the Hybrid Nicotine-Degrading Pathway in Agrobacterium tumefaciens S33
Authors: Li Huili , Xie Kebo , Yu Wenjun , Hu Liejie , Huang Haiyan , Xie Huijun , Wang Shuning
Published: January 2016

Nicotine, a major toxic alkaloid in tobacco wastes, is degraded by bacteria, mainly via pyridine and pyrrolidine pathways. Previously, we discovered a new hybrid of the pyridine and pyrrolidine pathways in
Agrobacterium tumefaciens
S33 and characterized its key enzyme 6-hydroxy-3-succinoylpyridine (HSP) hydroxylase. Here, we purified the nicotine dehydrogenase initializing the nicotine degradation from the strain and found that it forms a complex with a novel 6-hydroxypseudooxynicotine oxidase. The purified complex is composed of three different subunits encoded by
ndhAB
and
pno
, where
ndhA
and
ndhB
overlap by 4 bp and are ∼26 kb away from
pno
. As predicted from the gene sequences and from chemical analyses, NdhA (82.4 kDa) and NdhB (17.1 kDa) harbor a molybdopterin cofactor and two [2Fe-2S] clusters, respectively, whereas Pno (73.3 kDa) harbors an flavin mononucleotide and a [4Fe-4S] cluster. Mutants with disrupted
ndhA
or
ndhB
genes did not grow on nicotine but grew well on 6-hydroxynicotine and HSP, whereas the
pno
mutant did not grow on nicotine or 6-hydroxynicotine but grew well on HSP, indicating that NdhA and NdhB are responsible for initialization of nicotine oxidation. We successfully expressed
pno
in
Escherichia coli
and found that the recombinant Pno presented 2,6-dichlorophenolindophenol reduction activity when it was coupled with 6-hydroxynicotine oxidation. The determination of reaction products catalyzed by the purified enzymes or mutants indicated that NdhAB catalyzed nicotine oxidation to 6-hydroxynicotine, whereas Pno oxidized 6-hydroxypseudooxynicotine to 6-hydroxy-3-succinoylsemialdehyde pyridine. These results provide new insights into this novel hybrid pathway of nicotine degradation in
A. tumefaciens
S33.
Efficacy of T-705 (Favipiravir) in the Treatment of Infections with Lethal Severe Fever with Thrombocytopenia Syndrome Virus
Authors: Tani Hideki , Fukuma Aiko , Fukushi Shuetsu , Taniguchi Satoshi , Yoshikawa Tomoki , Iwata-Yoshikawa Naoko , Sato Yuko , Suzuki Tadaki , Nagata Noriyo , Hasegawa Hideki , Kawai Yasuhiro , Uda Akihiko , Morikawa Shigeru , Shimojima Masayuki , Watanabe Haruo , Saijo Masayuki
Published: January 2016

Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), is a recently identified emerging viral infectious disease. Despite the medical importance of this disease, there are currently neither vaccines nor effective therapeutics for SFTS. T-705, which is a pyrazine derivative, has shown broad antiviral activity against various RNA viruses. The present study demonstrated, for the first time to our knowledge, the efficacy of T-705 in treating SFTSV infection in a mouse lethal model. T-705 showed a high efficacy in the treatment of SFTSV infection in the mouse model, even when treatments were initiated after onset of the disease.
Evidence of Chinese herbal medicine Duhuo Jisheng decoction for knee osteoarthritis: a systematic review of randomised clinical trials
Authors: Zhang Wenming , Wang Shangquan , Zhang Ranxing , Zhang Yuanyuan , Li Xinjian , Lin Yanping , Wei Xu
Published: January 2016

Objectives

Duhuo Jisheng decoction (DJD) is considered beneficial for controlling knee osteoarthritis (KOA)-related symptoms in some Asian countries. This review compiles the evidence from randomised clinical trials and quantifies the effects of DJD on KOA.

Designs

7 online databases were investigated up to 12 October 2015. Randomised clinical trials investigating treatment of KOA for which DJD was used either as a monotherapy or in combination with conventional therapy compared to no intervention, placebo or conventional therapy, were included. The outcomes included the evaluation of functional activities, pain and adverse effect. The risk of bias was evaluated using the Cochrane Collaboration tool. The estimated mean difference (MD) and SMD was within a 95% CI with respect to interstudy heterogeneity.

Results

12 studies with 982 participants were identified. The quality presented a high risk of bias. Meta-analysis found that DJD combined with glucosamine (MD 4.20 (1.72 to 6.69); p<0.001) or DJD plus meloxicam and glucosamine (MD 3.48 (1.59 to 5.37); p<0.001) had a more significant effect in improving Western Ontario and McMaster Universities Arthritis Index (total WOMAC scores). Also, meta-analysis presented more remarkable pain improvement when DJD plus sodium hyaluronate injection (MD 0.89 (0.26 to 1.53); p=0.006) was used. These studies demonstrated that active treatment of DJD in combination should be practiced for at least 4 weeks. Information on the safety of DJD or comprehensive therapies was insufficient in few studies.

Conclusions

DJD combined with Western medicine or sodium hyaluronate injection appears to have benefits for KOA. However, the effectiveness and safety of DJD is uncertain because of the limited number of trials and low methodological quality. Therefore, practitioners should be cautious when applying DJD in daily practice. Future clinical trials should be well designed; more research is needed.
Outcomes of domestic violence screening at an acute London trust: are there missed opportunities for intervention?
Authors: Warren-Gash Charlotte , Bartley Angela , Bayly Jude , Dutey-Magni Peter , Edwards Sarah , Madge Sara , Miller Charlotte , Nicholas Rachel , Radhakrishnan Sheila , Sathia Leena , Swarbrick Helen , Blaikie Dee , Rodger Alison
Published: January 2016

Objectives

Domestic violence screening is advocated in some healthcare settings. Evidence that it increases referral to support agencies or improves health outcomes is limited. This study aimed to (1) investigate the proportion of hospital patients reporting domestic violence, (2) describe characteristics and previous hospital attendances of affected patients and (3) assess referrals to an in-house domestic violence advisor from Camden Safety Net.

Design

A series of observational studies.

Setting

Three outpatient clinics at the Royal Free London NHS Foundation Trust.

Participants

10 158 patients screened for domestic violence in community gynaecology, genitourinary medicine (GUM) and HIV medicine clinics between 1 October 2013 and 30 June 2014. Also 2253 Camden Safety Net referrals over the same period.

Main outcome measures

(1) Percentage reporting domestic violence by age group gender, ethnicity and clinic. (2) Rates of hospital attendances in the past 3 years for those screening positive and negative. (3) Characteristics, uptake and risk assessment results for hospital in-house domestic violence referrals compared with Camden Safety Net referrals from other sources.

Results

Of the 10 158 patients screened, 57.4% were female with a median age of 30 years. Overall, 7.1% reported ever-experiencing domestic violence, ranging from 5.7% in GUM to 29.4% in HIV services. People screening positive for domestic violence had higher rates of previous emergency department attendances (rate ratio (RR) 1.63, 95% CI 1.09 to 2.48), emergency inpatient admissions (RR 2.27, 95% CI 1.37 to 3.84) and day-case admissions (RR 2.03, 95% CI 1.23 to 3.43) than those screening negative. The 77 hospital referrals to the hospital-based domestic violence advisor during the study period were more likely to be taken up and to be classified as high risk than referrals from elsewhere.

Conclusions

Selective screening for domestic violence in high-risk hospital clinic populations has the potential to identify affected patients and promote good uptake of referrals for in-house domestic violence support.
Management of the anticoagulated trauma patient in the emergency department: a survey of current practice in England and Wales
Authors: Battle Ceri E , Lecky Fiona E , Stacey Tom , Edwards Antoinette , Evans Phillip A
Published: January 2016

Objective

The aim of this study was to investigate current management of the anticoagulated trauma patient in the emergency departments (EDs) in England and Wales.

Methods

A survey exploring management strategies for anticoagulated trauma patients presenting to the ED was developed with two patient scenarios concerning assessment of coagulation status, reversal of international normalised ratio (INR), management of hypotension and management strategies for each patient. Numerical data are presented as percentages of total respondents to that particular question.

Results

106 respondents from 166 hospitals replied to the survey, with 24% of respondents working in a major trauma unit with a specialist neurosurgical unit. Variation was reported in the assessment and management strategies of the elderly anticoagulated poly-trauma patient described in scenario one. Variation was also evident in the responses between the neurosurgical and non-neurosurgical units for the head-injured, anticoagulated trauma patient in scenario two.

Conclusion

The results of this study highlight the similarities and variation in the management strategies used in the EDs in England and Wales for the elderly, anticoagulated trauma patient. The variations in practice reported may be due to the differences evident in the available guidelines for these patients.
Helmet regulation in Vietnam: impact on health, equity and medical impoverishment
Authors: Olson Zachary , Staples John A , Mock Charles , Nguyen Nam Phuong , Bachani Abdulgafoor M , Nugent Rachel , Verguet Stéphane
Published: January 2016

Background

Vietnam's 2007 comprehensive motorcycle helmet policy increased helmet use from about 30% of riders to about 93%. We aimed to simulate the effect that this legislation might have on: (a) road traffic deaths and non-fatal injuries, (b) individuals’ direct acute care injury treatment costs, (c) individuals’ income losses from missed work and (d) individuals’ protection against medical impoverishment.

Methods and findings

We used published secondary data from the literature to perform a retrospective extended cost-effectiveness analysis simulation study of the policy. Our model indicates that in the year following its introduction a helmet policy employing standard helmets likely prevented approximately 2200 deaths and 29 000 head injuries, saved individuals US$18 million in acute care costs and averted US$31 million in income losses. From a societal perspective, such a comprehensive helmet policy would have saved $11 000 per averted death or $830 per averted non-fatal injury. In terms of financial risk protection, traffic injury is so expensive to treat that any injury averted would necessarily entail a case of catastrophic health expenditure averted.

Conclusions

The high costs associated with traffic injury suggest that helmet legislation can decrease the burden of out-of-pocket payments and reduced injuries decrease the need for access to and coverage for treatment, allowing the government and individuals to spend resources elsewhere. These findings suggest that comprehensive motorcycle helmet policies should be adopted by low-income and middle-income countries where motorcycles are pervasive yet helmet use is less common.
Effects and feasibility of exercise therapy combined with branched-chain amino acid supplementation on muscle strengthening in frail and pre-frail elderly people requiring long-term care: a crossover trial
Authors: Ikeda Takashi , Aizawa Junya , Nagasawa Hiroshi , Gomi Ikuko , Kugota Hiroyuki , Nanjo Keigo , Jinno Tetsuya , Masuda Tadashi , Morita Sadao
Published: January 2016

This study examined the effects and feasibility of a twice-weekly combined therapy of branched-chain amino acids (BCAAs) and exercise on physical function improvement in frail and pre-frail elderly people requiring long-term care. We used a crossover design in which the combination of exercise and nutritional interventions was carried out twice a week during cycles A (3 months) and B (3 months) and the exercise intervention alone was performed during the washout period. The exercise intervention entailed the following 5 training sets: 3 sets of muscle training at 30% of maximum voluntary contraction, 1 set of aerobic exercise, and 1 set of balance training. For the nutritional intervention, 6 g of BCAAs or 6 g of maltodextrin was consumed 10 min before starting the exercise. We determined upper and lower limb isometric strength, performance on the Functional Reach Test (FRT) and the Timed Up and Go test, and activity level. In the comparison between the BCAA group and the control group after crossover, the improvement rates in gross lower limb muscle strength (leg press, knee extension) and FRT performance were significantly greater (by approximately 10%) in the BCAA group. In the comparison between different orders of BCAA administration, significant effects were shown for the leg press in both groups only when BCAAs were given. The combination of BCAA intake and exercise therapy yielded significant improvements in gross lower limb muscle strength and dynamic balance ability.
Expansion of subalpine woody vegetation over 40 years on Vancouver Island, British Columbia, Canada
Authors: Jackson Michelle M. , Topp Emmeline , Gergel Sarah E. , Martin Kathy , Pirotti Francesco , Sitzia Tommaso
Published: January 2016

Climate change is leading to the global loss of open montane meadows by facilitating tree and shrub encroachment at high elevations. North America’s coastal mountains are particularly vulnerable to these changes, as they are relatively low elevation compared with interior mountains and contain only small areas of alpine tundra. We compared aerial photographs from 1962 with those from 2005 covering three subalpine regions on Vancouver Island, British Columbia, to document the extent of changes in woody vegetation and investigate associations between vegetation change and topography. Mean proportional woody vegetation cover increased significantly from 0.75±0.03 to 0.81±0.03 between 1962 and 2005 (p < 0.0001). Relative increase in woody vegetation cover was greater at higher elevations and on northerly aspects. These findings confirm an upward expansion and infilling of trees and shrubs and a reduction of the area encompassed by open alpine tundra on Vancouver Island. Loss of open meadow conditions at high elevations in this region will likely have consequences for alpine plant and animal communities.
Gauge concepts in theoretical applied physics
Authors: Tan Seng Ghee , Jalil Mansoor B. A.
Published: January 2016

Gauge concept evolves in the course of nearly one century from Faraday’s rather obscure electrotonic state of matter to the physically significant Yang–Mills that underpin today’s standard model. As gauge theories improve, links are established with modern observations, e.g. in the Aharonov–Bohm effect, the Pancharatnam–Berry’s phase, superconductivity, and quantum Hall effects. In this century, emergent gauge theory is formulated in numerous fields of applied physics like topological insulators, spintronics, and graphene. We will show in this paper the application of gauge theory in two particularly useful spin-based phenomena, namely the spin orbit spin torque and the spin Hall effect. These are important fields of study in the engineering community due to great commercial interest in the technology of magnetic memory (MRAM), and magnetic field sensors. Both spin orbit torque and spin Hall perform magnetic switching at low power and high speed. Furthermore, spin Hall is also a promising source of pure spin current, as well as a reliable form of detection mechanism for the magnetic state of a material.
Stability Analysis and Mapping of Multiple Dynamics of Chua’s Circuit in Full Four-Parameter Spaces
Authors: Rocha Ronilson , Medrano-T. Rene Orlando
Published: January 2016

The stability analysis is used in order to identify and to map different dynamics of Chua’s circuit in full four-parameter spaces. The study is performed using describing functions that allow to identify fixed point, periodic orbit, and unstable states with relative accuracy, as well as to predict route to chaos and hidden dynamics that conventional computational methods do not detect. Numerical investigations based on the computation of eigenvalues and Lyapunov exponents partially support the predictions obtained from the theoretical analysis since they do not capture the multiple dynamics that can coexist in the operation of Chua’s circuit. Attractors obtained from initial conditions outside of neighborhoods of the equilibrium points confirm the multiplicity of dynamics in the operation of Chua’s circuit and corroborate the theoretical analysis.
Multitype Activity Coexistence in an Inertial Two-Neuron System with Multiple Delays
Authors: Song Zigen , Xu Jian , Zhen Bin
Published: January 2016

In this paper, an inertial two-neuron system with multiple delays is analyzed to exhibit the effect of time delays on system dynamics. The parameter region with multiple equilibria is obtained employing the pitchfork bifurcation of trivial equilibrium. The stability analysis illustrates that two nontrivial equilibria are both stable for any delays. It implies that the neural system exhibits a stability coexistence of two resting states. Further, due to the existence of multiple delays, the neural system has a periodic activity around the trivial equilibrium via Hopf bifurcation. Finally, numerical simulations are employed to illustrate many richness coexistence for multitype activity patterns. Employing the period-adding route and fold bifurcation of periodic orbit, the neural system may have multistability coexistence of two resting states, two ASP-3s (anti-symmetric periodic activity with period three), one SSP-1 (self-symmetric periodic activity with period one), and one quasi-periodic spiking. Additionally, with increasing delay, quasi-periodic spiking evolves into chaos behavior.
Polynomial Normal Forms for Some Germs of Nonstrongly 1-Resonant Diffeomorphisms
Authors: Guo Lingling , Ren Zhihua
Published: January 2016

We study in this paper a class of smoothly finite determined germs of diffeomorphisms which have infinitely many resonant relations near a nonstrongly 1-resonant fixed point on [Formula: see text] and derive the simplest normal forms of such germs with nondegenerated nonlinear parts.
Limit Cycles Near a Piecewise Smooth Generalized Homoclinic Loop with a Nonelementary Singular Point
Authors: Liang Feng , Yang Junmin
Published: January 2016

In this paper, we deal with limit cycle bifurcations by perturbing a piecewise smooth Hamiltonian system with a generalized homoclinic loop passing through a nonelementary singular point. We first give an expansion of the first Melnikov function corresponding to a period annulus near the generalized homoclinic loop. Then, based on the first coefficients in the expansion we obtain a lower bound for the maximal number of limit cycles bifurcated from the period annulus. As applications, two concrete systems are considered.
Periodic Solutions of a Periodic FitzHugh–Nagumo System
Authors: Llibre Jaume , Vidal Claudio
Published: January 2016

Recently some interest has appeared for the periodic FitzHugh–Nagumo differential systems. Here, we provide sufficient conditions for the existence of periodic solutions in such differential systems.
The Chaotic Saddle in the Lozi Map, Autonomous and Nonautonomous Versions
Authors: Lopesino Carlos , Balibrea-Iniesta Francisco , Wiggins Stephen , Mancho Ana M.
Published: January 2016

In this paper, we prove the existence of a chaotic saddle for a piecewise-linear map of the plane, referred to as the Lozi map. We study the Lozi map in its orientation and area preserving version. First, we consider the autonomous version of the Lozi map to which we apply the Conley–Moser conditions to obtain the proof of a chaotic saddle. Then we generalize the Lozi map on a nonautonomous version and we prove that the first and the third Conley–Moser conditions are satisfied, which imply the existence of a chaotic saddle. Finally, we numerically demonstrate how the structure of this nonautonomous chaotic saddle varies as parameters are varied.
Thermal time shifting
Authors: Skach Matt , Arora Manish , Hsu Chang-Hong , Li Qi , Tullsen Dean , Tang Lingjia , Mars Jason
Published: January 2016

Datacenters, or warehouse scale computers, are rapidly increasing in size and power consumption. However, this growth comes at the cost of an increasing thermal load that must be removed to prevent overheating and server failure. In this paper, we propose to use phase changing materials (PCM) to shape the thermal load of a datacenter, absorbing and releasing heat when it is advantageous to do so. We present and validate a methodology to study the impact of PCM on a datacenter, and evaluate two important opportunities for cost savings. We find that in a datacenter with full cooling system subscription, PCM can reduce the necessary cooling system size by up to 12% without impacting peak throughput, or increase the number of servers by up to 14.6% without increasing the cooling load. In a thermally constrained setting, PCM can increase peak throughput up to 69% while delaying the onset of thermal limits by over 3 hours.
Page overlays
Authors: Seshadri Vivek , Pekhimenko Gennady , Ruwase Olatunji , Mutlu Onur , Gibbons Phillip B. , Kozuch Michael A. , Mowry Todd C. , Chilimbi Trishul
Published: January 2016

Many recent works propose mechanisms demonstrating the potential advantages of managing memory at a fine (e.g., cache line) granularity---e.g., fine-grained deduplication and fine-grained memory protection. Unfortunately, existing virtual memory systems track memory at a larger granularity (e.g., 4 KB pages), inhibiting efficient implementation of such techniques. Simply reducing the page size results in an unacceptable increase in page table overhead and TLB pressure.

We propose a new virtual memory framework that enables efficient implementation of a variety of fine-grained memory management techniques. In our framework, each virtual page can be mapped to a structure called a page overlay, in addition to a regular physical page. An overlay contains a subset of cache lines from the virtual page. Cache lines that are present in the overlay are accessed from there and all other cache lines are accessed from the regular physical page. Our page-overlay framework enables cache-line-granularity memory management without significantly altering the existing virtual memory framework or introducing high overheads.

We show that our framework can enable simple and efficient implementations of seven memory management techniques, each of which has a wide variety of applications. We quantitatively evaluate the potential benefits of two of these techniques: overlay-on-write and sparse-data-structure computation. Our evaluations show that overlay-on-write, when applied to fork, can improve performance by 15% and reduce memory capacity requirements by 53% on average compared to traditional copy-on-write. For sparse data computation, our framework can outperform a state-of-the-art software-based sparse representation on a number of real-world sparse matrices. Our framework is general, powerful, and effective in enabling fine-grained memory management at low cost.
Profiling a warehouse-scale computer
Authors: Kanev Svilen , Darago Juan Pablo , Hazelwood Kim , Ranganathan Parthasarathy , Moseley Tipp , Wei Gu-Yeon , Brooks David
Published: January 2016

With the increasing prevalence of warehouse-scale (WSC) and cloud computing, understanding the interactions of server applications with the underlying microarchitecture becomes ever more important in order to extract maximum performance out of server hardware. To aid such understanding, this paper presents a detailed microarchitectural analysis of live datacenter jobs, measured on more than 20,000 Google machines over a three year period, and comprising thousands of different applications.

We first find that WSC workloads are extremely diverse, breeding the need for architectures that can tolerate application variability without performance loss. However, some patterns emerge, offering opportunities for co-optimization of hardware and software. For example, we identify common building blocks in the lower levels of the software stack. This "datacenter tax" can comprise nearly 30% of cycles across jobs running in the fleet, which makes its constituents prime candidates for hardware specialization in future server systems-on-chips. We also uncover opportunities for classic microarchitectural optimizations for server processors, especially in the cache hierarchy. Typical workloads place significant stress on instruction caches and prefer memory latency over bandwidth. They also stall cores often, but compute heavily in bursts. These observations motivate several interesting directions for future warehouse-scale computers.
Multiple clone row DRAM
Authors: Choi Jungwhan , Shin Wongyu , Jang Jaemin , Suh Jinwoong , Kwon Yongkee , Moon Youngsuk , Kim Lee-Sup
Published: January 2016

Several previous works have changed DRAM bank structure to reduce memory access latency and have shown performance improvement. However, changes in the area-optimized DRAM bank can incur large area-overhead. To solve this problem, we propose Multiple Clone Row DRAM (MCR-DRAM), which uses existing DRAM bank structure without any modification.

Our key idea is Multiple Clone Row (MCR), in which multiple rows are simultaneously turned on or off to consist of a logically single row. MCR provides two advantages which enable our low-latency mechanisms (Early-Access, Early-Precharge and Fast-Refresh). First, MCR increases the speed of the sensing process by increasing the number of sensed-cells. Thus, it enables a READ/WRITE command to an MCR to be issued earlier than possible for a normal row (Early-Access). Second, DRAM cells in an MCR exhibit more frequent refreshes without additional REFRESH commands, thereby reducing the amount of charge leakage during the refresh interval for the identical cell. The reduced amount of charge leakage enables a PRECHARGE command to be served before the activated-cells are fully restored (Early-Precharge) and a REFRESH operation to be completed before the refreshed-cells are fully restored (Fast-Refresh).

Even though MCR-DRAM sacrifices memory capacity for low-latency, it can be dynamically reconfigured from low-latency to full-capacity DRAM. MCR-DRAM improves both performance and energy efficiency for both single-core and multi-core systems.
PrORAM
Authors: Yu Xiangyao , Haider Syed Kamran , Ren Ling , Fletcher Christopher , Kwon Albert , van Dijk Marten , Devadas Srinivas
Published: January 2016

Oblivious RAM (ORAM) is an established technique to hide the access pattern to an untrusted storage system. With ORAM, a curious adversary cannot tell what address the user is accessing when observing the bits moving between the user and the storage system. All existing ORAM schemes achieve obliviousness by adding redundancy to the storage system, i.e., each access is turned into multiple random accesses. Such redundancy incurs a large performance overhead.

Although traditional data prefetching techniques successfully hide memory latency in DRAM based systems, it turns out that they do not work well for ORAM because ORAM does not have enough memory bandwidth available for issuing prefetch requests. In this paper, we exploit ORAM locality by taking advantage of the ORAM internal structures. While it might seem apparent that obliviousness and locality are two contradictory concepts, we challenge this intuition by exploiting data locality in ORAM without sacrificing security. In particular, we propose a dynamic ORAM prefetching technique called PrORAM (Dynamic Prefetcher for ORAM) and comprehensively explore its design space. PrORAM detects data locality in programs at runtime, and exploits the locality without leaking any information on the access pattern.

Our simulation results show that with PrORAM, the performance of ORAM can be significantly improved. PrORAM achieves an average performance gain of 20% over the baseline ORAM for memory intensive benchmarks among Splash2 and 5.5% for SPEC06 workloads. The performance gain for YCSB and TPCC in DBMS benchmarks is 23.6% and 5% respectively. On average, PrORAM offers twice the performance gain than that offered by a static super block scheme.
Unified address translation for memory-mapped SSDs with FlashMap
Authors: Huang Jian , Badam Anirudh , Qureshi Moinuddin K. , Schwan Karsten
Published: January 2016

Applications can map data on SSDs into virtual memory to transparently scale beyond DRAM capacity, permitting them to leverage high SSD capacities with few code changes. Obtaining good performance for memory-mapped SSD content, however, is hard because the virtual memory layer, the file system and the flash translation layer (FTL) perform address translations, sanity and permission checks independently from each other. We introduce FlashMap, an SSD interface that is optimized for memory-mapped SSD-files. FlashMap combines all the address translations into page tables that are used to index files and also to store the FTL-level mappings without altering the guarantees of the file system or the FTL. It uses the state in the OS memory manager and the page tables to perform sanity and permission checks respectively. By combining these layers, FlashMap reduces critical-path latency and improves DRAM caching efficiency. We find that this increases performance for applications by up to 3.32x compared to state-of-the-art SSD file-mapping mechanisms. Additionally, latency of SSD accesses reduces by up to 53.2%.