bluuebunny/crossref_metadata_2025 huggingface dataset:
Southern Methodist University Football and the Stadia: Moving toward Modernization
Authors: Seifried Chad Stephen , Tutka Patrick
Published: November 2016

The specific information provided in this paper offers a descriptive history regarding the attempts of Southern Methodist University (SMU) to be “modern” through tracing the institution’s movement from one playing field to another. Like other southern universities, SMU started football and built an on-campus stadium of concrete and steel believing their legitimacy as an institution could be enhanced through providing football as a product for consumption. However, SMU is unique among many of its contemporaries because soon after building an on-campus facility, it decided to move off campus in the pursuit of greater name recognition and revenue. Collectively, such efforts were recognized as helping to make SMU the “educational surprise of the decade, if not the century,” following its opening in 1915. The modernization of SMU football stadia involves construction and renovation of facilities from Armstrong Field (1915) to Gerald J. Ford Stadium (current).
Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive Organisms Using Data from Murine Infection Models
Authors: Bulik Catharine C. , Okusanya Ólanrewaju O. , Lakota Elizabeth A. , Forrest Alan , Bhavnani Sujata M. , Hoover Jennifer L. , Andes David R. , Ambrose Paul G.
Published: November 2016

Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with
in vitro
activity against conventional and biothreat pathogens, including
Staphylococcus aureus
and
Streptococcus pneumoniae
. Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against
S. aureus
and
S. pneumoniae
were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for
S. aureus
and 0.125 to 1 mg/liter for
S. pneumoniae
) were conducted. The presence of an
in vivo
postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log
10
CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (
C
max
) to the MIC (
C
max
/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (%
T
>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (
r
2
= 0.936 and 0.897 for
S. aureus
and
S. pneumoniae
, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for
S. aureus
, and 7.86 and 16.9 for
S. pneumoniae
, were associated with net bacterial stasis and a 1-log
10
CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for
S. aureus
and
S. pneumoniae
, respectively.
Antischistosomiasis Liver Fibrosis Effects of Chlorogenic Acid through IL-13/miR-21/Smad7 Signaling Interactions
In Vivo
and
In Vitro
Authors: Wang Yao , Yang Fan , Xue Jun , Zhou Xuan , Luo Lei , Ma Qian , Chen Yun-Fei , Zhang Juan , Zhang Shu-Ling , Zhao Lei
Published: November 2016

This study investigated the antischistosomiasis liver fibrosis effects of chlorogenic acid (CGA) on interleukin 13 (IL-13)/microRNA-21 (miR-21)/Smad7 signaling interactions in the hepatic stellate LX2 cell line and schistosome-infected mice. The transfection was based on the ability of the GV273–miR-21–enhanced green fluorescent protein (EGFP) and GV369–miR-21–EGFP lentiviral system to up- or downregulate the miR-21 gene in LX2 cells. The mRNA expression of miR-21, Smad7, and connective tissue growth factor (CTGF) and the protein expression of Smad7, CTGF, Smad1, phosphor-Smad1 (p-Smad1), Smad2, p-Smad2, Smad2/3, p-Smad2/3, transforming growth factor β (TGF-β) receptor I, and α-smooth muscle actin (α-SMA) was assayed. Pathological manifestation of hepatic tissue was assessed for the degree of liver fibrosis in animals. The results showed that CGA could inhibit the mRNA expression of miR-21, promote Smad7, and inhibit CTGF mRNA expression. Meanwhile, CGA could significantly lower the protein levels of CTGF, p-Smad1, p-Smad2, p-Smad2/3, TGF-β receptor I, and α-SMA and elevate the Smad7 protein level.
In vivo
, with treatment with CGA, the signaling molecules of IL-13/miR-21/Smad7 interactions were markedly regulated. CGA could also reduce the degree of liver fibrosis in pathological manifestations. In conclusion, CGA could inhibit schistosomiasis-induced hepatic fibrosis through IL-13/miR-21/Smad7 signaling interactions in LX2 cells and schistosome-infected mice and might serve as an antifibrosis agent for treating schistosomiasis liver fibrosis.
The Paradoxical Effect of Echinocandins in Aspergillus fumigatus Relies on Recovery of the β-1,3-Glucan Synthase Fks1
Authors: Loiko Veronika , Wagener Johannes
Published: November 2016

Echinocandins target the fungal cell wall by inhibiting biosynthesis of the cell wall carbohydrate β-1,3-glucan. This antifungal drug class exhibits a paradoxical effect that is characterized by the resumption of growth of otherwise susceptible strains at higher drug concentrations (approximately 4 to 32 μg/ml). The nature of this phenomenon is still unknown. In this study, we analyzed the paradoxical effect of the echinocandin caspofungin on the pathogenic moldAspergillus fumigatus. Using a conditionalfks1mutant, we show that very high caspofungin concentrations exert an additional antifungal activity besides inhibition of the β-1,3-glucan synthase. This activity could explain the suppression of paradoxical growth at very high caspofungin concentrations. Additionally, we found that exposure to inhibitory caspofungin concentrations always causes initial growth deprivation independently of the capability of the drug concentration to induce the paradoxical effect. Paradoxically growing hyphae emerge from microcolonies essentially devoid of β-1,3-glucan. However, these hyphae expose β-1,3-glucan again, suggesting that β-1,3-glucan synthesis is restored. In agreement with this hypothesis, we found that expression of the β-1,3-glucan synthase Fks1 is an essential requirement for the paradoxical effect. Surprisingly, overexpression offks1rendersA. fumigatusmore susceptible, whereas reduced expression leads to hyphae that are more resistant to the growth-inhibitory and limited fungicidal activity of caspofungin. Upregulation of chitin synthesis appears to be of minor importance for the paradoxical effect, since paradoxically growing hyphae exhibit significantly less chitin than the growth-deprived parental microcolonies. Our results argue for a model where the paradoxical effect primarily relies on recovery of β-1,3-glucan synthase activity.
Identification of IncA/C Plasmid Replication and Maintenance Genes and Development of a Plasmid Multilocus Sequence Typing Scheme
Authors: Hancock Steven J. , Phan Minh-Duy , Peters Kate M. , Forde Brian M. , Chong Teik Min , Yin Wai-Fong , Chan Kok-Gan , Paterson David L. , Walsh Timothy R. , Beatson Scott A. , Schembri Mark A.
Published: November 2016

Plasmids of incompatibility group A/C (IncA/C) are becoming increasingly prevalent within pathogenicEnterobacteriaceae. They are associated with the dissemination of multiple clinically relevant resistance genes, includingblaCMYandblaNDM. Current typing methods for IncA/C plasmids offer limited resolution. In this study, we present the complete sequence of ablaNDM-1-positive IncA/C plasmid, pMS6198A, isolated from a multidrug-resistant uropathogenicEscherichia colistrain. Hypersaturated transposon mutagenesis, coupled with transposon-directed insertion site sequencing (TraDIS), was employed to identify conserved genetic elements required for replication and maintenance of pMS6198A. Our analysis of TraDIS data identified roles for the replicon, includingrepA, a toxin-antitoxin system; two putative partitioning genes,parAB; and a putative gene,053. Construction of mini-IncA/C plasmids and examination of their stability withinE. coliconfirmed that the region encompassing053contributes to the stable maintenance of IncA/C plasmids. Subsequently, the four major maintenance genes (repA,parAB, and053) were used to construct a new plasmid multilocus sequence typing (PMLST) scheme for IncA/C plasmids. Application of this scheme to a database of 82 IncA/C plasmids identified 11 unique sequence types (STs), with two dominant STs. The majority ofblaNDM-positive plasmids examined (15/17; 88%) fall into ST1, suggesting acquisition and subsequent expansion of thisblaNDM-containing plasmid lineage. The IncA/C PMLST scheme represents a standardized tool to identify, track, and analyze the dissemination of important IncA/C plasmid lineages, particularly in the context of epidemiological studies.
Classical β-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii
Authors: Sakoulas George , Rose Warren , Berti Andrew , Olson Joshua , Munguia Jason , Nonejuie Poochit , Sakoulas Eleanna , Rybak Michael J. , Pogliano Joseph , Nizet Victor
Published: November 2016

We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant
Staphylococcus aureus
(MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen
Acinetobacter baumannii
, and the human host defense peptide cathelicidin LL37 against either pathogen. DAP and LL37 kill curves were performed with or without BLIs against MRSA, vancomycin-intermediate
S. aureus
(VISA), and heterogeneous VISA (hVISA). COL and LL37 kill curves were performed against
A. baumannii
. Boron-dipyrromethene (BODIPY)-labeled DAP binding to MRSA grown with the BLI tazobactam (TAZ) was assessed microscopically. The combination of COL plus TAZ was studied in a murine model of
A. baumannii
pneumonia. TAZ alone lacked
in vitro
activity against MRSA or
A. baumannii
. The addition of TAZ to DAP resulted in a 2- to 5-log
10
reduction in recoverable MRSA CFU at 24 h compared to the recoverable CFU with DAP alone. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of
A. baumannii
tested. Growth with 20 mg/liter TAZ resulted in 2- to 2.5-fold increases in the intensity of BODIPY-DAP binding to MRSA and hVISA strains. TAZ significantly increased the killing of MRSA and
A. baumannii
by LL37
in vitro
. TAZ increased the activity of COL in a murine model of
A. baumannii
pneumonia. Classical BLIs demonstrate synergy with peptide antibiotics. Since BLIs have scant antimicrobial activity on their own and are thus not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study.
Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects
Authors: Yee Ka Lai , Sanchez Rosa I. , Auger Patrice , Liu Rachael , Fan Li , Triantafyllou Ilias , Lai Ming-Tain , Di Spirito Mike , Iwamoto Marian , Khalilieh Sauzanne G.
Published: November 2016

Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC
0–24
), maximum observed plasma concentration (
C
max
), and observed plasma concentration at 24 h postdosing (
C
24
) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC
0–24
,
C
max
, and
C
24
, respectively, by day 14 after efavirenz cessation. The doravirine
C
24
reached projected therapeutic trough concentrations, based on
in vitro
efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.
Telavancin Is Active against Experimental Aortic Valve Endocarditis Caused by Daptomycin- and Methicillin-Resistant Staphylococcus aureus Strains
Authors: Abdelhady Wessam , Bayer Arnold S. , Gonzales Rachelle , Li Liang , Xiong Yan Q.
Published: November 2016

We compared the efficacy of telavancin (TLV) and daptomycin (DAP) in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant (DAP
r
) methicillin-resistant
Staphylococcus aureus
(MRSA) strains. TLV treatment significantly reduced MRSA densities in all target tissues and increased the percentage of these organs rendered culture negative compared to those with the untreated control or DAP-treated animals. These results demonstrate that TLV has potent
in vivo
efficacy against DAP
r
MRSA isolates in this invasive endovascular infection model.
Pharmacokinetics of Anidulafungin in Critically Ill Intensive Care Unit Patients with Suspected or Proven Invasive Fungal Infections
Authors: Brüggemann R. J. M. , Middel-Baars V. , de Lange D. W. , Colbers A. , Girbes A. R. J. , Pickkers P. , Swart E. L.
Published: November 2016

Echinocandins, such as anidulafungin, are the first-line treatment for candidemia or invasive candidiasis in critically ill patients. There are conflicting data on the pharmacokinetic properties of anidulafungin in intensive care unit (ICU) patients. Adult ICU patients (from 3 hospitals) receiving anidulafungin for suspected or proven fungal infections were included in the present study. Patients were considered evaluable if a pharmacokinetic curve for day 3 could be completed. Twenty-three of 36 patients (7 female and 16 male) were evaluable. The median (range) age and body weight were 66 (28 to 88) years and 76 (50 to 115) kg, respectively. Pharmacokinetic sampling on day 3 (
n
= 23) resulted in a median anidulafungin area under the concentration-time curve from 0 to 24 h (AUC
0–24
) of 72.1 (interquartile range [IQR], 61.3 to 94.0) mg · h · liter
−1
, a median daily trough concentration (
C
24
) of 2.2 (IQR, 1.9 to 2.9) mg/liter, a median maximum concentration of drug in serum (
C
max
) of 5.3 (IQR, 4.1 to 6.0) mg/liter, a median volume of distribution (
V
) of 46.0 (IQR, 32.2 to 60.2) liters, and a median clearance (CL) of 1.4 (IQR, 1.1 to 1.6) liters · h
−1
. Pharmacokinetic sampling on day 7 (
n
= 13) resulted in a median AUC
0–24
of 82.7 (IQR, 73.0 to 129.5) mg · h · liter
−1
, a median minimum concentration of drug in serum (
C
min
) of 2.8 (IQR, 2.2 to 4.2) mg/liter, a median
C
max
of 5.9 (IQR, 4.6 to 8.0) mg/liter, a median
V
of 39.7 (IQR, 32.2 to 54.4) liters, and a median CL of 1.2 (IQR, 0.8 to 1.4) liters · h
−1
. The geometric mean ratio for the AUC
day7
/AUC
day3
term was 1.13 (90% confidence interval [CI], 1.03 to 1.25). The exposure in the ICU patient population was in accordance with previous reports on anidulafungin pharmacokinetics in ICU patients but was lower than that for healthy volunteers or other patient populations. Larger cohorts of patients or pooled data analyses are necessary to retrieve relevant covariates. (This study has been registered at ClinicalTrials.gov under identifier NCT01438216.)
Estimation of the
In Vivo
MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria
Authors: Hien Tran Tinh , White Nicholas J. , Thuy-Nhien Nguyen Thanh , Hoa Nhu Thi , Thuan Phung Duc , Tarning Joel , Nosten François , Magnusson Baldur , Jain Jay Prakash , Hamed Kamal
Published: November 2016

The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the
in vivo
MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated
Plasmodium falciparum
malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute
P. falciparum
malaria were allocated sequentially to treatment with a single 30-mg (
n
= 6), 20-mg (
n
= 5), 10-mg (
n
= 7), or 15-mg (
n
= 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median
in vivo
MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.)
Control of Biofilm Formation: Antibiotics and Beyond
Authors: Algburi Ammar , Comito Nicole , Kashtanov Dimitri , Dicks Leon M. T. , Chikindas Michael L.
Published: November 2016

Biofilm-associated bacteria are less sensitive to antibiotics than free-living (planktonic) cells. Furthermore, with variations in the concentration of antibiotics throughout a biofilm, microbial cells are often exposed to levels below inhibitory concentrations and may develop resistance. This, as well as the irresponsible use of antibiotics, leads to the selection of pathogens that are difficult to eradicate. The Centers for Disease Control and Prevention use the terms “antibiotic” and “antimicrobial agent” interchangeably. However, a clear distinction between these two terms is required for the purpose of this assessment. Therefore, we define “antibiotics” as pharmaceutically formulated and medically administered substances and “antimicrobials” as a broad category of substances which are not regulated as drugs. This comprehensive minireview evaluates the effect of natural antimicrobials on pathogens in biofilms when used instead of, or in combination with, commonly prescribed antibiotics.
Systematic Analysis of Two-Component Systems in Citrobacter rodentium Reveals Positive and Negative Roles in Virulence
Authors: Thomassin Jenny-Lee , Leclerc Jean-Mathieu , Giannakopoulou Natalia , Zhu Lei , Salmon Kristiana , Portt Andrea , Daigle France , Le Moual Hervé , Gruenheid Samantha
Published: November 2016

Citrobacter rodentium
is a murine pathogen used to model intestinal infections caused by the human diarrheal pathogens enterohemorrhagic and enteropathogenic
Escherichia coli
. During infection, bacteria use two-component systems (TCSs) to detect changing environmental cues within the host, allowing for rapid adaptation by altering the expression of specific genes. In this study, 26 TCSs were identified in
C. rodentium
, and quantitative PCR (qPCR) analysis showed that they are all expressed during murine infection. These TCSs were individually deleted, and the
in vitro
and
in vivo
effects were analyzed to determine the functional consequences.
In vitro
analyses only revealed minor differences, and surprisingly, type III secretion (T3S) was only affected in the Δ
arcA
strain. Murine infections identified 7 mutants with either attenuated or increased virulence. In agreement with the
in vitro
T3S assay, the Δ
arcA
strain was attenuated and defective in colonization and cell adherence. The Δ
rcsB
strain was among the most highly attenuated strains. The decrease in virulence of this strain may be associated with changes to the cell surface, as Congo red binding was altered, and qPCR revealed that expression of the
wcaA
gene, which has been implicated in colanic acid production in other bacteria, was drastically downregulated. The Δ
uvrY
strain exhibited increased virulence compared to the wild type, which was associated with a significant increase in bacterial burden within the mesenteric lymph nodes. The systematic analysis of virulence-associated TCSs and investigation of their functions during infection may open new avenues for drug development.
How old is Kīlauea Volcano (Hawai‘i)? Insights from 40Ar/39Ar dating of the 1.7-km-deep SOH-1 core
Authors: Garcia Michael O. , Jicha Brian R. , Marske Jared P. , Pietruszka Aaron J.
Published: November 2016

Reliable estimates for lava accumulation rates are essential for interpreting magma fluxes to intraplate volcanoes and inferring the thermal and compositional structure of mantle plumes. Kīlauea Volcano’s (Hawai‘i) 1.7-km-deep SOH-1 scientific drill hole provides an opportunity to assess the lava accumulation rate and duration of the early shield stage for Hawaiian volcanoes. New 40Ar/39Ar ages were determined for four SOH-1 tholeiitic samples. Combining these results with two previous 40Ar/39Ar ages and the age of the drill-site surface flow, and correcting sample depth to remove intervening dikes, yields a good correlation (R2 = 0.97) for a 4.4 m/k.y. accumulation rate, which may have increased to 5.9 m/k.y. during the last 50 k.y. These rates contrast with a predicted 40% decrease during the last 200 k.y. from a simple shield volcano growth model. Mauna Loa, a massive shield volcano that buttresses the north flank of Kīlauea, may have contributed to this nearly constant lava accumulation rate. Extending the correlation to the base of the SOH-1 core indicates that Kīlauea’s tholeiitic volcanism probably started by 240 ka. Assuming an ∼400 k.y. duration for the preshield stage, Kīlauea is much older than some previous estimates (ca. 600 ka versus 150–275 ka) and has been vigorously erupting tholeiitic lavas for at least the past 200 k.y. During this period, it has been competing with Mauna Loa for the higher-temperature output of the Hawaiian mantle plume, which is contrary to previous models. New models that assess the magmatic output and thermal history of the Hawaiian mantle plume need to consider a steep increase in magma supply during the transition from preshield to shield stages to explain the near-constant lava accumulation rate during early shield growth.
Preservation or piracy: Diagnosing low-relief, high-elevation surface formation mechanisms
Authors: Whipple Kelin X. , DiBiase Roman A. , Ouimet William B. , Forte Adam M.
Published: November 2016

Absent clear lithologic control, the presence of elevated, low-relief topography in upland landscapes has traditionally been interpreted as a signature of relative surface uplift and incision of a paleo-landscape. Such interpretations are commonly supported and quantified using analyses of river longitudinal profiles under the assumption of a static drainage network topology. Drainage networks, however, are not static, and it has been proposed recently that divide migration and drainage capture can lead to the generation of low-relief upland topography that mimics that of incised paleo-landscapes and that might be falsely interpreted as recording surface uplift and/or the onset of accelerated incision. Indeed, the interpretation of the incised southeastern Tibetan Plateau, and thus the associated geodynamic implications, have been called into question. Here we use theory and one- and two-dimensional landscape evolution models to develop a set of morphometric criteria to distinguish these alternative mechanisms of low-relief upland formation. Application to the southeastern Tibetan Plateau illustrates the utility of these metrics and demonstrates that the topography is in no way consistent with the drainage network dynamics mechanism and is fully consistent with incision into an elevated, preexisting low-relief landscape.
Water concentration profiles in natural mantle orthopyroxenes: A geochronometer for long annealing of xenoliths within magma
Authors: Tian Zhen-Zhen , Liu Jia , Xia Qun-Ke , Ingrin Jannick , Hao Yan-Tao , Christophe Depecker
Published: November 2016

Both mantle-derived clinopyroxene and orthopyroxene are generally homogeneous in water concentration, while water content in the coexisting olivine is affected by partial or complete loss during the ascent of the hosting magma. Here, we report the first record of water content profiles (higher water in the cores than in the rims) in natural orthopyroxene grains in peridotite xenoliths hosted by Cenozoic alkali basalts in Tianchang volcano, eastern China. The water contents of the coexisting clinopyroxene grains are homogeneous and are twice that measured in the cores of orthopyroxene grains, confirming previous chemical equilibrium between the two pyroxenes. The olivines (ol) are nearly dry (∼0 ppm). These observations demonstrate that H diffusion in mantle orthopyroxene (opx) is faster than in clinopyroxene (cpx), and the relative mobility of H in each mineral phase could be quantified as: (where is the chemical diffusion coefficient of hydrogen). Combining this with experimental diffusion coefficients from the literature, we infer that (1) the xenoliths remained in contact with the magma below 900 °C for several months, and (2) clinopyroxene remains the more reliable recorder of water from depth, and orthopyroxene should be used more cautiously but can be considered with olivine for tracing slow transport and cooling of magma.
Validation of the German Diabetes Risk Score among the general adult population: findings from the German Health Interview and Examination Surveys
Authors: Paprott Rebecca , Mühlenbruch Kristin , Mensink Gert B M , Thiele Silke , Schulze Matthias B , Scheidt-Nave Christa , Heidemann Christin
Published: November 2016

Objective

To evaluate the German Diabetes Risk Score (GDRS) among the general adult German population for prediction of incident type 2 diabetes and detection of prevalent undiagnosed diabetes.

Methods

The longitudinal sample for prediction of incident diagnosed type 2 diabetes included 3625 persons who participated both in the examination survey in 1997–1999 and the examination survey in 2008–2011. Incident diagnosed type 2 diabetes was defined as first-time physician diagnosis or antidiabetic medication during 5 years of follow-up excluding potential incident type 1 and gestational diabetes. The cross-sectional sample for detection of prevalent undiagnosed diabetes included 6048 participants without diagnosed diabetes of the examination survey in 2008–2011. Prevalent undiagnosed diabetes was defined as glycated haemoglobin ≥6.5% (48 mmol/mol). We assessed discrimination as area under the receiver operating characteristic curve (ROC-AUC (95% CI)) and calibration through calibration plots.

Results

In longitudinal analyses, 82 subjects with incident diagnosed type 2 diabetes were identified after 5 years of follow-up. For prediction of incident diagnosed diabetes, the GDRS yielded an ROC-AUC of 0.87 (0.83 to 0.90). Calibration plots indicated excellent prediction for low diabetes risk and overestimation for intermediate and high diabetes risk. When considering the entire follow-up period of 11.9 years (ROC-AUC: 0.84 (0.82 to 0.86)) and including incident undiagnosed diabetes (ROC-AUC: 0.81 (0.78 to 0.84)), discrimination decreased somewhat. A previously simplified paper version of the GDRS yielded a similar predictive ability (ROC-AUC: 0.86 (0.82 to 0.89)). In cross-sectional analyses, 128 subjects with undiagnosed diabetes were identified. For detection of prevalent undiagnosed diabetes, the ROC-AUC was 0.84 (0.81 to 0.86). Again, the simplified version yielded a similar result (ROC-AUC: 0.83 (0.80 to 0.86)).

Conclusions

The GDRS might be applied for public health monitoring of diabetes risk in the German adult population. Future research needs to evaluate whether the GDRS is useful to improve diabetes risk awareness and prevention among the general population.
Relationship between women's smoking and laryngeal disorders based on the urine cotinine test: results of a national population-based survey
Authors: Byeon Haewon , Lee Dongwoo , Cho Sunghyoun
Published: November 2016

Objectives

There is a possibility of underestimation in the smoking rate surveyed by self-reported questionnaires. This study investigated the difference between the Korean female smoking rate as determined by self-reports and that determined by a biochemical test and elucidated the relationship between women's smoking and laryngeal disorders.

Design

Nationwide cross-sectional survey.

Setting

2008 Korea National Health and Nutrition Examination Survey.

Participants

1849 women who completed the health survey, urinary cotinine test and laryngoscope examinations.

Main outcome measure

This study defined smokers as those with urine cotinine contents of 50 ng/mL and over. Confounding factors included age, level of education, household income, occupation and problem drinking in the past year. For statistical tests, OR and 95% CI were presented by using complex samples logistic regression.

Results

While there was no relationship between smoking as determined by a self-reported questionnaire and laryngeal disorders, smoking as determined by the urine cotinine test had a significant relationship with laryngeal disorders (p<0.05). After all the confounding factors were adjusted, those with urine cotinine concentrations of over 50 ng/mL had a 2.1 times higher risk of laryngeal disorders than those with urine cotinine concentrations of <50 ng/mL (OR=2.05, 95% CI 1.11 to 3.78) (p<0.05).

Conclusions

This national cross-sectional study verified that smoking is a significant risk factor for laryngeal disorders. Longitudinal studies are required to identify the causal relationship between smoking and laryngeal disorders.
Early Diagnosis of Gestational Diabetes Mellitus (EDoGDM) study: a protocol for a prospective, longitudinal cohort study
Authors: Liu Bin , Xu Yun , Zhang Ying , Cai Jian , Deng Langhui , Yang Jianbo , Zhou Yi , Long Yuhang , Zhang Jinxin , Wang Zilian
Published: November 2016

Introduction

A diagnosis of gestational diabetes mellitus (GDM) in low-risk pregnant women is based on an oral glucose tolerance test (OGTT) between 24 and 28 gestational weeks. However, there is insufficient evidence for why the test is performed in this time period. Moreover, the fetus may be exposed to hyperglycaemia prior to the current testing time frame, making earlier administration potentially advantageous. The main purpose of the present study is to investigate the GDM diagnostic value of an OGTT performed at 18–20 gestational weeks. The results of the study may provide scientific insight into the most beneficial time of OGTT for pregnant women.

Methods and analysis

As a prospective, longitudinal cohort study, the Early Diagnosis of Gestational Diabetes Mellitus (EDoGDM) study will recruit 570 pregnant women who meet the inclusion and exclusion criteria outlined below. OGTTs will be performed between 18 and 20 gestational weeks (early OGTT) and 24–28 gestational weeks (regular OGTT). Clinical and laboratory information of the mother and their offspring will be collected for analysis. The prevalence of GDM at 18–20 gestational weeks will be described, and the sensitivity, specificity, positive predictive value and negative predictive value of early OGTT on diagnosis of GDM will be studied. Clinical outcomes associated with hyperglycaemia will be compared between groups diagnosed by early or regular OGTT.

Ethics and dissemination

The study was approved by The Ethical Committees of The First Affiliated Hospital of Sun Yat-sen University (number 2016-042). Signed informed consent will be obtained from all participants. The results of this study will be disseminated in peer-reviewed journals.

Trial registration number

NCT02740283.
Protocol for a multicentre randomised feasibility trial evaluating early Surgery Alone In LOw Rectal cancer (SAILOR)
Authors: Harris Dean A , Thorne Kymberley , Hutchings Hayley , Islam Saiful , Holland Gail , Hatcher Olivia , Gwynne Sarah , Jenkins Ian , Coyne Peter , Duff Michael , Feldman Melanie , Winter Des C , Gollins Simon , Quirke Phil , West Nick , Brown Gina , Fitzsimmons Deborah , Brown Alan , Beynon John
Published: November 2016

Introduction

There are 11 500 rectal cancers diagnosed annually in the UK. Although surgery remains the primary treatment, there is evidence that preoperative radiotherapy (RT) improves local recurrence rates. High-quality surgery in rectal cancer is equally important in minimising local recurrence. Advances in MRI-guided prediction of resection margin status and improvements in abdominoperineal excision of the rectum (APER) technique supports a reassessment of the contribution of preoperative RT. A more selective approach to RT may be appropriate given the associated toxicity.

Methods and analysis

This trial will explore the feasibility of a definitive trial evaluating the omission of RT in resectable low rectal cancer requiring APER. It will test the feasibility of randomising patients to (1) standard care (neoadjuvant long course RT±chemotherapy and APER, or (2) APER surgery alone for cT2/T3ab N0/1 low rectal cancer with clear predicted resection margins on MRI. RT schedule will be 45 Gy over 5 weeks as current standard, with restaging and surgery after 8–12 weeks. Recruitment will be for 24 months with a minimum 12-month follow-up.

Objectives

Objectives include testing the ability to recruit, consent and retain patients, to quantify the number of patients eligible for a definitive trial and to test feasibility of outcomes measures. These include locoregional recurrence rates, distance to circumferential resection margin, toxicity and surgical complications including perineal wound healing, quality of life and economic analysis. The quality of MRI staging, RT delivery and surgical specimen quality will be closely monitored.

Ethics and dissemination

The trial is approved by the Regional Ethics Committee and Health Research Authority (HRA) or equivalent. Written informed consent will be obtained. Serious adverse events will be reported to Swansea Trials Unit (STU), the ethics committee and trial sites. Trial results will be submitted for peer review publication and to trial participants.

Trial registration number

ISRCTN02406823.
Cost burden of type 2 diabetes in Germany: results from the population-based KORA studies
Authors: Ulrich Susanne , Holle Rolf , Wacker Margarethe , Stark Renee , Icks Andrea , Thorand Barbara , Peters Annette , Laxy Michael
Published: November 2016

Objective

To examine the impact of type 2 diabetes on direct and indirect costs and to describe the effect of relevant diabetes-related factors, such as type of treatment or glycaemic control on direct costs.

Design

Bottom-up excess cost analysis from a societal perspective based on population-based survey data.

Participants

9160 observations from 6803 individuals aged 31–96 years (9.6% with type 2 diabetes) from the population-based KORA (Cooperative Health Research in the Region of Augsburg) studies in Southern Germany.

Outcome measures

Healthcare usage, productivity losses, and resulting direct and indirect costs.

Methods

Information on diabetes status, biomedical/sociodemographic variables, medical history and on healthcare usage and productivity losses was assessed in standardised interviews and examinations. Healthcare usage and productivity losses were costed with reference to unit prices and excess costs of type 2 diabetes were calculated using generalised linear models.

Results

Individuals with type 2 diabetes had 1.81 (95% CI 1.56 to 2.11) times higher direct (€3352 vs €1849) and 2.07 (1.51 to 2.84) times higher indirect (€4103 vs €1981) annual costs than those without diabetes. Cardiovascular complications, a long diabetes duration and treatment with insulin were significantly associated with increased direct costs; however, glycaemic control was only weakly insignificantly associated with costs.

Conclusions

This study illustrates the substantial direct and indirect societal cost burden of type 2 diabetes in Germany. Strong effort is needed to optimise care to avoid progression of the disease and costly complications.
The Challenge of Universal Eye Health in Latin America: distributive inequality of ophthalmologists in 14 countries
Authors: Hong Hannah , Mújica Oscar J , Anaya José , Lansingh Van C , López Ellery , Silva Juan Carlos
Published: November 2016

Background

No comprehensive study currently exists on the supply of ophthalmologists across Latin America. We explored sociogeographic inequalities in the availability and distribution of ophthalmologists across 14 Latin American countries.

Methods

The National Ophthalmologic Societies of Argentina, Bolivia, Brazil, Colombia, Costa Rica, Chile, the Dominican Republic, Ecuador, Guatemala, Mexico, Paraguay, Peru, Uruguay and Venezuela provided data on affiliated ophthalmologists by first-order subnational divisions in 2013. Human Development Index (HDI) estimates at the corresponding subnational division were used as equity stratifiers. Distributional inequality of ophthalmologists within each country was assessed by the health concentration index (HCI) and the index of dissimilarity (ID), along with the mean level of ophthalmologists per population.

Results

Across all countries studied, there were 5.2 ophthalmologists per 100 000 population on average (95% CI 5.0 to 5.4) in 2013, with a mean HCI of 0.26 (0.16 to 0.37) and a mean relative ID of 22.7% (20.9% to 24.7%). There was wide inequality in ophthalmologist availability between countries, ranging from 1.2 (1.1 to 1.4) in Ecuador to 8.6 (8.5 to 8.8) in Brazil. All countries had positive (ie, pro-rich) HCI values ranging from 0.68 (0.66 to 0.71) in Guatemala to 0.02 (−0.11 to 0.14) in Venezuela. Correspondingly, redistributive potential to achieve equity was closest in Venezuela (ID: 1.5%) and farthest in Guatemala (ID: 60.3%). Benchmarked against regional averages, most countries had a lower availability of ophthalmologists and higher relative inequality.

Conclusions

There is high inequality in the level and distribution of ophthalmologists between and within countries in Latin America, with a disproportionate number concentrated in more developed, socially advantaged areas. More equitable access to ophthalmologists could be achieved by implementing incentivised human resources redistribution programmes and by improving the social determinants of health in underserved areas.
Polymyxin B-immobilised haemoperfusion and mortality in critically ill patients with sepsis/septic shock: a protocol for a systematic review and meta-analysis
Authors: Fujii Tomoko , Ganeko Riki , Kataoka Yuki , Featherstone Robin , Bagshaw Sean M , Furukawa Toshi A
Published: November 2016

Introduction

Polymyxin-B immobilised haemoperfusion (PMX-HP) is a promising adjuvant strategy for the treatment of sepsis and septic shock. PMX-HP therapy works by clearing circulating endotoxin through binding to polymyxin-immobilised fibres during haemoperfusion. Small clinical trials have shown that PMX-HP therapy is associated with improved haemodynamic profile, oxygenation and survival. However, clear inferences have been largely inconclusive due to limitations in study design (eg, small, unblinded) and generalisability. We therefore propose to perform an up-to-date systematic review and evidence synthesis to describe the efficacy, safety and effectiveness of PMX-HP for adult patients with sepsis or septic shock.

Methods and analysis

We will search the following databases from 1946 to 2016 MEDLINE (Ovid), EMBASE (Ovid), Cochrane Library, Health Technology Assessment Database (HTA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed and ‘Igaku Chuo Zasshi’ (ICHUSHI) for randomised controlled trials of PMX-HP in critically ill patients with sepsis or septic shock. There will be no language restrictions in the electronic search for studies. Two reviewers will extract data and appraise the quality of each study independently. The primary outcome will be the pooled risk ratio of 28-day all-cause mortality. Serious adverse events and changes in organ dysfunction scores will also be evaluated. The secondary outcomes will be 90-day all-cause mortality, changes in haemodynamic profile and endotoxin levels, and health services use.

Ethics and dissemination

Our systematic review will synthesise the evidence on use of the PMX-HP as an adjuvant therapy in sepsis/septic shock to improve patient-centred, physiological and health services outcomes. Research ethics is not required for this review. The study will be disseminated by peer-reviewed publication and conference presentation.

Trial registration number

CRD42016038356.
Railway suicide clusters: how common are they and what predicts them?
Authors: Too Lay San , Pirkis Jane , Milner Allison , Bugeja Lyndal , Spittal Matthew J
Published: November 2016

Background

A growing number of studies have sought to detect clusters of all suicides, but few have sought to identify clusters of method-specific suicides.

Methods

Data on railway suicides occurring in Victoria, Australia, between 2001 and 2012 were obtained from the National Coronial Information System. We used the Poisson discrete scan statistic to identify railway suicides that occurred close together in space and/or time. We then used a case–control design to compare clustered railway suicides with non-clustered railway suicides on a range of individual and neighbourhood factors.

Results

We detected four spatial clusters that accounted for 35% of all railway suicides. Railway suicides by individuals who were hospitalised for mental illness had nearly double the odds of being in a cluster compared with those individuals who had never been hospitalised (OR 1.80, 95% CI 1.02 to 3.18). Higher frequency train services were associated with increased odds of being in a cluster (OR 1.11, 95% CI 1.03 to 1.19). No other predictors were associated with being in a cluster.

Conclusions

Railway suicides that occur in clusters warrant particular attention because of the ripple effect they can have for communities and the risk that they may lead to copycat acts. Railway suicide prevention strategies should consider the fact that these suicides can occur in clusters, particularly among individuals who had previous hospitalisations for mental illness or live in areas with high-frequency train services.
Preliminary conceptual design about the CEPC calorimeters
Authors: Yang Haijun
Published: November 2016

The Circular Electron Positron Collider (CEPC) as a Higgs factory was proposed in September 2013. The preliminary conceptual design report was completed in 2015.1 The CEPC detector design was using International Linear Collider Detector — ILD2 as an initial baseline. The CEPC calorimeters, including the high granularity electromagnetic calorimeter (ECAL) and the hadron calorimeter (HCAL), are designed for precise energy measurements of electrons, photons, taus and hadronic jets. The basic resolution requirements for the ECAL and HCAL are about 16%[Formula: see text][Formula: see text] (GeV) and 50%[Formula: see text][Formula: see text] (GeV), respectively. To fully exploit the physics potential of the Higgs, [Formula: see text], [Formula: see text] and related Standard Model processes, the jet energy resolution is required to reach 3%–4%, or 30%/[Formula: see text] (GeV) at energies below about 100 GeV. To achieve the required performance, a Particle Flow Algorithm (PFA) — oriented calorimetry system is being considered as the baseline design. The CEPC ECAL detector options include silicon–tungsten or scintillator–tungsten structures with analog readout, while the HCAL detector options have scintillator or gaseous detector as the active sensor and iron as the absorber. Some latest R&D studies about ECAL and HCAL within the CEPC working group is also presented.
Fast-Scale Bifurcation Analysis in One-Cycle Controlled H-Bridge Inverter
Authors: Yang Fang , Yang Lihui , Ma Xikui
Published: November 2016

This paper discusses the fast-scale instability in the one-cycle controlled H-bridge inverter which is widely used in practical applications. Simulations show that the fast-scale instability which occurs around the peak value of the inductive current is a type of local instability. The discrete-time model is derived to analyze the fast-scale instability. According to the Jacobian matrix derived from the discrete-time model, the theoretical analysis shows that the fast-scale instability manifests itself as a period-doubling bifurcation occurs, which reveals the intrinsic mechanism of the instability of one-cycle controlled H-bridge inverter. Furthermore, with the approximation of the matrix exponential in the discrete-time model and based on the Jacobian matrix, the stability boundary is obtained by the analytical expression which is helpful to select the proper values of parameters for avoiding the fast-scale instability. The experiments are carried out to validate the results of the simulation and theoretical analysis. It is shown that the analysis method is able to facilitate the design of the inverter.
Slow-Scale Instability in Voltage-Mode Controlled H-Bridge Inverter with Memristive Load
Authors: Liu Wei , Wang Faqiang , Ma Xikui
Published: November 2016

In recent years, memristor has become one of the research focuses. Considerable open literature has shown that many devices and systems possess memristive properties. Thus, research into supplying power source to these special devices and making them work steadily has been a meaningful study. This paper investigates the slow-scale instability whose oscillating frequency is between the line frequency and the switch frequency that occurs in a voltage controlled H-bridge inverter with memristive load. The mechanism of this medium-frequency oscillation is identified via harmonic balance method and Floquet theory. The results show that it is due to the occurrence of Hopf bifurcation. Finally, experimental results are presented to verify the theoretical analysis.