bluuebunny/crossref_metadata_2025 huggingface dataset:
Pregnancy weight gain by gestational age and stillbirth: a population‐based cohort study
Authors: Johansson K , Hutcheon JA , Bodnar LM , Cnattingius S , Stephansson O
Published: November 2017

Objective

To study the association between total and early pregnancy (<22 completed weeks) weight gain and risk of stillbirth, stratified by early‐pregnancy body mass index (BMI).

Design

Population‐based cohort study.

Setting

Stockholm‐Gotland Region, Sweden.

Population

Pregnant women with singleton births (n = 160 560).

Methods

Pregnancy weight gain was standardised into gestational age‐specific z‐scores. For analyses of total pregnancy weight gain, a matched design with an incidence density sampling approach was used. Findings were also contrasted with current Institute of Medicine (IOM) weight gain recommendations.

Main outcome measures

Stillbirth defined as fetal death at ≥22 completed weeks of gestation.

Results

For all BMI categories, there was no statistical association between total or early pregnancy weight gain and stillbirth within the range of a weight gain z‐score of −2.0 SD to +2.0 SD. Among normal‐weight women, the adjusted odds ratio of stillbirth for lower (−2.0 to −1.0 SD) and higher (+1.0 to +1.9 SD) total weight gain was 0.85 (95% CI; 0.48–1.49) and 1.03 (0.60–1.77), respectively, as compared with the reference category. Further, there were no associations between total or early pregnancy weight gain and stillbirth within the range of weight gain currently recommended by the IOM. For the majority of the BMI categories, the point estimates at the extremes of weight gain values (<−2.0SD and ≥2.0 SD) suggested protective effects of low weight gain and increased risks of high weight gain, but estimates were imprecise and not statistically significant.

Conclusion

We found no associations between total or early pregnancy weight gain and stillbirth across the range of weight gain experienced by most women.

Tweetable abstract

There was no association between weight gain during pregnancy and stillbirth among most women.
Enrichment of syngas‐converting communities from a multi‐orifice baffled bioreactor
Authors: Arantes Ana L. , Alves Joana I. , Stams Alfons J. M. , Alves M. Madalena , Sousa Diana Z.
Published: November 2017

The substitution of natural gas by renewable biomethane is an interesting option to reduce global carbon footprint. Syngas fermentation has potential in this context, as a diverse range of low‐biodegradable materials that can be used. In this study, anaerobic sludge acclimatized to syngas in a multi‐orifice baffled bioreactor (MOBB) was used to start enrichments with CO. The main goals were to identify the key players in CO conversion and evaluate potential interspecies metabolic interactions conferring robustness to the process. Anaerobic sludge incubated with 0.7 × 105 Pa CO produced methane and acetate. When the antibiotics vancomycin and/or erythromycin were added, no methane was produced, indicating that direct methanogenesis from CO did not occur. Acetobacterium and Sporomusa were the predominant bacterial species in CO‐converting enrichments, together with methanogens from the genera Methanobacterium and Methanospirillum. Subsequently, a highly enriched culture mainly composed of a Sporomusa sp. was obtained that could convert up to 1.7 × 105 Pa CO to hydrogen and acetate. These results attest the role of Sporomusa species in the enrichment as primary CO utilizers and show their importance for methane production as conveyers of hydrogen to methanogens present in the culture.
Development of a specific fluorescent phage endolysin for in situ detection of Clostridium species associated with cheese spoilage
Authors: Gómez‐Torres Natalia , Dunne Matthew , Garde Sonia , Meijers Rob , Narbad Arjan , Ávila Marta , Mayer Melinda J.
Published: November 2017

Late blowing defect (LBD) is a major cause of spoilage in cheeses, caused by the growth of Clostridium spp. in the cheese matrix. We investigated the application of CTP1L, a bacteriophage endolysin active against Clostridium tyrobutyricum, and its enzymatically active and cell wall‐binding domains (EAD and CBD) attached to green fluorescent protein (GFP) to detect dairy‐related Clostridium species by fluorescence microscopy. GFP‐CTP1L and GFP‐CBD demonstrated specificity for Clostridium spp. by labelling 15 and 17 of 20 Clostridium strains, respectively, but neither bound to other members of the cheese microbiota. However, GFP‐EAD did not label any Clostridium strain tested. Unexpectedly, GFP‐CTP1L and GFP‐CBD were also able to bind to clostridial spores. In addition, GFP‐CBD allowed us to visualize the vegetative cells of C. tyrobutyricum directly in the matrix of a LBD cheese. Site‐directed mutants of GFP‐CTP1L and GFP‐CBD were made to examine the amino acids involved in binding and oligomer formation. Oligomerization was not essential for binding, but specific mutations in the CBD which affected oligomer formation also affected binding and lytic activity. We conclude that GFP‐CTP1L and GFP‐CBD could be good biomarkers for rapid detection of Clostridium spores in milk, so measures can be taken for the prevention of LBD in cheese, and also provide effective tools to study the development of Clostridium populations during cheese ripening.
Assessment of Future Drought Conditions in the Chesapeake Bay Watershed
Authors: Kang Hyunwoo , Sridhar Venkataramana
Published: November 2017

Impacts of climate change on the severity and intensity of future droughts can be evaluated based on precipitation and temperature projections, multiple hydrological models, simulated hydrometeorological variables, and various drought indices. The objective of this study was to assess climate change impacts on future drought conditions and water resources in the Chesapeake Bay (CB) watershed. In this study, the Soil and Water Assessment Tool (SWAT) and the Variable Infiltration Capacity model were used to simulate a Modified Palmer Drought Severity Index (MPDSI), a Standardized Soil Moisture index (SSI), a Multivariate Standardized Drought Index (MSDI), along with Coupled Model Intercomparison Project Phase 5 (CMIP5) climate models for both historical and future periods (f1: 2020‐2049, f2: 2050‐2079). The results of the SSI suggested that there was a general increase in agricultural droughts in the entire CB watershed because of increases in surface and groundwater flow and evapotranspiration. However, MPDSI and MSDI showed an overall decrease in projected drought occurrences due to the increases in precipitation in the future. The results of this study suggest that it is crucial to use multiple modeling approaches with specific drought indices that combine the effects of both precipitation and temperature changes.
S100β in newborns after C‐section with general vs. epidural anesthesia: a prospective observational study
Authors: Xu Z. , Liu Z. , Zhang Y. , Jin C. , Shen F. , Yu Y. , Cheek T. , Onuoha O. , Liang G. , Month R. , Atkins J. , Tran K. M. , Wei H.
Published: November 2017

Background

Preclinical evidence suggests that general anesthetics can dose dependently induce neurodegeneration in the developing brains of animals which can be reliably determined by measurement of blood S100β, but this correlation remains unclear in humans. We hypothesized that S100β would not be increased in cord arterial blood of fetuses exposed briefly to general anesthetics during a C‐section, compared with epidural anesthesia.

Methods

A prospective observational clinical study comparatively measured changes of brain damage biomarker S100β ratio of umbilical artery over vein (changes after fetus circulation) immediately after delivery under C‐section with either epidural or general anesthesia. Newborn blood gas measurements, APGAR scores, and maternal well‐being were also compared.

Results

Compared with epidural anesthesia, general anesthesia resulted in the lower S100β ratio of umbilical artery over the vein (medium 2.64 [quartiles 1.39, 3.45] vs. medium 1.59 [quartiles 0.88, 2.01], P = 0.031), without changing the S100β level in the vein of the mother. There was no significant difference between general and epidural anesthesia when comparing other maternal and newborn parameters.

Conclusion

S100β levels in newborn after C‐section is lower with general anesthesia than epidural anesthesia, with unclear mechanisms.
Evaluation of a Low‐risk Mild Traumatic Brain Injury and Intracranial Hemorrhage Emergency Department Observation Protocol
Authors: Yun Brian J. , Borczuk Pierre , Wang Lulu , Dorner Stephen , White Benjamin A. , Raja Ali S.
Published: November 2017

Objectives

Among emergency physicians, there is wide variation in admitting practices for patients who suffered a mild traumatic brain injury (TBI) with an intracranial hemorrhage (ICH). The purpose of this study was to evaluate the effects of implementing a protocol in the emergency department (ED) observation unit for patients with mild TBI and ICH.

Methods

This retrospective cohort study was approved by the institutional review board. Study subjects were patients ≥ 18 years of age with an International Classification of Diseases code corresponding to a traumatic ICH and admitted to an ED observation unit (EDOU) of an urban, academic Level I trauma center between February 1, 2015, and January 31, 2017. Patient data and discharge disposition were abstracted from the electronic health record, and imaging data, from the final neuroradiologist report. To measure kappa, two abstractors independently collected data for presence of neuro deficit from a 10% random sample of the medical charts. Using a multivariable logistic regression model with a propensity score of the probability of placement in the EDOU before and after protocol implementation as a covariate, we sought to determine the pre‐post effects of implementing a protocol on the composite outcome of admission to the floor, intensive care unit, or operating room from the EDOU and the proportion of patients with worsening findings on repeat computed tomography (CT) head scan in the EDOU.

Results

A total of 379 patients were identified during the study period; 83 were excluded as they were found to have no ICH on chart review. Inter‐rater reliability kappa statistic was 0.63 for 30 charts. Among the 296 patients who remained eligible and comprised the study population, 143 were in the preprotocol period and 153 after protocol implementation. The EDOU protocol was associated with an independently statistically significant decreased odds ratio (OR) for admission or worsening ICH on repeat CT scan (OR = 0.45, 95% confidence interval [CI] = 0.25–0.82, p = 0.009) in the observation unit. After a stay in the EDOU, 26% (37/143) of patients required an inpatient admission before implementation of the protocol and 13% (20/153) of patients required an inpatient admission after protocol implementation. There was no statistically significant difference in log transformed EDOU length of stay (LOS) between the groups after adjusting for propensity score (p = 0.34).

Conclusions

While there was no difference in EDOU LOS, implementing a low‐risk mild TBI and ICH protocol in the EDOU may decrease the rate of inpatient admissions from the EDOU. A protocol‐driven observation unit may help physicians by standardizing eligibility criteria and by providing guidance on management. As the propensity score method limits our ability to create a straightforward predictive model, a future larger study should validate the results.
Risk of Past Year Injury Related to Hours of Exposure to an Elevated Blood Alcohol Concentration and Average Monthly Alcohol Volume: Data from 4 National Alcohol Surveys (2000 to 2015)
Authors: Cherpitel Cheryl J. , Ye Yu , Kerr William C.
Published: November 2017

Background

While a strong association exists between alcohol and injury in emergency department (ED) studies, these studies are not representative of the general population.

Methods

The association of injury with the number of hours of exposure to a blood alcohol concentration (BAC) ≥ 0.05 and average monthly volume in drinks, both based on self‐report of quantity and frequency of drinking in the last year, in a merged sample of respondents (n = 29,571) from 4 U.S. National Alcohol Surveys (2000 to 2015) are analyzed. Risk curves based on categorical step function and fractional polynomial modeling were analyzed separately by gender, and by age and race/ethnicity for males.

Results

Risk of injury increased at 1 hour of a BAC exposure of ≥ 0.05 and at an average monthly volume of 1 drink. Risk of injury for spirits increased to an average daily volume of 1 drink, but no association was found for injury risk and average volume for either wine or beer. Risk of injury increased with both exposure hours and monthly volume among males, but little association was found for either consumption measure with risk of injury for females. Among males, increased risk of injury was greater for whites than for blacks or Hispanics for BAC exposure; Hispanics showed a continued elevated risk up to 8 hours of exposure. After peaking at a monthly volume of 1 drink, injury risk decreased substantially for blacks, but was more gradual for whites, while risk increased very slightly for Hispanics to about 4 drinks per day. Males aged 18 to 29 showed the largest increase in risk associated with the number of hours of exposure to a BAC of ≥0.05, with risk doubling at 1 hour of exposure, but subsequently falling.

Conclusions

While findings here are weaker than those from ED studies and likely due to the context of drinking, risk of injury appears to increase at relatively low levels of consumption, suggesting the importance of preventive efforts to reduce injury not only for heavier drinkers but also for more moderate drinkers.
The effect of inspections, rotations and client preferences on staffing decisions
Authors: Moroney Robyn , Knechel W. Robert , Dowling Carlin
Published: November 2017

With increased regulatory focus on audits and concerns about whether audit regulation is achieving its stated aims, it is timely to investigate how regulator inspection of audit files and partner rotations may be affecting staffing decisions. This is an important issue, which affects all audits, as the calibre of staff allocated across engagements impacts the quality of audit work delivered. This study reports the results of an experiment where auditor participants allocate staff across two audits, where regulation anticipated (none, inspection, rotation) and a client request for the best staff (absent, present) are manipulated between‐subjects. We find that auditors allocate lower calibre staff when neither an inspection nor rotation is anticipated than when either is anticipated. When an inspection is anticipated, auditors allocate staff with more knowledge and compliance skills. When a rotation is anticipated, auditors allocate staff with more people skills. A client request for the best staff only has an effect when a partner is due to be rotated, where auditors allocate staff with more people skills in response to the client request. Our findings provide greater understanding of staffing decisions, which may affect audit quality if concerns around audit inspections and partner rotations are perceived by auditors as more important than the underlying risk or complexity of an engagement when allocating staff.
Chronic pain and opioid abuse: Factors associated with health‐related quality of life
Authors: Jones Jermaine D. , Vogelman Jonathan S. , Luba Rachel , Mumtaz Mudassir , Comer Sandra D.
Published: November 2017

Background and Objectives

While research on the separate relationships between health‐related quality of life (HRQOL) and chronic pain, and HRQOL and opioid abuse has been sparse, even less work has investigated the factors associated with HRQOL in individuals who have both chronic pain and meet criteria for opioid use disorder. The data presented in this analysis should allow a better understanding the factors important to quality of life among this dual‐diagnosed population.

Methods

Individuals with dual diagnoses of chronic pain and opioid use disorder were recruited for clinical research studies at Columbia University Medical Center. Participants (n = 47) completed inventories to assess pain (Brief Pain Inventory), opioid (ab)use, and depression (Beck Depression Inventory). Variable from these and other inventories, along with demographic factors (age, race, sex, pain severity, depressive symptoms, duration of opioid use, route of opioid use, amount of opioid use) were entered into a regression analysis in order to identify the strongest predictors of SF‐36 Health Survey score.

Results

In the bivariate analysis we found that demographic and drug use variables were rarely associated with HRQOL. Typically, ratings of pain severity and pain interference were the best predictors. In the multivariate analysis, we found that across the several HRQOL dimensions greater Brief Pain Inventory (BPI) ratings of pain “interference” and Beck Depression Inventory (BDI) scores were consistently associated with lower HRQOL.

Conclusions and Scientific Significance

These data suggest that insufficient pain management and depression are significant variables contributing to lower quality of life among individuals with chronic pain and opioid use disorder. (Am J Addict 2017;26:815–821)
The microenvironment of naked mole‐rat burrows in East Africa
Authors: Holtze Susanne , Braude Stanton , Lemma Alemayehu , Koch Rosie , Morhart Michaela , Szafranski Karol , Platzer Matthias , Alemayehu Fitsum , Goeritz Frank , Hildebrandt Thomas Bernd
Published: November 2017

Naked mole‐rats (Heterocephalus glaber) can be extremely long‐lived and are resistant to cancer. Hence, they have been proposed as a model organism for delayed ageing. Adaptation to a constant hypoxic and hypercapnic environment has been suggested as reason for their apparent ability to tolerate oxidative stress. Nevertheless, little is known about the natural habitat to which the species evolved. Naked mole‐rat burrow environments were assessed in Ethiopia and Kenya. Despite reported thermolability of naked mole‐rats, skin temperature upon capture varied (23.7–35.4°C), mostly within the species’ thermoneutral zone, demonstrating their ability to maintain homoiothermy even under wide fluctuations of burrow temperature (24.6–48.8°C) and humidity (31.2%–92.8%), which are far greater than previously reported. Burrow temperature regularly alternates during the daytime and night‐time, driving convective currents that circulate air in the tunnels. Consequently, concentrations of CO2 and O2 in burrows only slightly deviated from surface atmosphere. This contradicts the assumption of constant hypoxia/hypercapnia in subterranean burrows. In addition to diffusion, animal movement and occasional wind‐driven ventilation, our data support the temperature‐driven convective model of circulation. The naked mole‐rat burrow is a relatively normoxic subterranean microenvironment with considerable fluctuations in temperature and humidity.
Beneficial effects of pro‐social behaviour on physical well‐being in Chinese samples
Authors: Guo Qingke , Wu Rui , Li Xiaoxiao
Published: November 2017

To confirm the relationship between pro‐social behaviour and increased physical functioning revealed by previous researchers in Western samples, we conducted four experiments with 378 Chinese undergraduates. The participants' strength to hold, to grip and to lift, as well as their vitality (walking speed), were measured after thinking of acts of kindness. The results showed that recalling pro‐social behaviour (helping others or spending money on others) that had occurred in the past or imagining pro‐social behaviour happening in the future imbued people with more physical strength and vitality. In three experiments, pro‐social behaviour boosted the positive mood of the actors, but the effect was only significant in one experiment, suggesting that the hidden gift may include increased happiness, but that enhanced physical functioning cannot be accounted for by differences in emotions. These results add to the evidence that the function of pro‐social behaviour in promoting physical functioning may be culturally universal.
Renal hypoxia in kidney disease: Cause or consequence?
Authors: Ow C. P. C. , Ngo J. P. , Ullah M. M. , Hilliard L. M. , Evans R. G.
Published: November 2017

Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a “common pathway” to both AKI and CKD still remains to be adequately tested.
The I in autism: Severity and social functioning in autism are related to self‐processing
Authors: Gillespie‐Smith Karri , Ballantyne Carrie , Branigan Holly P. , Turk David J. , Cunningham Sheila J.
Published: November 2017

It is well established that children with autism spectrum disorder (ASD) show impaired understanding of others and deficits within social functioning. However, it is still unknown whether self‐processing is related to these impairments and to what extent self impacts social functioning and communication. Using an ownership paradigm, we show that children with ASD and chronological‐ and verbal‐age‐matched typically developing (TD) children do show the self‐referential effect in memory. In addition, the self‐bias was dependent on symptom severity and socio‐communicative ability. Children with milder ASD symptoms were more likely to have a high self‐bias, consistent with a low attention to others relative to self. In contrast, severe ASD symptoms were associated with reduced self‐bias, consistent with an ‘absent‐self’ hypothesis. These findings indicate that deficits in self‐processing may be related to impairments in social cognition for those on the lower end of the autism spectrum.

Statement of contribution

What is already known on this subject?

Impaired self‐processing in autism is linked to social and cognitive deficits.

There are discrepancies across the literature, with reports of both intact and impaired self‐processing in autism.

Ownership tasks are developmentally appropriate and have shown to induce self‐memory bias in young children.

What does this study add?

Using an ownership task, children with autism showed a significant self‐memory bias, greater than typical peers.

Severity was negatively correlated with level of self‐bias, potentially explaining the previous discrepancies.

Severe autism symptoms are associated with an ‘absent self’, and mild autism symptoms reduce attention to others.
Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (HIV)‐protease inhibitors lopinavir or nelfinavir
Authors: Abt Dominik , Besse Andrej , Sedlarikova Lenka , Kraus Marianne , Bader Juergen , Silzle Tobias , Vodinska Martina , Slaby Ondrej , Schmid Hans‐Peter , Engeler Daniel Stephan , Driessen Christoph , Besse Lenka
Published: November 2017

Objectives

To assess the potential of second‐generation proteasome inhibition by carfilzomib and its combination with the human immunodeficiency virus (HIV) protease inhibitors (HIV‐PIs) lopinavir and nelfinavir in vitro for improved treatment of clear cell renal cell cancer (ccRCC).

Materials and Methods

Cytotoxicity, reactive oxygen species (ROS) production, and unfolded protein response (UPR) activation of proteasome inhibitors, HIV‐PIs, and their combination were assessed in three cell lines and primary cells derived from three ccRCC tumours by MTS assay, flow cytometry, quantitative reverse transcriptase‐polymerase chain reaction and western blot, respectively. Proteasome activity was determined by activity based probes. Flow cytometry was used to assess apoptosis by annexin V/propidium iodide assay and ATP‐binding cassette sub‐family B member 1 (ABCB1) activity by MitoTracker™ Green FM efflux assay (Thermo Fisher Scientific, MA, USA).

Results

Lopinavir and nelfinavir significantly increased the cytotoxic effect of carfilzomib in all cell lines and primary cells. ABCB1 efflux pump inhibition, induction of ROS production, and UPR pre‐activation by lopinavir were identified as underlying mechanisms of this strong synergistic effect. Combined treatment led to unresolved protein stress, increased activation of pro‐apoptotic UPR pathway, and a significant increase in apoptosis.

Conclusion

The combination of the proteasome inhibitor carfilzomib and the HIV‐PIs lopinavir and nelfinavir has a strong synergistic cytotoxic activity against ccRCCin vitro at therapeutically relevant drug concentrations. This effect is most likely explained by synergistic UPR triggering and ABCB1‐modulation caused by HIV‐PIs. Our findings suggest that combined treatment of second‐generation proteasome inhibitors and HIV‐PIs should be investigated in patients with metastatic RCC within a clinical trial.
Simultaneous use of erythropoietin and LFM‐A13 as a new therapeutic approach for colorectal cancer
Authors: Tankiewicz‐Kwedlo Anna , Hermanowicz Justyna Magdalena , Domaniewski Tomasz , Pawlak Krystyna , Rusak Małgorzata , Pryczynicz Anna , Surazynski Arkadiusz , Kaminski Tomasz , Kazberuk Adam , Pawlak Dariusz
Published: November 2017

Background and Purpose

Bruton's tyrosine kinase (Btk) is a non‐receptor tyrosine kinase involved in the activation of signalling pathways responsible for cell maturation and viability. Btk has previously been reported to be overexpressed in colon cancers. This kind of cancer is often accompanied by anaemia, which is treated with an erythropoietin supplement. The goal of the present study was to assess the effects of combination therapy with erythropoietin β (Epo) and LFM‐A13 (Btk inhibitor) on colon cancer in in vitro and in vivo models.

Experimental Approach

DLD‐1 and HT‐29 human colon adenocarcinoma cells were cultured with Epo and LFM‐A13. Cell number and viability, and mRNA and protein levels of Epo receptors, Btk and Akt were assessed. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM‐A13.

Key Results

The combination of Epo and LFM‐A13 mostly exerted a synergistic inhibitory effect on colon cancer cell growth. The therapeutic scheme used effectively killed the cancer cells and attenuated the Btk signalling pathways. Epo + LFM‐A13 also prevented the normal process of microtubule assembly during mitosis by down‐regulating the expression of Polo‐like kinase 1. The combination of Epo and LFM‐A13 significantly reduced the growth rate of tumour cells, while it showed high safety profile, inducing no nephrotoxicity, hepatotoxicity or changes in the haematological parameters.

Conclusion and Implications

Epo significantly enhances the antitumour activity of LFM‐A13, indicating that a combination of Epo and LFM‐A13 has potential as an effective therapeutic approach for patients with colorectal cancer.
Quantifying the relationship between inhibition of VEGF receptor 2, drug‐induced blood pressure elevation and hypertension
Authors: Collins Teresa , Gray Kelly , Bista Michal , Skinner Matt , Hardy Christopher , Wang Haiyun , Mettetal Jerome T , Harmer Alexander R
Published: November 2017

Background and Purpose

Several anti‐angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15–60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off‐target activity at VEGFR‐2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR‐2 off‐target potency into blood pressure elevation would be useful in development of novel TKIs. Here, we have sought to quantify the relationship between VEGFR‐2 inhibition and blood pressure elevation for a range of kinase inhibitors.

Experimental Approach

Porcine aortic endothelial cells overexpressing VEGFR‐2 (PAE) were used to determine IC50 for VEGFR‐2 phosphorylation. These IC50 values were compared with published reports of exposure attained during clinical use and the corresponding incidence of all‐grade hypertension. Unbound average plasma concentration (Cav,u) was selected to be the most appropriate pharmacokinetic parameter. The pharmacokinetic‐pharmacodynamic (PKPD) relationship for blood pressure elevation was investigated for selected kinase inhibitors, using data derived either from clinical papers or from rat telemetry experiments.

Key Results

All‐grade hypertension was predominantly observed when the Cav,u was >0.1‐fold of the VEGFR‐2 (PAE) IC50. Furthermore, based on the PKPD analysis, an exposure‐dependent blood pressure elevation >1 mmHg was observed only when the Cav,u was >0.1‐fold of the VEGFR‐2 (PAE) IC50.

Conclusions and Implications

Taken together, these data show that the risk of blood pressure elevation is proportional to the amount of VEGFR‐2 inhibition, and a margin of >10‐fold between VEGFR‐2 IC50 and Cav,u appears to confer a minimal risk of hypertension.
Fostering a culture of family‐centred care: Child welfare professionals' beliefs about fathers, family instability, and the value of relationship education
Authors: Mallette Jacquelyn K. , Futris Ted G. , Schramm David G.
Published: November 2017

Guided by the Cultural Competence Attainment Model, the purpose of this study is to examine how socio‐demographic and work characteristics are associated with variations in child welfare professionals' (CWPs) attitudes about father involvement and family instability and how these attitudes are linked with whether they view relationship and marriage education as relevant to their efforts to support families. Drawing from a sample of 624 CWPs and using latent profile analysis, the results revealed three latent classes of CWPs, with most professionals being labelled as either “moderately” or “highly” concerned about father involvement and family instability, with a smaller class of professionals labelled as having less concern about these family issues. Those labelled as highly concerned tended to be older, male, African American, married, and had worked longer in the child welfare field. As well, those labelled as highly concerned were more likely to agree that strengthening the couple and coparenting relationship would benefit children and were most amenable to receiving RME training. Implications for relationship and marriage education training for child welfare professionals and other practitioners are provided.
Bayesian Occam's Razor Is a Razor of the People
Authors: Blanchard Thomas , Lombrozo Tania , Nichols Shaun
Published: November 2017

Occam's razor—the idea that all else being equal, we should pick the simpler hypothesis—plays a prominent role in ordinary and scientific inference. But why are simpler hypotheses better? One attractive hypothesis known as Bayesian Occam's razor (BOR) is that more complex hypotheses tend to be more flexible—they can accommodate a wider range of possible data—and that flexibility is automatically penalized by Bayesian inference. In two experiments, we provide evidence that people's intuitive probabilistic and explanatory judgments follow the prescriptions of BOR. In particular, people's judgments are consistent with the two most distinctive characteristics of BOR: They penalize hypotheses as a function not only of their numbers of free parameters but also as a function of the size of the parameter space, and they penalize those hypotheses even when their parameters can be “tuned” to fit the data better than comparatively simpler hypotheses.
Solitary soft tissue Langerhans cell histiocytosis of the neck. Cytohistological correlation and review of the literature
Authors: Gonzalez M. F. , Azar A. , Jamal S. M. E.
Published: November 2017

In this paper, we highlight the importance of the cytomorphologic findings for the diagnosis of LCH. The majority of published data on LCH describes secondary soft tissue involvement in patients with osseous LCH. In our case, the cytomorphologic features of the cells identified on the fine needle aspiration smears were the most important tool for suspecting LCH on this 38 year old female patient who was treated with antibiotics for chronic otitis without improvement. The cell block slides of the concurrent core biopsy of the soft tissue failed to reveal the characteristic features of the Langerhans cells despite the presence of eosinophils in the background
Wolves at the crossroad: Fission–fusion range biogeography in the Western Carpathians and Central Europe
Authors: Hulva Pavel , Černá Bolfíková Barbora , Woznicová Vendula , Jindřichová Milena , Benešová Markéta , Mysłajek Robert W. , Nowak Sabina , Szewczyk Maciej , Niedźwiecka Natalia , Figura Michał , Hájková Andrea , Sándor Atilla D. , Zyka Vladimír , Romportl Dušan , Kutal Miroslav , Finďo Slavomír , Antal Vladimír
Published: November 2017

Aim

Population fragmentation represents a leitmotif of conservation biology, but the impact of population reconnection is less well studied. The recent recolonization of large carnivores in Europe is a good model for studying this phenomenon. We aim to show novel data regarding distribution and population genetic structure of the grey wolf in Central Europe, a region considered a frequent crossroad and contact zone of different phylogeographic lineages, in a biogeographic context.

Location

Western Carpathians, Central Europe.

Methods

In concordance with the presumption of a highly mobile mammal, individual‐based Bayesian clustering and a posteriori definition of populations were used. Integrating the frameworks of landscape genetics and biogeography enabled the identification of transitions in population architecture. These patterns could be ascribed to isolating factors based on historical knowledge about species demography.

Results

Genetic differentiation mirrors population isolation and recognized environmental clusters, suggesting ecotypic variation. The east–west split in the Western Carpathians likely represents the signature of range fragmentation during bottlenecks in the 20th century. Mitochondrial variability is more depleted than nuclear variability, indicating founder‐flush demography. Microsatellites show finer‐scale differentiation in the Carpathians compared to the European plain, corresponding to topographic heterogeneity. Long‐range dispersal of a Carpathian wolf (ca. 300 km), the establishment of enclaves originated from the lowland population and admixture with mountain wolves were ascertained, indicating a population fraction producing large‐scale gene flow.

Main conclusion

Carpathian wolves are characterized by periods of population and range decline due to eradication, facilitating refugial role of alpine habitats and peripatric effects, followed by expansions and fusions probably caused by forest transition, population adaptation and efforts in conservation management. New occurrence and hybridization events predict further contacts between formerly isolated populations, with potential opposing effects of heterosis and outbreeding depression. Population recovery might be hindered due to isolation by environment and anthropogenic impacts.
Appropriate use criteria for transthoracic echocardiography: Are they relevant to European centers?
Authors: Kerley Robert N. , Thornton Kenneth P. , Kelly Raymond M. , O'Flynn Siun
Published: November 2017

Background

There is a growing interest in appropriate use criteria (AUC) for cardiovascular imaging referrals in Europe. These criteria, developed by American subspecialty societies, have been in use since 2007 and show a temporal reduction in inappropriate transthoracic echocardiogram (TTE) requests. When applied to European centers, inappropriate referral rates as high as 15% have been observed.

Methods

A retrospective analysis of TTE referrals for appropriateness and major abnormality detection was conducted over a two‐month period at Cork University Hospital (CUH).

Results

Overall, 1277 requests were assessed, of which 97.7% were classifiable. Of the 1235 classifiable studies, 1049 (84.9%) were appropriate, 135 (10.9%) were inappropriate, and 51 (4.1%) were uncertain. Main indications were the evaluation of cardiac structure and function (496, 40.2%), hypertension, heart failure or cardiomyopathy (349, 28.3%), and valvular function (228, 18.5%). Inappropriate referral rates were significantly higher for outpatients compared to inpatients (13.8% vs 7.1%, P < .05) and cardiologist referrals compared to noncardiologists (13.1 vs 8.0%, P < .05), while one in three requests for the evaluation of valvular function (32.5%) were inappropriate. Compared to inappropriate studies, appropriate and uncertain scans had a greater prevalence of ≥1 major abnormalities (33.6% vs 19.3%, P < .001) and greater detection rates of new abnormalities (27.6% vs 13.3%, P < .001).

Conclusion

Application of the 2011 AUC yields similar results to those reported from the US. The application of said criteria to our center could avoid one of every ten scans currently ordered.
Mechanisms of proton relay and product release by Class A β‐lactamase at ultrahigh resolution
Authors: Lewandowski Eric M. , Lethbridge Kathryn G. , Sanishvili Ruslan , Skiba Joanna , Kowalski Konrad , Chen Yu
Published: November 2017

The β‐lactam antibiotics inhibit penicillin‐binding proteins (PBPs) by forming a stable, covalent, acyl‐enzyme complex. During the evolution from PBPs to Class A β‐lactamases, the β‐lactamases acquired Glu166 to activate a catalytic water and cleave the acyl‐enzyme bond. Here we present three product complex crystal structures of CTX‐M‐14 Class A β‐lactamase with a ruthenocene‐conjugated penicillin—a 0.85 Å resolution structure of E166A mutant complexed with the penilloate product, a 1.30 Å resolution complex structure of the same mutant with the penicilloate product, and a 1.18 Å resolution complex structure of S70G mutant with a penicilloate product epimer—shedding light on the catalytic mechanisms and product inhibition of PBPs and Class A β‐lactamases. The E166A–penilloate complex captured the hydrogen bonding network following the protonation of the leaving group and, for the first time, unambiguously show that the ring nitrogen donates a proton to Ser130, which in turn donates a proton to Lys73. These observations indicate that in the absence of Glu166, the equivalent lysine would be neutral in PBPs and therefore capable of serving as the general base to activate the catalytic serine. Together with previous results, this structure suggests a common proton relay network shared by Class A β‐lactamases and PBPs, from the catalytic serine to the lysine, and ultimately to the ring nitrogen. Additionally, the E166A–penicilloate complex reveals previously unseen conformational changes of key catalytic residues during the release of the product, and is the first structure to capture the hydrolyzed product in the presence of an unmutated catalytic serine.

Database

Structural data are available in the PDB database under the accession numbers 5TOP, 5TOY, and 5VLE
Commercial alkaline earth boroaluminosilicate glasses for sealing solid oxide cell stacks. Part II: Characterization of devitrification and glass‐ceramic phase assemblages
Authors: Agersted Karsten , Balic‐Zunic Tonci
Published: November 2017

The devitrification process and formation of crystalline phases from commercial alkaline earth boroaluminosilicate glasses containing 48‐61 mol% SiO2, 18‐28 mol% CaO, 1‐7 mol% MgO, 7‐10 mol% Al2O3, 1‐11 mol% B2O3 plus minor amounts of Na2O, K2O, FeO, and TiO2 were quantified through analysis of phase assemblages as function of heat treatments above the glass transition temperatures, using the electron microprobe and powder X‐ray diffraction. Treatments at 800 and 850°C lasted up to 6 weeks. Results indicate that devitrification was strongly activated through presence of heterogeneous nucleation, and that the growth mechanism gradually changed from three‐dimensional growth at the onset of devitrification toward one‐dimensional growth in later stages, when heterogeneous nucleation was absent or less dominating. Most glasses developed entangled and fibrous microstructures with little or no residual glass phase, which are adequate for rigid sealants, and only one of the laboratory analogue glasses, MCAS, developed microstructures with both more equiaxed grains and a considerable amount of residual glass phase, which may be adequate for more compliant and self‐healing sealants as often required in SOC‐applications. Even though the glasses lie within a relatively narrow compositional range, resulting phase assemblages differed significantly. Anorthite (plagioclase) developed as the main crystalline phase in all samples together with pyroxene (or pyroxenoide) and cristobalite. Calcium‐magnesium‐silicate pyroxene (diopside) was in a large part replaced by the calcium‐silicate pyroxenoid (wollastonite) in the samples where the mol‐proportion MgO:CaO was 1:5 or lower. In samples with a very low MgO proportion and consequently a high CaO proportion, calcium metaborate and calcium aluminum borosilicate (okayamalite) crystallized among the main phases and these glasses crystallized completely within the period of heat treatment. Although cristobalite is metastable at the annealing temperatures, both α and β forms were rapidly formed in most of the samples, likely due to kinetic reasons. The presence of the latter is explained by the stabilization effect of Al and B substitution for Si compensated by Ca stuffing in the structure. The stuffed cristobalite transformed with time to quartz (at 800°C) or quartz plus tridymite (at 850°C). Boron was incorporated in the first crystallizing phases, especially diopside, substituting for Al and Si, but the so established substitution partly disappeared with time during the heat treatment.
Smart phone accessibility and mHealth use in a limited resource setting
Authors: Garner Shelby L. , Sudia Tanya , Rachaprolu Spurgeon
Published: November 2017

Aim

To determine smartphone access and use including future opportunities for mHealth and potential ethical implications among health care professionals practicing at a health care facility in Bengaluru, India.

Background

The evolution of smart phones can provide convenient, portable, and rapid access to resources for health care professionals. While mobile phone accessibility has improved in recent years in many low and middle‐income countries, the use of smart phones to address health priorities remains limited in some limited resource settings.

Design

A quantitative descriptive design was used.

Methods

A survey was administered in November of 2016 to nurses and physicians at a tertiary care hospital in India.

Results/Findings

All respondents had a mobile phone, and the majority owned a smart phone that was used for text messaging, email, accessing internet, and downloading apps. Participants recommended smart phone use to improve health care provider access to continuing education and to improve patient knowledge about health. Physicians had better access to mHealth resources compared with nurses.

Conclusion

Credible, evidence‐based, affordable mobile applications are needed to provide a platform for continuing health education to health professionals and patients in India and limited resource settings. Nurses need equitable access to mHealth resources to build successful mHealth initiatives.
CaTiO3 induced ferroelectric phase coexistence and low temperature dielectric relaxation in BaTiO3–BaZrO3 ceramics
Authors: Sutapun Manoon , Charoonsuk Thitirat , Kolodiazhnyi Taras , Vittayakorn Naratip
Published: November 2017

The series of 0.86BaTiO3–(0.14−x)BaZrO3–xCaTiO3 (abbreviated as BT–BZ–xCT) ceramics with 0.03 ≤ x ≤ 0.11 were studied to obtain high piezoelectric properties. Rietveld refinement analysis indicated that the BT–BZ–CT compositions follow a gradual rhombohedral (R) → orthorhombic (O) + R → O + tetragonal (T) → T phase transformation with increasing x. Clear evidence of the series of ferroelectric phase transitions was also found in the dielectric results. The R‐O and O‐T transition temperature shifted close to ambient temperature, while the Curie temperature slightly increased with increasing x. In addition to the dielectric loss peaks associated with the structural phase transitions, a broad low‐temperature dielectric loss peak was detected in the R phase at T = 90‐150 K. This dielectric relaxation was attributed to the domain wall freezing and fits well to the Vogel‐Fulcher model with activation energy Ea ≈ 60‐300 meV and freezing temperature TVF ≈ 75‐140 K. High piezoelectric strain coefficient (d33*) of about 1030 pm/V at 10 kV was achieved at x = 0.07, and a high Curie temperature (TC) was maintained at about 375 K.
Role of PI3K in myocardial ischaemic preconditioning: mapping pro‐survival cascades at the trigger phase and at reperfusion
Authors: Rossello Xavier , Riquelme Jaime A , Davidson Sean M , Yellon Derek M
Published: November 2017

The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro‐survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K‐Akt, its negative regulator PTEN and other pro‐survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3β and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3β was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K‐dependent during the IPC phase. In conclusion, PI3K‐Akt plays a major role in IPC‐induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K‐independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade.