bluuebunny/crossref_metadata_2025 huggingface dataset:
Variation in bulk‐leaf 13C discrimination, leaf traits and water‐use efficiency–trait relationships along a continental‐scale climate gradient in Australia
Authors: Rumman Rizwana , Atkin Owen K. , Bloomfield Keith J. , Eamus Derek
Published: September 2017

Large spatial and temporal gradients in rainfall and temperature occur across Australia. This heterogeneity drives ecological differentiation in vegetation structure and ecophysiology. We examined multiple leaf‐scale traits, including foliar 13C isotope discrimination (Δ13C), rates of photosynthesis and foliar N concentration and their relationships with multiple climate variables. Fifty‐five species across 27 families were examined across eight sites spanning contrasting biomes. Key questions addressed include: (i) Does Δ13C and intrinsic water‐use efficiency (WUEi) vary with climate at a continental scale? (ii) What are the seasonal and spatial patterns in Δ13C/WUEi across biomes and species? (iii) To what extent does Δ13C reflect variation in leaf structural, functional and nutrient traits across climate gradients? and (iv) Does the relative importance of assimilation and stomatal conductance in driving variation in Δ13C differ across seasons? We found that MAP, temperature seasonality, isothermality and annual temperature range exerted independent effects on foliar Δ13C/WUEi. Temperature‐related variables exerted larger effects than rainfall‐related variables. The relative importance of photosynthesis and stomatal conductance (gs) in determining Δ13C differed across seasons: Δ13C was more strongly regulated by gs during the dry‐season and by photosynthetic capacity during the wet‐season. Δ13C was most strongly correlated, inversely, with leaf mass area ratio among all leaf attributes considered. Leaf Nmass was significantly and positively correlated with MAP during dry‐ and wet‐seasons and with moisture index (MI) during the wet‐season but was not correlated with Δ13C. Leaf Pmass showed significant positive relationship with MAP and Δ13C only during the dry‐season. For all leaf nutrient‐related traits, the relationships obtained for Δ13C with MAP or MI indicated that Δ13C at the species level reliably reflects the water status at the site level. Temperature and water availability, not foliar nutrient content, are the principal factors influencing Δ13C across Australia.
The Direct and Indirect (Spillover) Effects of Productive Government Spending on State Economic Growth
Authors: Ojede Andrew , Atems Bebonchu , Yamarik Steven
Published: September 2017

Using data on 48 contiguous U.S. states and a spatial econometric approach, this paper examines short‐ and long‐run effects of productive higher education and highway infrastructure spending financed by different revenue sources on state economic growth. Following the Lagrange Multiplier, Wald, and Likelihood Ratio tests, the data are found to be characterized by both spatial lag and spatial error processes, leading to the estimation of a dynamic spatial Durbin model. By decomposing results of the dynamic spatial Durbin model into short‐ and long‐run direct as well as indirect (spillover) effects, we show that accounting for spillover effects provides a more comprehensive approach to uncovering the effects of productive government spending on growth. We find that, regardless of the financing source, productive higher education and highway spending have statistically significant short‐ and long‐run direct as well as spillover effects on state income growth.
Efficacy and safety of combination therapy with an α‐glucosidase inhibitor and a dipeptidyl peptidase‐4 inhibitor in patients with type 2 diabetes mellitus: A systematic review with meta‐analysis
Authors: Min Se Hee , Yoon Jeong‐Hwa , Hahn Seokyung , Cho Young Min
Published: September 2017

Aims/Introduction

The combination of dipeptidyl peptidase‐4 (DPP4) inhibitors and α‐glucosidase inhibitors (AGIs) might provide an additive or synergistic glucose‐lowering effect, as they have a complementary mode of action. In the present study, we examined the efficacy and safety of the addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI.

Materials and Methods

We carried out an electronic search of MEDLINE, EMBASE, the Cochrane Library and Clinicaltrials.gov through October 2016. Randomized controlled trials written in English that compared DPP4 inhibitors plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with type 2 diabetes were selected. Data on the study characteristics, efficacy and safety outcomes were extracted, and the risk of potential biases was assessed. The efficacy and safety of DPP4i/AGI and PCB/AGI were compared.

Results

Of 756 potentially relevant published articles and 40 registered trials, five studies including 845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI were included for meta‐analysis. Compared with PCB/AGI, DPP4i/AGI showed a greater reduction in glycated hemoglobin (weighted mean difference −1.2%, 95% confidence interval −1.6 to −0.8), fasting plasma glucose and 2‐h postprandial plasma glucose levels, with no increase in bodyweight. The risks of hypoglycemia and gastrointestinal adverse events were similar between DPP4i/AGI and PCB/AGI.

Conclusions

The addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI achieved better glycemic control without further increasing the risk of weight gain and hypoglycemia.
Improving performances of the knee replacement surgery process by applying DMAIC principles
Authors: Improta Giovanni , Balato Giovanni , Romano Maria , Ponsiglione Alfonso Maria , Raiola Eliana , Russo Mario Alessandro , Cuccaro Patrizia , Santillo Liberatina Carmela , Cesarelli Mario
Published: September 2017

Rationale, Aims, and Objectives

The work is a part of a project about the application of the Lean Six Sigma to improve health care processes. A previously published work regarding the hip replacement surgery has shown promising results. Here, we propose an application of the DMAIC (Define, Measure, Analyse, Improve, and Control) cycle to improve quality and reduce costs related to the prosthetic knee replacement surgery by decreasing patients' length of hospital stay (LOS)

Methods

The DMAIC cycle has been adopted to decrease the patients' LOS. The University Hospital “Federico II” of Naples, one of the most important university hospitals in Southern Italy, participated in this study. Data on 148 patients who underwent prosthetic knee replacement between 2010 and 2013 were used. Process mapping, statistical measures, brainstorming activities, and comparative analysis were performed to identify factors influencing LOS and improvement strategies.

Results

The study allowed the identification of variables influencing the prolongation of the LOS and the implementation of corrective actions to improve the process of care. The adopted actions reduced the LOS by 42%, from a mean value of 14.2 to 8.3 days (standard deviation also decreased from 5.2 to 2.3 days).

Conclusions

The DMAIC approach has proven to be a helpful strategy ensuring a significant decreasing of the LOS. Furthermore, through its implementation, a significant reduction of the average costs of hospital stay can be achieved. Such a versatile approach could be applied to improve a wide range of health care processes.
Development of the Optimality Index‐NL2015, an Instrument to Measure Outcomes of Maternity Care
Authors: Hermus Marieke , Boesveld Inge , van der Pal‐de Bruin Karin , Wiegers Therese
Published: September 2017

Introduction

An optimality index is a composite tool to measure maximum outcome with minimal intervention. It focuses on optimality instead of on normality and is useful in comparing differences in processes and perinatal outcomes for women at low risk of complications. The latest Dutch version dates from 2 decades ago, and international versions of the optimality index are not directly applicable to the Dutch maternity system. Most data for perinatal research in the Netherlands are derived from a national perinatal database: the Netherlands Perinatal Registry. The aim of this study was to develop a new Dutch version of the optimality index (OI‐NL2015) that could be calculated from data derived from this national perinatal database and to assess the reliability of these data for use in the index.

Methods

Potential items were collected by a thorough comparison of earlier (inter)national optimality indexes and the current data collection of the national database. All items were reviewed by 2 experts in maternity care and assessed for importance, relevance for the Dutch maternity care system, and feasibility to retrieve information on these items. For each item a criterion for optimality was formulated based on evidence‐based or consensus‐based effectiveness of care in pregnancy and childbirth. All selected items were scored on potential problems, with reliability by 20 randomly selected community midwives. The level of agreement was calculated comparing these 2 data sets, which included data of the same women.

Results

The final OI‐NL2015 consists of 31 items in 3 different components: 22 intrapartum, 7 neonatal, and 2 postpartum. Of the 7 items that were examined because of expected potential problems with reliability, in 6 items a level of 90% agreement was found.

Discussion

An optimality index is not a standard measurement instrument but must be validated and adapted to local circumstances and available data.
A practical guide to cardiovascular 3D printing in clinical practice: Overview and examples
Authors: Abudayyeh Islam , Gordon Brent , Ansari Mohammad M. , Jutzy Kenneth , Stoletniy Liset , Hilliard Anthony
Published: September 2017

The advent of more advanced 3D image processing, reconstruction, and a variety of three‐dimensional (3D) printing technologies using different materials has made rapid and fairly affordable anatomically accurate models much more achievable. These models show great promise in facilitating procedural and surgical planning for complex congenital and structural heart disease. Refinements in 3D printing technology lend itself to advanced applications in the fields of bio‐printing, hemodynamic modeling, and implantable devices. As a novel technology with a large variability in software, processing tools and printing techniques, there is not a standardized method by which a clinician can go from an imaging data‐set to a complete model. Furthermore, anatomy of interest and how the model is used can determine the most appropriate technology. In this over‐view we discuss, from the standpoint of a clinical professional, image acquisition, processing, and segmentation by which a printable file is created. We then review the various printing technologies, advantages and disadvantages when printing the completed model file, and describe clinical scenarios where 3D printing can be utilized to address therapeutic challenges.
The impact of bargaining delays under the threat of eminent domain
Authors: Portillo Javier E.
Published: September 2017

Developers seeking to assemble complementary parcels of land will likely encounter strategic behavior by landowners. Using a property‐level data set from Florida's Department of Transportation covering the period January 2000 to July 2014, I test whether bargaining delays lead to higher final transaction prices. Given the nature of the data, I can compare properties within the same roadway project to estimate the effect of delayed negotiations. My empirical estimates indicate that bargaining delays lead to increased final transaction prices. The magnitude of this effect is approximately 7 percent for the average holdout, however, the effect is nonlinear and diminishes over time.
Performance of fibrosis prediction scores in paediatric non‐alcoholic fatty liver disease
Authors: Jackson Jasmine A , Konomi Juna V , Mendoza Michael V , Krasinskas Alyssa , Jin Ran , Caltharp Shelley , Mouzaki Marialena , Vos Miriam B
Published: September 2017

Aim

Non‐alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. The phenotype of NAFLD varies widely, and non‐invasive predictors of disease severity are scarce and are needed to tailor clinical management.

Methods

We compared liver fibrosis by histology with proposed non‐invasive predictors of fibrosis, including alanine transaminase (ALT), aspartate transaminase (AST), AST/ALT ratio, AST to platelet ratio index, fibrosis‐4, paediatric NAFLD fibrosis index and paediatric NAFLD fibrosis score.

Results

The area under the curve of scores obtained while predicting fibrosis in children with NAFLD ranged from 0.51 to 0.67.

Conclusion

The tested non‐invasive fibrosis scoring systems, some of which were originally designed for adult populations, did not adequately predict fibrosis in a paediatric cohort. Further development of risk prediction scores in children are needed for the management of paediatric patients and will likely need to be developed within a large paediatric data set in order to improve specificity and sensitivity.
Invasiveness, chimerism and genetic diversity
Authors: Ben‐Shlomo Rachel
Published: September 2017

Adaptation for invasiveness should comprise the capability to exploit and prosper in a wide range of ecological conditions and is therefore expected to be associated with a certain level of genetic diversity. Paradoxically, however, invasive populations are established by only a few founders, resulting in low genetic diversity. As a conceivable way of attaining high genetic diversity and high variance of gene expression even when a small number of founders is involved in invasiveness, I suggest here chimerism, a fusion between different individuals—a common phenomenon found in numerous phyla. The composite entity offers the chimeric organism genetic flexibility and higher inclusive fitness that depends on the joint genomic fitness of the original partners. The ability to form a chimeric entity is also applied to subsequent generations, and consequently, the level of genetic diversity does not decline over generations of population establishment following invasion.
Mild cognitive impairment in older adults with pre‐dialysis patients with chronic kidney disease: Prevalence and association with physical function
Authors: Otobe Yuhei , Hiraki Koji , Hotta Chiharu , Nishizawa Hajime , Izawa Kazuhiro P. , Taki Yasuhiro , Imai Naohiko , Sakurada Tsutomu , Shibagaki Yugo
Published: September 2017

Aim

Chronic kidney disease (CKD) is a risk factor for declining cognitive and physical function. However, the prevalence of mild cognitive impairment (MCI) and its relationship with physical function is not clear. Therefore, our aim was to evaluate the prevalence of MCI and the relationship between MCI and physical function among older adults with pre‐dialysis CKD.

Methods

We conducted a cross‐sectional study of 120 patients, aged ≥65 years (mean age, 77.3 years), with pre‐dialysis CKD but without probable dementia (Mini Mental State Examination <24). MCI was evaluated using the Japanese version of the Montreal Cognitive Assessment (MoCA‐J). For analysis, patients were classified into two cognitive function groups: normal (MoCA‐J ≥ 26) and MCI (MoCA‐J < 26). Physical, clinical, and biochemical parameters were compared between the groups. Logistic and linear regression analyses were used to evaluate the specific association between cognitive and physical function.

Results

Seventy‐five (62.5%) patients belonged to the MCI group. Significant differences between the two groups were identified for gait speed, balance, age, and haemoglobin concentration. After adjustment for covariates, only gait speed was significantly associated with MCI (odds ratio, 0.06; 95% confidence interval, 0.009–0,411).

Conclusion

The prevalence of MCI among older adults with pre‐dialysis CKD was as high as 62.5%. The association between MCI and reduced gait speed supports the possible interaction between physical and cognitive functions and the need for early screening.
Variation in esophageal physiology testing in clinical practice: Results from an international survey
Authors: Sweis R. , Heinrich H. , Fox M. ,   the International Working Group for GI Motility and Function
Published: September 2017

Background

Advances in clinical measurement of esophageal motility and function have improved the assessment of swallowing disorders and reflux symptoms. Variation in data acquisition, analysis, and reporting exists and impacts on diagnosis and management.

Aims and Methods

This study examined variation in esophageal manometry methodology between institutions to establish the status in current practice. A structured survey was distributed through international NGM societies using an Internet‐based platform. Questions explored infrastructure, technology, analysis, and reporting.

Key Results

Responses were received from 91 centers from 29 countries. Eighteen (20%) centers used “conventional” manometry, 75 (82%) high‐resolution manometry, and 53 (58%) HR impedance manometry.

All centers documented motility for single water swallows. The Chicago Classification was applied by 65 (71.4%) centers. In contrast, analysis of EGJ morphology varied widely. Adjunctive testing was often applied: multiple rapid swallows (77%), rapid drink challenge (77%), single solid swallows (63%), and a standard test meal (18%).

Of 86 (94.5%) units that offered pH impedance (pH‐Z) studies, approximately half (53.5%) performed tests on acid‐suppressant medication in patients with a high pretest probability (eg, erosive esophagitis). Most (75.6%) centers manually reviewed every reflux event. Others examined pH‐Z data only prior to symptoms. To assess symptom association with reflux events, 73.6% centers analyzed each symptom separately, whereas 29.7% centers pooled symptoms.

Conclusions and Inferences

There is marked variation in the data acquisition, analysis, and reporting of esophageal manometry studies. Further efforts to improve quality and uniformity in testing and reporting are required. This survey provides information upon which best‐practice guidelines can be developed.
Melanocortin 1 receptor (MC1R) polymorphisms’ influence on size and dermoscopic features of nevi
Authors: Vallone María Gabriela , Tell‐Marti Gemma , Potrony Miriam , Rebollo‐Morell Aida , Badenas Celia , Puig‐Butille Joan Anton , Gimenez‐Xavier Pol , Carrera Cristina , Malvehy Josep , Puig Susana
Published: September 2017

The melanocortin 1 receptor (MC1R) is a highly polymorphic gene. The loss‐of‐function MC1R variants (“R”) have been strongly associated with red hair color phenotype and an increased melanoma risk. We sequenced the MC1R gene in 175 healthy individuals to assess the influence of MC1R on nevus phenotype. We identified that MC1R variant carriers had larger nevi both on the back [p‐value = .016, adjusted for multiple parameters (adj. p‐value)] and on the upper limbs (adj. p‐value = .007). Specifically, we identified a positive association between the “R” MC1R variants and visible vessels in nevi [p‐value = .033, corrected using the FDR method for multiple comparisons (corrected p‐value)], dots and globules in nevi (corrected p‐value = .033), nevi with eccentric hyperpigmentation (corrected p‐value = .033), a high degree of freckling (adj. p‐value = .019), and an associative trend with presence of blue nevi (corrected p‐value = .120). In conclusion, the MC1R gene appears to influence the nevus phenotype.
The Impacts of Markets and Tax on a Multinational Firm's Procurement Strategy in China
Authors: Xu Jiayan , Hsu Vernon N. , Niu Baozhuang
Published: September 2017

Motivated by observations in the greater China region, this paper studies a multinational firm (MNF)'s preferences between two procurement strategies in a global business environment. The MNF relies on a contract manufacturer (CM) to produce its products, which serve both markets within (domestic market) and outside (overseas market) China. The MNF is assumed to be monopolistic in the overseas market but faces competition from a local original equipment manufacturer (OEM) who outsources both manufacturing and component procurement to the CM. The MNF will decide whether to control its component procurement (consignment strategy) or delegate that function to the CM (turnkey strategy). Our study indicates that a number of factors unique to the global supply chain environment, such as a multi‐market structure with different sizes and natures of competition, and a set of tax rules that gives differential treatment to products serving different markets, have the potential of impacting the MNF's choice of consignment vs. turnkey strategies, sometimes in interesting ways. In particular, we find that when attempting to balance the pros and cons of cooperating with the local OEM under turnkey while competing against it in the domestic market, the MNF's preference could switch twice from turnkey to consignment and back to turnkey, and its global profits could first decrease and then increase, as the domestic market grows. Our study also highlights the importance of making a company's global supply chain management decisions while considering international tax rules.
Event‐related potential components as measures of aversive conditioning in humans
Authors: Bacigalupo Felix , Luck Steven J.
Published: September 2017

For more than 60 years, the gold standard for assessing aversive conditioning in humans has been the skin conductance response (SCR), which arises from the activation of the peripheral nervous system. Although the SCR has been proven useful, it has some properties that impact the kinds of questions it can be used to answer. In particular, the SCR is slow, reaching a peak 4–5 s after stimulus onset, and it decreases in amplitude after a few trials (habituation). The present study asked whether the late positive potential (LPP) of the ERP waveform could be a useful complementary method for assessing aversive conditioning in humans. The SCR and LPP were measured in an aversive conditioning paradigm consisting of three blocks in which one color was paired with a loud noise (CS+) and other colors were not paired with the noise (CS−). Participants also reported the perceived likelihood of being exposed to the noise for each color. Both SCR and LPP were significantly larger on CS+ trials than on CS− trials. However, SCR decreased steeply after the first conditioning block, whereas LPP and self‐reports were stable over blocks. These results indicate that the LPP can be used to assess aversive conditioning and has several useful properties: (a) it is a direct response of the central nervous system, (b) it is fast, with an onset latency of 300 ms, (c) it does not habituate over time.
Toward an optimal degree of openness in IT innovation projects
Authors: Bürger Olga , Moser Florian
Published: September 2017

In spite of substantial interest in open innovation (OI), both research and practice lack methods that support companies in managing their IT innovation projects (ITIPs) relative to OI. We contribute to the closure of this gap by providing an approach for anex antefinancial evaluation of OI application, which involves developing a theoretical model that determines the optimal degree of openness in ITIPs. Based on our model, we examine relevant causal relationships by analyzing the influence of a company's ability to manage OI and the probability of success in OI application on the theoretical optimum. We find that the optimal openness level is linked with the company's ability to manage OI, which can incorporate organizational, cultural, and technological maturity. To increase the value contribution of OI, companies should focus on a steady improvement in managing OI. The results provide both an indicator for practical decision‐making and a starting point for future research.
Sustained sympathetic activity in altitude acclimatizing lowlanders and high‐altitude natives
Authors: Lundby C. , Calbet J. , van Hall G. , Saltin B. , Sander M.
Published: September 2017

Combined results from different independent studies suggest that acclimatization to high altitude induces a slowly developing sympathetic activation, even at levels of hypoxia that cause no acute chemoreflex‐mediated sympathoexcitation. We here provide direct neurophysiological evidence for this phenomenon. In eight Danish lowlanders, we quantified mean arterial blood pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA), twice at sea level (normoxia and with acute hypoxic exposure to 12.6% O2) and twice at high altitude (after 10 and 50 days of exposure to 4100 m). Measurements were also obtained in eight Bolivian highlanders on one occasion at high altitude. Acute hypoxic exposure caused no increase in MSNA (15 ± 2 vs 16 ± 2 bursts per min, respectively, and also MAP and HR remained stable). In contrast, from sea level to 10 and 50 days in high‐altitude increases were observed in MAP: 72 ± 2 vs 78 ± 2 and 75 ± 2 mm Hg; HR: 54 ± 3 vs 67 ± 3 and 65 ± 3 beats per min; MSNA: 15 ± 2 vs 42 ± 5 and 42 ± 5 bursts per min, all P < .05. Bolivian subjects had high levels of MSNA: 34 ± 4 bursts per min. The simultaneous increase in MAP, HR, and MSNA suggests high altitude‐induced sympathetic activity, which is sustained in well‐acclimatized lowlanders. The high MSNA levels in the Bolivian highlanders suggest lifelong sympathetic activation at high altitude.
Applying physical science principles to mid‐substance Achilles tendinopathy and the relationship to eccentric lengthening exercises
Authors: Verrall G. M. , Dolman B. K. , Best T. M.
Published: September 2017

Mid‐substance Achilles tendinopathy is common in the active population. Eccentric (lengthening) exercises are known to be effective in alleviating the clinical condition. To better understand mid‐substance Achilles tendinopathy and the response to lengthening exercises physical science principles of elasticity are applied. We apply elastic motion laws to the spring‐like tendon as well as the normal and pathological adaptation seen with this common injury. We will validate important assumptions of the spring‐like behavior of the tendon and then apply these findings to the injured and rehabilitating states. Our analysis considers that the tendon can be viewed as being spring‐like with elasticity principles being applicable and the force exerted on the tendon during lengthening is primarily in a uniaxial direction. This applied lengthening force results in tendon mechanical and structural adaptation. Injury, and ultimately the clinical condition, occurs when the applied force exceeds the ability of the tendon to normally adapt. Morphological changes of the injured tendon are an attempt by the body to make the tendon more compliant. Lengthening exercises can be assessed as achieving this task with an improvement of tendon compliance. Physical science analysis proposes that the preferred rehabilitation tendon pathway is to try and decrease tendon stiffness to allow for more tendon lengthening. The body's morphological alterations of the pathological tendon are also consistent with this approach. For mid‐substance Achilles tendinopathy, this adaptation of decreased stiffness ultimately increases the tendons ability to withstand applied force during lengthening.
Constrained displacement boundary condition in embedment testing of dowel‐type fasteners in LVL
Authors: Schweigler Michael , Bader Thomas K. , Vessby Johan , Eberhardsteiner Josef
Published: September 2017

The influence of the loading orientation with respect to the grain direction of wood and the influence of the lateral dowel displacement boundary condition on the embedment behaviour of steel dowels in laminated veneer lumber (with parallel‐laminated veneers) are investigated in this study. For limit states of the lateral boundary condition, the load‐displacement behaviour was experimentally studied by means of full‐hole embedment tests on screw‐reinforced laminated veneer lumber, for two dowel diameters and up to large dowel displacements. A novel biaxial test set‐up is proposed for embedment tests with constrained lateral dowel displacement boundary condition, in order to quantify laterally evoked reaction forces. Corresponding forces were found to change orientation with increasing dowel displacement and amounted to about 20% and 40% of the vertical reaction force for dowel displacements of 5 mm and twice the dowel diameter, respectively. The influence of the lateral displacement boundary condition was highlighted by comparison of the test data with a previously established data set for unconstrained embedment testing. Constrained loading showed a stiffer response and higher nominal embedment stresses, as well as a more pronounced displacement hardening, compared to unconstrained loading.
Vitamin D deficiency accelerates ageing and age‐related diseases: a novel hypothesis
Authors: Berridge Michael J.
Published: September 2017

Ageing can occur at different rates, but what controls this variable rate is unknown. Here I have developed a hypothesis that vitamin D may act to control the rate of ageing. The basis of this hypothesis emerged from studyng the various cellular processes that control ageing. These processes such as autophagy, mitochondrial dysfunction, inflammation, oxidative stress, epigenetic changes, DNA disorders and alterations in Ca2+ and reactive oxygen species (ROS) signalling are all known to be regulated by vitamin D. The activity of these processes will be enhanced in individuals that are deficient in vitamin D. Not only will this increase the rate of ageing, but it will also increase the probability of developing age‐related diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and cardiovascular disease. In individual with normal vitamin D levels, these ageing‐related processes will occur at lower rates resulting in a reduced rate of ageing and enhanced protection against these age‐related diseases.

image
Camera for transmission He+ ion microscopy
Authors: Kavanagh Karen L. , Herrmann Christoph , Notte John A.
Published: September 2017

The intensity of transmitted He+ ions and atoms from a focused He+ beam was measured using a direct impact onto a camera located 20 cm below the sample. The camera consisted of a 256 × 256 array of Si p-i-n diodes (pixels) each 55 × 55 μm2 in area. Static, focused beam intensity profiles show a uniform distribution, as expected from the small de Broglie wavelength (80 fm) and coherent source. From the size of the beam spot, the half-angle beam convergence angle can be directly measured and compared with theoretical predictions based on column geometries. The detector count rate was consistent with an efficiency of 75%, when compared to the current measured by electrostatic beam blanking. The intensity profile of a neutral atom component was measured to have a 17% peak or 1.3% integrated intensity at a beam energy of 25 keV, compared to the ion beam. The intensity of transmitted particles through 50 nm amorphous carbon was less than that of graphite flakes, likely affected by thickness and channeling. Transmission images as a function of time to form 20 nm holes in graphite were obtained.
Perception and prediction of apparent source width and listener envelopment in binaural spherical microphone array auralizations
Authors: Nowak Johannes , Klockgether Stefan
Published: September 2017

This article deals with the assessment and prediction of the reproduction quality when binaurally auralizing spherical microphone array data for room simulation applications. The auralization is perceptually assessed in a listening experiment using the two attributes, apparent source width (ASW) and listener envelopment (LEV), for spatial quality description, whereas the technical analysis employs a psychoacoustically motivated model for room acoustical perception (RAP) which is specifically designed to estimate ASW and LEV. Both analyses focus on the array configuration in terms of varying modal resolutions and its influence on the spatial reproduction quality. The auralizations comprise three simulated environments, i.e., free-field sound fields as well as a dry and a reverberant room. Ten different audio signals are used as test material. Perceptual results show that the array configuration strongly influences the perception of ASW and LEV which also depends on the reflection properties of the simulated room. The ASW and LEV predictions by the RAP model correlate well with the results from the listening experiment.
Dimerization of the adaptor Gads facilitates antigen receptor signaling by promoting the cooperative binding of Gads to the adaptor LAT
Authors: Sukenik Sigalit , Frushicheva Maria P. , Waknin-Lellouche Cecilia , Hallumi Enas , Ifrach Talia , Shalah Rose , Beach Dvora , Avidan Reuven , Oz Ilana , Libman Evgeny , Aronheim Ami , Lewinson Oded , Yablonski Deborah
Published: September 2017

Constitutive dimerization of an adaptor molecule enables it to selectively amplify signaling by binding cooperatively to signaling complexes downstream of antigen receptors.
Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies
Authors: Waters Andrew M. , Ozkan-Dagliyan Irem , Vaseva Angelina V. , Fer Nicole , Strathern Leslie A. , Hobbs G. Aaron , Tessier-Cloutier Basile , Gillette William K. , Bagni Rachel , Whiteley Gordon R. , Hartley James L. , McCormick Frank , Cox Adrienne D. , Houghton Peter J. , Huntsman David G. , Philips Mark R. , Der Channing J.
Published: September 2017

Validation studies reveal the reliability of isoform- and mutation-specific anti-RAS antibodies.
Papers of note in
Science
357
(6357)
Authors: VanHook Annalisa M.
Published: September 2017

This week’s articles identify a mutation in the acetylcholine receptor that protects poison frogs from the neurotoxin that they produce; explain a key difference between neurons from Parkinson’s patients and those from mouse models of the disease; and review the intermolecular interactions that drive the formation of membraneless intracellular compartments.
Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor
Authors: Caro Luzelena , Wenning Larissa , Guo Zifang , Fraser Iain P. , Fandozzi Christine , Talaty Jennifer , Panebianco Deborah , Ho Maureen , Uemura Naoto , Reitmann Christina , Angus Peter , Gane Edward , Marbury Thomas , Smith William B. , Iwamoto Marian , Butterton Joan R. , Yeh Wendy W.
Published: September 2017

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC
0–24
(area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.
Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Cefepime in an
In Vitro
Infection Model
Authors: VanScoy Brian D. , Tenero David , Turner Simon , Livermore David M. , McCauley Jennifer , Conde Haley , Bhavnani Sujata M. , Rubino Christopher M. , Ambrose Paul G.
Published: September 2017

We previously demonstrated that for tazobactam administered in combination with ceftolozane, the pharmacokinetic-pharmacodynamic (PK-PD) index that best described tazobactam efficacy was the percentage of the dosing interval that tazobactam concentrations were above a threshold (%
T
>threshold). Using data from studies of
Enterobacteriaceae
producing extended-spectrum β-lactamases (ESBLs), a relationship between tazobactam %
T
>threshold and reduction in log
10
CFU/ml from baseline, for which the tazobactam threshold concentration was the product of the isolate's ceftolozane-tazobactam MIC value and 0.5, was identified. However, since the kinetics of cephalosporin hydrolysis vary among ESBLs and compounds, it is likely that the translational relationship used to derive the tazobactam threshold concentration varies among enzymes and compounds. Using a one-compartment
in vitro
infection model, the PK-PD of tazobactam administered in combination with cefepime was characterized, and a translational relationship across ESBL-producing
Enterobacteriaceae
was developed. Four clinical isolates, two
Escherichia coli
and two
Klebsiella pneumoniae
isolates, known to produce CTX-M-15 β-lactamase enzymes and displaying cefepime MIC values of 2 to 4 mg/liter in the presence of 4 mg/liter tazobactam, were evaluated. Tazobactam threshold concentrations from 0.0625× to 1× the tazobactam-potentiated cefepime MIC value were considered. The threshold that best described the relationship between tazobactam %
T
>threshold and change in log
10
CFU/ml from the baseline at 24 h was the product of 0.125 and the cefepime-tazobactam MIC (
R
2
= 0.813). The magnitudes of %
T
>threshold associated with net bacterial stasis and a 1-log
10
CFU/ml reduction from baseline at 24 h were 21.9% and 52.8%, respectively. These data will be useful in supporting the identification of tazobactam dosing regimens in combination with cefepime for evaluation in future clinical studies.
Killing of Pseudomonas aeruginosa by Chicken Cathelicidin-2 Is Immunogenically Silent, Preventing Lung Inflammation
In Vivo
Authors: Coorens Maarten , Banaschewski Brandon J. H. , Baer Brandon J. , Yamashita Cory , van Dijk Albert , Haagsman Henk P. , Veldhuizen Ruud A. W. , Veldhuizen Edwin J. A.
Published: September 2017

The development of antibiotic resistance by
Pseudomonas aeruginosa
is a major concern in the treatment of bacterial pneumonia. In the search for novel anti-infective therapies, the chicken-derived peptide cathelicidin-2 (CATH-2) has emerged as a potential candidate, with strong broad-spectrum antimicrobial activity and the ability to limit inflammation by inhibiting Toll-like receptor 2 (TLR2) and TLR4 activation. However, as it is unknown how CATH-2 affects inflammation
in vivo
, we investigated how CATH-2-mediated killing of
P. aeruginosa
affects lung inflammation in a murine model. First, murine macrophages were used to determine whether CATH-2-mediated killing of
P. aeruginosa
reduced proinflammatory cytokine production
in vitro
. Next, a murine lung model was used to analyze how CATH-2-mediated killing of
P. aeruginosa
affects neutrophil and macrophage recruitment as well as cytokine/chemokine production in the lung. Our results show that CATH-2 kills
P. aeruginosa
in an immunogenically silent manner both
in vitro
and
in vivo
. Treatment with CATH-2-killed
P. aeruginosa
showed reduced neutrophil recruitment to the lung as well as inhibition of cytokine and chemokine production, compared to treatment with heat- or gentamicin-killed bacteria. Together, these results show the potential for CATH-2 as a dual-activity antibiotic in bacterial pneumonia, which can both kill
P. aeruginosa
and prevent excessive inflammation.
A Small Periplasmic Protein with a Hydrophobic C-Terminal Residue Enhances DegP Proteolysis as a Suicide Activator
Authors: Kim Sungjae , Song Inseok , Eom Gaeul , Kim Seokhee
Published: September 2017

DegP is a highly conserved protease that performs regulated proteolysis to selectively remove misfolded proteins in the periplasm of
Escherichia coli
. Binding of misfolded proteins is known to be the main mechanism of DegP activation, but it is unknown whether any native proteins can alter DegP activity. Here, we show that a small periplasmic protein, YjfN, which is highly upregulated by the Cpx envelope stress response, functions as a “suicide activator” for DegP and promotes efficient degradation of misfolded proteins. YjfN readily binds to and is degraded by DegP, for which a hydrophobic C-terminal residue and transient unfolding of YjfN are critical. YjfN also activates DegP in
trans
while it is being degraded and accelerates degradation of a denatured outer membrane protein, OmpA, that is not easily recognized by DegP. Although YjfN also prevents OmpA aggregation, the
trans
-activation effect is mainly responsible for efficient OmpA degradation. Overexpression of YjfN enhances the viability of cells in misfolded protein stress that is induced by the presence of a less-active variant of DegP at high temperature. Collectively, we suggest that YjfN can enhance DegP proteolysis for relieving envelope stresses that may generate toxic misfolded proteins.

IMPORTANCE
Proper degradation of toxic misfolded proteins is essential for bacterial survival. This function is mainly performed by a highly conserved protease, DegP, in the periplasm of
Escherichia coli
. It is known that binding of misfolded proteins is the main mechanism for activating the DegP protease. Here, we find that a small periplasmic protein, YjfN, can be a substrate and an activator of DegP. It is the first example of a native protein showing an ability to directly alter DegP activity. The YjfN-mediated
trans
activation of DegP promotes efficient degradation of misfolded proteins. Our results suggest that YjfN is a novel “suicide activator” for DegP that enhances DegP proteolysis under misfolded protein stress.
An unexpected complication following uterine artery embolisation
Authors: Peters Sarah , Wise Michelle , Buckley Brendan
Published: September 2017

A 35-year-old nulliparous woman underwent uterine artery embolisation (UAE) for heavy menstrual bleeding and anaemia due to fibroids, refractive to medical and surgical treatment.

Bilateral UAE was performed after cephazolin prophylaxis and analgesia. Postoperatively, pain and abdominal bloating were prominent. Symptoms were initially treated as postembolisation syndrome, and analgesia was escalated. By the third day, pain was worsening and the woman developed marked tachypnoea and tachycardia, with raised inflammatory markers and lactate. An abdominal X-ray and CT showed dilated colon. A colonoscopy demonstrated severe mucosal ulceration down to the muscular layer.

A subtotal colectomy and end ileostomy formation was performed with intraoperative findings of toxic megacolon with near perforation. The cause of the toxic megacolon, in the absence of previous bowel pathology, was attributed to pseudomembranous colitis as a consequence of single dose prophylactic antibiotic.
Wells syndrome associated with lung cancer
Authors: Santos Rui Pedro , Carvalho Sofia Daniela , Ferreira Olga , Brito Celeste
Published: September 2017

Wells syndrome (WS) or eosinophilic cellulitis is a rare, idiopathic, inflammatory dermatosis. The typical clinical presentation is urticarial plaque without preferential location that usually heals without scarring. We present a 62-year-old man with history of lung cancer that had undergone a right superior lobectomy 12 months previously. The patient had a relapsing dermatosis beginning about 6 months before the diagnosis of the lung cancer, characterised by pruritic, erythematous plaques located on the trunk and arms. These lesions spontaneously resolved within a few weeks without scarring. A skin biopsy revealed findings compatible with WS. Several diseases have been associated with WS. These include haematological diseases, fungal, parasitic and viral infections, drug reactions and rarely non-haematological malignancies. We present a case of this rare syndrome in a patient with history of lung cancer that we believe acted as a triggering event. To our knowledge, this is the second case reporting this association.
From disability to ability: comprehensive rehabilitation providing a holistic functional improvement in a child with neglected neural tube defect
Authors: Mishra Kriti , Siddharth V
Published: September 2017

Neural Tube defects are one of the most common congenital disorders, presenting in a paediatric rehabilitation set-up. With its wide spectrum of clinical presentation and possible complications, the condition can significantly impact an individual’s functional capacity and quality of life. The condition also affects the family of the child leaving them with a lifelong impairment to cope up with. Through this 16-year-old child, we shed light on the effects of providing rehabilitation, even at a later stage and its benefits. We also get a glimpse of difficulties in availing rehabilitation services in developing countries and the need to reach out many more neglected children like him with good functional abilities.
Overview of the uptake and implementation of non-medical prescribing in Wales: a national survey
Authors: Courtenay Molly , Khanfer Riyad , Harries-Huntly Gail , Deslandes Rhain , Gillespie David , Hodson Karen , Morris Gary , Pritchard Anthony , Williams Elizabeth
Published: September 2017

Objectives

To identify (1) the non-medical healthcare professionals in Wales qualified to prescribe medicines (including job title, employer, where the prescribing qualification is used, care setting and service provided); (2) the mode of prescribing used by these healthcare professionals, the frequency with which medicines are prescribed and the different ways in which the prescribing qualification is used; and (3) the safety and clinical governance systems within which these healthcare professionals practise.

Design

National questionnaire survey.

Setting

All three National Health Service (NHS) Trusts and seven Health Boards (HB) in Wales.

Participants

Non-medical prescribers.

Results

379 (63%) participants responded to the survey. Most of these prescribers (41.1%) were specialist nurses who work in a variety of healthcare settings (primarily in secondary care) within each HB/NHS Trust, and regularly use independent prescribing to prescribe for a broad range of conditions. Nearly a quarter of the sample (22%) reported that prior to undertaking the prescribing programme, they had completed master’s level specialist training and 65.5% had 5 years qualified experience. Over half (55.8%) reported that there were plans to increase non-medical prescriber numbers within the team in which they worked. Only 7.1% reported they did not prescribe and the median number of items prescribed per week was between 21 and 30. Nearly all (87.8%) of the sample reported that they perceived prescribing to have ensured better use of their skills and 91.5% indicated that they believed it had improved the quality of care they were able to provide.

Conclusion

Non-medical prescribing has been implemented across the whole of Wales; however, its uptake within HBs and NHS Trusts has been inconsistent, and it has not been considered across all services, particularly those in primary care. Opportunities therefore exist to share learning across organisations.