bluuebunny/crossref_metadata_2025 huggingface dataset:
Unexpected opposing biological effect of genetic risk factors for Parkinson’s disease
Authors: Keatinge Marcus , Gegg Matthew E. , Watson Lisa , Mortiboys Heather , Li Nan , Dunning Mark , Ailani Deepak , Bui Hai , van Rens Astrid , Lefeber Dirk J. , MacDonald Ryan B. , Schapira Anthony H.V. , Bandmann Oliver
Published: July 2019

The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. To test this hypothesis, we assessed the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency. Variants in both glucocerebrosidase1 (GBA1) and sphingomyelinase (SMPD1) are genetic risk factors for Parkinson’s disease. Unexpectedly, ASM deficiency resulted in normalized behaviour and prolonged survival in gba1−/−;smpd1−/− double-mutant zebrafish compared to gba1−/−. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1−/−;smpd1−/− compared to gba1−/− or smpd1−/− as the underlying rescue mechanism. Complementing in vitro experiments demonstrated an unexpected reduction of α-synuclein levels in human cell lines with combined GCase and ASM deficiency. Our study highlights the importance of functional validation for any putative interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.

The additive effect of genetic risk variants on disease risk is a popular but typically unproven hypothesis. We investigated this hypothesis mechanistically for Parkinson’s disease risk factors and provide evidence of an unexpected rescue effect on neuronal function and survival.
Incorporating polygenic scores in the twin model to estimate genotype-environment covariance: exploration of statistical power
Authors: Dolan Conor V. , Huijskens Roel C. A. , Minică Camelia C. , Neale Michael C. , Boomsma Dorret I.
Published: July 2019

The assumption in the twin model that genotypic and environmental variables are uncorrelated is primarily made to ensure parameter identification, not because researchers necessarily think that these variables are uncorrelated. Although the biasing effects of such correlations are well understood, it would be useful to be able to estimate these parameters in the twin model. Here we consider the possibility of relaxing this assumption by adding polygenic score to the (univariate) twin model. We demonstrated numerically and analytically this extension renders the additive genetic (A) – unshared environmental correlation (E) and the additive genetic (A) - shared environmental (C) correlations simultaneously identified. We studied the statistical power to detect A-C and A-E correlations in the ACE model, and to detect A-E correlation in the AE model. The results showed that the power to detect these covariance terms, given 1000 MZ and 1000 DZ twin pairs (α=0.05), depends greatly on the parameter settings of the model. We show fixing the estimated percentage of variance in the outcome trait that is due to the polygenic scores greatly increases statistical power.
The role of multiple observations in small-molecule single-crystal service X-ray structure determination
Authors: Williams Alice E. , Thompson Amber L. , Watkin David J.
Published: July 2019

In order to gain a better understanding of how to improve the quality of small-molecule single-crystal X-ray diffraction data achievable in a finite time, a study was carried out to investigate the effect of varying the multiplicity, acquisition time, detector binning, maximum resolution and completeness. The results suggest that, unless there are strong arguments for a different strategy, a good routine procedure might be to optimize the conditions necessary to get the best data from single scans, and then choose a multiplicity of observations (MoO) to utilize the available time fully. Different strategies may be required if the crystal is highly absorbing, is larger than the incident beam, is enclosed in a capillary tube or is unusual in some other way. The signal-to-noise ratio should be used with care, as collecting data for longer or at higher multiplicity appears to give a systematic underestimate of the intensity uncertainties. Further, the results demonstrate that including poor-quality data in a refinement may degrade the result and, in the general case, the accidental omission of reflections has a very small impact on the refinement as long as they are omitted at random. Systematic omission of reflections needs a convincing procedural justification.
Structural variety of clofaziminium salts: effect of the counter-ion on clofaziminium conformation and crystal packing
Authors: Bodart Laurie , Tumanov Nikolay , Wouters Johan
Published: July 2019

Clofazimine is a water-insoluble antimycobacterial agent gaining attention as a treatment for multi-drug resistant and extensively drug-resistant tuberculosis. Novel salts of clofazimine are reported with fumaric, succinic, 2,4-dihydroxybenzoic and terephthalic acids and with saccharin. The salt structures were obtained by single-crystal X-ray diffraction. The salts with 2,4-dihydroxybenzoic acid and with saccharin are solvated (methanol and acetonitrile, respectively). The reaction of clofazimine with terephthalic acid led to two salt cocrystals, one solvated and one non-solvated. These new clofaziminium salts are compared with the currently known ones in terms of crystal packing and clofazimine/ium conformation. Clofaziminium hydrogen succinate presents isostructurality with clofaziminium hydrogen malonate, an already described salt. In the structure of clofaziminium terephthalate terephthalic acid salt cocrystal, solvent evaporation leads to packing and hydrogen-bonding modifications. In all the new structures, the clofaziminium conformation is quite well conserved and steric hindrance is observed around the protonated site. Conformational optimization of clofaziminium reveals that this steric-hindrance energy penalty is compensated for by hydrogen-bond interactions with the salt counter-ions.
3D modelling of a frame assembly using deep learning and the Chu–Liu–Edmonds Algorithm
Authors: Cao Hao , Mo Rong , Wan Neng
Published: July 2019

Purpose

The proposed method is to generate the 3 D model of frame assemblies based on their topological model automatedly. It was a very demanding task and there was no appropriate automated method to facilitate this work.

Design/methodology/approach

The proposed method includes two stages. The first stage is decisive. In this stage, a deep learning network and the Chu–Liu–Edmonds algorithm are used to recognize contact relations among parts. Based on this recognition, the authors perform a geometrical computation in the second stage to finalize the 3 D model.

Findings

The authors verify the feasibility of the proposed method using a case study and find that the classification rate of the deep learning network for part contact relations is higher than 75 per cent. Furthermore, more accurate results could be achieved with modification by the Chu–Liu–Edmonds algorithm. The proposed method has lower computational complexity compared with traditional heuristic methods, and its results are more consistent with existing designs.

Research limitations/implications

The paper introduces machine learning method into assembly modelling issue. The proposed method divides the assembly modelling into two steps and solves the assemble relation creatively.

Practical implications

Frame assemblies are fundamental to many areas. The proposed method could automate frame assembly modelling in a viable way. It could benefit design and manufacture process significantly.

Originality/value

The proposed method expands the application of machine learning into a new field. It would be more useful than simple machine learning in industry. The proposed method is better than general heuristic algorithms. It outputs identical results when the inputs are the same. Meanwhile, the algorithmic complexity in worst situation is better than general heuristic algorithms.
Fast tolerance-aware design optimization of miniaturized microstrip couplers using variable-fidelity EM simulations and response features
Authors: Koziel Slawomir , Bekasiewicz Adrian
Published: July 2019

Purpose

This paper aims to investigate the strategy for low-cost yield optimization of miniaturized microstrip couplers using variable-fidelity electromagnetic (EM) simulations.

Design/methodology/approach

Usefulness of data-driven models constructed from structure frequency responses formulated in the form of suitably defined characteristic points for statistical analysis is investigated. Reformulation of the characteristics leads to a less nonlinear functional landscape and reduces the number of training samples required for accurate modeling. Further reduction of the cost associated with construction of the data-driven model, is achieved using variable-fidelity methods. Numerical case study is provided demonstrating feasibility of the feature-based modeling for low cost statistical analysis and yield optimization.

Findings

It is possible, through reformulation of the structure frequency responses in the form of suitably defined feature points, to reduce the number of training samples required for its data-driven modeling. The approximation model can be used as an accurate evaluation engine for a low-cost Monte Carlo analysis. Yield optimization can be realized through minimization of yield within the data-driven model bounds and subsequent model re-set around the optimized design.

Research limitations/implications

The investigated technique exceeds capabilities of conventional Monte Carlo-based approaches for statistical analysis in terms of computational cost without compromising its accuracy with respect to the conventional EM-based Monte Carlo.

Originality/value

The proposed tolerance-aware design approach proved useful for rapid yield optimization of compact microstrip couplers represented using EM-simulation models, which is extremely challenging when using conventional approaches due to tremendous number of EM evaluations required for statistical analysis.
Some advances in high-performance finite element methods
Authors: Cen Song , Wu Cheng Jin , Li Zhi , Shang Yan , Li Chenfeng
Published: July 2019

Purpose

The purpose of this paper is to give a review on the newest developments of high-performance finite element methods (FEMs), and exhibit the recent contributions achieved by the authors’ group, especially showing some breakthroughs against inherent difficulties existing in the traditional FEM for a long time.

Design/methodology/approach

Three kinds of new FEMs are emphasized and introduced, including the hybrid stress-function element method, the hybrid displacement-function element method for Mindlin–Reissner plate and the improved unsymmetric FEM. The distinguished feature of these three methods is that they all apply the fundamental analytical solutions of elasticity expressed in different coordinates as their trial functions.

Findings

The new FEMs show advantages from both analytical and numerical approaches. All the models exhibit outstanding capacity for resisting various severe mesh distortions, and even perform well when other models cannot work. Some difficulties in the history of FEM are also broken through, such as the limitations defined by MacNeal’s theorem and the edge-effect problems of Mindlin–Reissner plate.

Originality/value

These contributions possess high value for solving the difficulties in engineering computations, and promote the progress of FEM.
A three-layer mechanical model for the analysis of effects of pia matter on cortical folding
Authors: Wang Linlin , Yao Jianyao , Ning Huiming , Wu Liangke , Sun Dongyang , Hu Ning
Published: July 2019

Purpose

This paper aims to investigate the effects of the pia matter on cerebral cortical folding.

Design/methodology/approach

A three-layer buckling simulation model composited by the white matter, gray matter and the pia matter is adopted to analyze the effect of the pia matter on cortical folding. The volume growth of brain tissues is simulated using thermal expansion. The effects of the pia matter growth rate, thickness and stiffness on cortical folding is investigated.

Findings

The simulation results show that all of these three aforementioned factors of pia matter have obvious effects on cerebral cortical folding. Especially, the thickening of the pia matter may lead to cortical folding malformation such as polymicrogyria, which is in good agreement with the recent reported anatomical findings.

Originality/value

The three-layer model in this paper composited by the white matter, gray matter and the pia matter is different from the usually used two-layer model only composited by the white matter and gray matter. This three-layer model has successfully validated the effect of the pia matter on cerebral cortical folding. The simulation results can explain the anatomical findings very well.
Numerical study of crystal growth kinetics influence on prediction of different dendritic zones and macro-segregation in binary alloy solidification
Authors: Seredyński Mirosław , Banaszek Jerzy
Published: July 2019

Purpose

Proper selection of the stability parameter determines the accuracy of dendrite tip kinetics at a single crystal scale. Recently developed sophisticated phase field modelling of a single grain evolution provides evidence that this parameter is not constant during the process. Nevertheless, in the commonly used micro-macroscopic simulations of alloy solidification, it is a common practice to use a constant value of the stability parameter, resulting from the marginal stability theory. This paper aims to address the issue of how this inaccuracy in modelling crystal growth kinetics can influence numerically predicted zones of columnar and equiaxed dendrites and the macro-segregation formation.

Design/methodology/approach

Using the original authors’ micro-macroscopic computer simulation model of binary alloy solidification, the calculations have been performed for the Kurz-Giovanola-Trivedi (KGT) crystal growth kinetics with two different values of the stability parameter, and for two different compositions of Al-Cu alloys. The computational model is based on single domain-based formulation of transport equations, which are discretized on control-volume mesh. To identify zones of different grain structures, developing within the two-phase liquid-solid region, an envelope of columnar dendrite tips is tracked on a fixed non-orthogonal, triangular control volume grid. The models of porous and slurry media are used, along with the concept of the switching function, to account for diverse flow resistances in the columnar and equiaxed crystal zones. The numerical predictions are carefully studied to address the question of how the chosen stability parameter influences macroscopic structures of a cast, the most important issue from the engineering point of view.

Findings

The carried-out comprehensive numerical analysis shows that the value of the stability parameter of the KGT-constrained dendrite growth model does not have a direct significant impact on the macrosegregation formation. It, however, visibly influences the undercooling along the front, separating different dendritic structures and the size of the undercooled melt region where the equiaxed grains can develop. It also affects the amount of eutectic phase created.

Originality/value

To the best of the authors’ knowledge, this is the first attempt at estimating the influence of some inaccuracies, caused by possible ambiguities in choosing the stability constant of the KGT law, on numerically predicted macroscopic fields of solute concentration, the developing zones of columnar and equiaxed crystals and the macrosegregation patterns.
When a stigmatized brand is doing good
Authors: Choi Jihee , Seo Soobin
Published: July 2019

Purpose

This study aims to investigate consumer responses to cause-related marketing (CRM) implemented by socially stigmatized industries, especially in fast food restaurants.

Design/methodology/approach

This experimental study uses a 2 (degree of perceived fit) × 2 (complementary fit) × 2 (brand equity) between-subjects design.

Findings

Results show significant interaction effects between the degree of fit and brand equity and complementary fit and brand equity on consumers’ brand evaluation. When a company with high brand equity chooses a high fit (vs low fit) or complementary fit (vs non-complimentary fit) for CRM promotion, this leads to consumers’ more positive attitude and higher intent to participate in CRM promotion.

Practical implications

This study provides practical implications for designing effective CRM promotion in the stigmatized industry such as fast food restaurants and casino.

Originality/value

Given the increased demand on CRM in the hospitality industry, the paper contributes to extend the realm of CRM literatures by investigating antecedents affecting consumers’ responses toward the CRM in the stigmatized companies or brands.
Responding to youth gangs in England: a public health model?
Authors: Pitts John
Published: July 2019

Purpose

The purpose of this paper is to consider youth gangs and county lines with reference to the current drive for a public health response to these issues.

Design/methodology/approach

This viewpoint paper traces the development of gang and serious youth violence responses in England, exploring the shift from a punitive to safeguarding response to young people affected by these issues.

Findings

Drawing on the learning from both Scotland and the USA, this paper considers the relevance of a public health model to responding to youth gangs and county lines, highlighting the key facets of such an approach.

Originality/value

This paper provides a historical context to the issues surrounding previous responses to youth gangs and goes on to consider the practicalities and relevance of a public health model response.
How to detect potential sport intrapreneurs? Validation of the intrapreneurial intention scale with sport science students
Authors: González-Serrano Maria Huertas , Calabuig Moreno Ferran , Valantine Irena , Crespo Hervás Josep
Published: July 2019

Purpose

The sport sector is a very competitive and dynamic industry, son intrapreneurial employees are needed. However, although entrepreneurial intentions in sport sciences students have been studied, less is known about intrapreneurial intentions. It is, therefore, the purpose of this paper to validate a scale to measure the intrapreneurial intentions of sports science students from two different countries.

Design/methodology/approach

A sample of 304 final-year students from the sport sector of two different countries (Spain and Lithuania) was analyzed. First, an exploratory factorial analysis of the two samples was performed separately, and then a confirmatory factorial analysis was carried out to performed. Finally, in order to check the invariance of the measuring instrument, a multi-group analysis was performed with the constraints of all factors variances and all factors loading.

Findings

The entrepreneurial intentions scale works well both in its English version in the Lithuanian sports students’ and in its Spanish version with the university sports students from Spain. Therefore, it can be said that there is a metric invariance. However, the scale presents better fit indexes, reliability and validity in its English version. Lithuanian sports students scored significantly higher on the risk-taking dimension than Spanish students.

Research limitations/implications

The scale has only been validated with final-year sport science students from two countries. It is necessary to test this scale with a larger sample of students from different fields and countries.

Practical implications

This scale can be used in both in Spanish and English versions to detect potential entrepreneurs in the sports sector, so it can help universities and employers to detect future intraentrepreneurs in the sports sector.

Social implications

Social implication of this paper is the detection of potential entrepreneurs who can improve economic, social or sports performance in organizations or sports companies.

Originality/value

A new tool to detect the potential sport intrapreneurs in university students has been created. Moreover, a cross-cultural validation of the intrapreneurial intentions scale (in English and Spanish version) with sport sciences students from two different countries has been performed.
An extension of the socioemotional wealth perspective
Authors: Saleem Irfan , Siddique Irfan , Ahmed Aqeel
Published: July 2019

Purpose

Socioemotional wealth (SEW) has emerged as the most differentiating aspect in family firms and has become the focal issue in family firm decision making. Family firms have to face the jeopardy of financial gains and socioemotional. The purpose of this paper is to investigate the different dimensions of SEW in developing the firm as corporate entrepreneurial and which dimensions engage stakeholders.

Design/methodology/approach

The authors designed a survey questionnaire to obtain primary data for the study using purposive sampling method. The study conducted on the family firm using the questionnaire to investigate for corporate entrepreneurship (CE), and stakeholder engagement (SE) depended on family control and influence, family identity, binding social ties, emotional attachment and renewal of family bonds.

Findings

The study identified different SEW factors affecting CE and SE. The authors found that binding social ties and renewal of family bonds has a statistically significant impact on SE, whereas family identity and social ties have a statistically significant impact on CE.

Research limitations/implications

The authors receive data from the CEOs with low response rate and expected to have better results with more observations. The same study been conducted in different parts of the world may give different results and a cultural bias may restrict the findings.

Practical implications

From the research, family firms can take twofold benefits. In short term, a family firm with better SE can generate satisfied employees with lesser turnover intentions. For long-term objectives with respect to CE, a firm can get a result in terms of market innovations through for better firm’s performance.

Social implications

Since her inception, Pakistan has emerged as a society of commodity traders and technology importers. This society can easily generate an import-driven business. Nonetheless this import-driven economy always remains under great economic distress due to limited potential for actual innovations and market disruptions. The family businesses of any emerging market like Pakistan need to learn CE and SE while safeguarding social-emotional wealth, thereby being successful as firm to become export-driven economy at large.

Originality/value

The study identifies different SEW factors that help in developing a firm as corporate entrepreneurial and stakeholder’s engagement. Findings of the study are valuable for managing the family firms in developing economies where the family structures are very vibrant and businesses have a clear dependency on family formations.
Implementing evidence-based mental health practices in schools: Feasibility of a coaching strategy
Authors: Koschmann Elizabeth , Abelson James L. , Kilbourne Amy M. , Smith Shawna N. , Fitzgerald Kate , Pasternak Anna
Published: July 2019

Purpose

Mood and anxiety disorders affect 20–30 percent of school-age children, contributing to academic failure, substance abuse, and adult psychopathology, with immense social and economic impact. These disorders are treatable, but only a fraction of students in need have access to evidence-based treatment practices (EBPs). Access could be substantially increased if school professionals were trained to identify students at risk and deliver EBPs in the context of school-based support services. However, current training for school professionals is largely ineffective because it lacks follow-up supported practice, an essential element for producing lasting behavioral change. The paper aims to discuss these issues.

Design/methodology/approach

In this pilot feasibility study, the authors explored whether a coaching-based implementation strategy could be used to integrate common elements of evidence-based cognitive behavioral therapy (CBT) into schools. The strategy incorporated didactic training in CBT for school professionals followed by coaching from an expert during co-facilitation of CBT groups offered to students.

Findings

In total, 17 school professionals in nine high schools with significant cultural and socioe-conomic diversity participated, serving 105 students. School professionals were assessed for changes in confidence in CBT delivery, frequency of generalized use of CBT skills and attitudes about the utility of CBT for the school setting. Students were assessed for symptom improvement. The school professionals showed increased confidence in, utilization of, and attitudes toward CBT. Student participants showed significant reductions in depression and anxiety symptoms pre- to post-group.

Originality/value

These findings support the feasibility and potential impact of a coaching-based implementation strategy for school settings, as well as student symptom improvement associated with receipt of school-delivered CBT.
Time-varying herding behavior within the Eurozone stock markets during crisis periods
Authors: Stavroyiannis Stavros , Babalos Vassilios
Published: July 2019

Purpose

Motivated by the ongoing debate on the existence and magnitude of herding in financial markets, the purpose of this paper is to examine Eurozone stock markets for herding behavior. In the context of the present study, the authors seek for herding behavior of stock markets as a whole as opposed to previous studies that examine herding on stock level.

Design/methodology/approach

To this end, the authors employ data on benchmark stock market indices for a long sample starting from 2000 through 2016. The testing procedure entails the standard Capital Asset Pricing Model-based procedure along with an advanced econometric method allowing the coefficients of the model to vary over time.

Findings

Results provide evidence in favor of negative herding behavior (anti-herding) for the Eurozone as a whole with noteworthy transitions. Further analysis reveals that stock markets of the periphery exhibit scarce evidence of herding, whereas continental countries are mainly characterized by negative herding behavior.

Originality/value

The present study’s main contribution is twofold. First, herding is examined not in sector or stock level as previous studies but at market level. Second, the testing methodology entails a pure time-varying regression model with stochastic volatility proposed by Nakajima (2011) that has not been previously employed in stock market herding. The results entail significant implications for investors seeking for diversification across Eurozone stock markets.
The correlated evolution of social competence and social cognition
Authors: Varela Susana A. M. , Teles Magda C. , Oliveira Rui F.
Published: July 2019

Knowing which of correlated traits are more strongly targeted by selection is crucial to understand the evolutionary process. For example, it could help in understanding how behavioural and cognitive adaptations to social living have evolved.

Social competence is the ability of animals to optimize their social behaviours according to the demands of their social environment. It is a behavioural performance trait that expresses how well a whole organism performs complex social tasks, such as choosing mates, raising offspring, participating in dominance hierarchies, solving conflicts or forming social bonds. Non‐social competence, on the other hand, is the ability of animals to optimize their non‐social behaviours according to the demands of their non‐social environment, such as finding food or avoiding predators.

Social and non‐social cognition are correlated lower‐level traits of social and non‐social competence, respectively, encompassing the underlying psychological and neural mechanisms of behaviour that allow animals to acquire, encode, store and recall information about their social and non‐social environments.

Here, we employ the theoretical framework that selection acts on performance traits first and on lower‐level traits only secondarily, to propose a new approach to the study of the evolution of social cognition.

We hypothesize that when selection favours social competence, the cognitive system becomes more adapted to the social domain, making species biased for social information, and increasing their degree of sociality. The opposite can happen when selection favours non‐social competence.

The level of specialization that the cognitive system can attain depends on whether social and non‐social competence are correlated with the same cognitive lower‐level traits. This in turn will determine whether species will evolve a type of social cognition that is general—that contributes with cognitive abilities that can be used in both social and non‐social environments—or modular—that contributes with cognitive abilities that are specific to the social environment.

A free Plain Language Summary can be found within the Supporting Information of this article.
Enhancing intern emergency medicine education using a combined didactic and web‐based learning curriculum: The EDGE programme
Authors: Windish Ryan , Stuart Peter , de la Cruz Raymund , Murray Alistair
Published: July 2019

Objective

To assess the effectiveness of an education programme that integrates web‐based learning into classroom sessions.

Methods

This prospective study involved a convenience sample of ED interns rotating at two study site hospitals between April 2015 and January 2017. Interns undertook weekly ED classroom‐based education and were given access to a web‐based learning resource with completion being voluntary. To assess change in medical knowledge multiple choice examinations were administered during week 1 and week 10 of the term. The study's primary end‐point was the effect of the web‐based resource on participants' knowledge. The median % of online modules completed by participants (75%) was used as a cut‐off to create two groups. The % improvement between the test scores at week 1 and week 10 of each group were then compared. Intern satisfaction with the programme was also assessed using a satisfaction survey.

Results

The average examination score for all participants was significantly higher at week 10 than week 1 (80% vs 68%; P < 0.001). The primary end‐point, % improvement between the week 1 and week 10 scores of those that completed ≤75% of web‐based modules (mean 16%; 95% CI 12–20%) and those that completed >75% of web‐based modules (mean 27%; 95% CI 20–34%), showed a statistically significant difference (P = 0.03). Interns surveyed were also highly satisfied with programme.

Conclusions

This blended curriculum that integrates a web‐based resource into classroom learning shows promise in enhancing intern emergency medicine education.
A 24‐Week Anemia Correction Study of Daprodustat in Japanese Dialysis Patients
Authors: Tsubakihara Yoshiharu , Akizawa Tadao , Nangaku Masaomi , Onoue Tomohiro , Yonekawa Taeko , Matsushita Hideki , Endo Yukihiro , Cobitz Alexander
Published: July 2019

Daprodustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor developed for treating anemia of chronic kidney disease. This 24‐week, phase 3, open‐label study (NCT02829320) evaluated whether daprodustat could achieve and maintain target hemoglobin levels in Japanese hemodialysis patients with anemia not receiving an erythropoiesis‐stimulating agent. Twenty‐eight patients received daprodustat 4 mg once daily for 4 weeks, after which doses were adjusted to achieve a hemoglobin target of 10.0 to 12.0 g/dL (inclusive). Baseline mean hemoglobin was 9.10 g/dL and mean change from baseline at 4 weeks was 0.79 g/dL (95% CI, 0.53 to 1.05). Mean hemoglobin levels reached the target range by week 8 and were maintained within this range through week 24. Daprodustat 4 mg once daily increased hemoglobin over the first 4 weeks. Throughout the 24‐week study, daprodustat achieved and maintained hemoglobin within the target range and no new safety concerns were identified in hemodialysis patients not receiving erythropoiesis‐stimulating agents.
Changes in Hydrology of the Ganges Delta of Bangladesh and Corresponding Impacts on Water Resources
Authors: Murshed Sonia Binte , Rahman Md. Rezaur , Kaluarachchi Jagath J.
Published: July 2019

The Ganges Delta in Bangladesh is an example of water‐related catastrophes in a major rural river basin where limitations in quantity, quality, and timing of available water are producing disastrous conditions. Water availability limitations are modifying the hydrologic characteristics especially when water allocation is controlled from the upstream Farakka Barrage. This study presents the changes and consequences in the hydrologic regime due to climate‐ and human‐induced stresses. Flow duration curves (FDCs), rainfall elasticity, and temperature sensitivity were used to assess the pre‐ and post‐barrage water flow patterns. Hydrologic and climate indices were computed to provide insight on hydro‐climatic variability and trend. Significant increases in temperature, evapotranspiration, hot days, heating, and cooling degree days indicate the region is heading toward a warmer climate. Moreover, increase in high‐intensity rainfall of short duration is making the region prone to extreme floods. FDCs depict a large reduction in river flows between pre‐ and post‐barrage periods, resulting in lower water storage capacity. The reduction in freshwater flow increased the extent and intensity of salinity intrusion. This freshwater scarcity is reducing livelihood options considerably and indirectly forcing population migration from the delta region. Understanding the causes and directions of hydrologic changes is essential to formulate improve water resources management in the region.
Ultrasound power Doppler and gray scale joint inflammation: What they reveal in rheumatoid arthritis
Authors: Tan York Kiat , Li HuiHua , Allen John Carson , Thumboo Julian
Published: July 2019

Aim

Power Doppler (PD) and gray scale (GS) imaging are commonly employed during ultrasonography in rheumatoid arthritis (RA). While PD vascularity is often regarded as an ultrasound feature of more active joint inflammation, the true clinical significance of GS joint inflammation is less understood. We aimed to gain further insight into ultrasound PD and GS joint inflammation by studying their association with Disease Activity Score of 28 joints (DAS28) (a disease activity measure) and ultrasound‐detected bone erosion (a structural damage measure).

Method

In this cross‐sectional study, ultrasound PD and GS joint inflammation were graded 0‐3 (semi‐quantitatively) and bone erosion was graded as yes = 1/no = 0 at each joint recess. Linear regression and Pearson correlation were used to characterize relationships and assess correlation of PD and GS scores with DAS28 and ultrasound erosion scores.

Results

One thousand and eighty joints and 1800 joint recesses from 36 peripheral joint sites (bilateral metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, metatarsophalangeal joints, elbow, wrist and ankle) were scanned in 30 adult RA patients. PD scores correlated with DAS28 (r = 0.46, P = 0.0104) but not with ultrasound erosion scores; GS scores correlated with ultrasound erosion (r = 0.64, P = 0.0001) but not with DAS28 scores. Simple linear regression revealed PD as predictive of DAS28 (P = 0.0104) and GS as predictive of ultrasound‐detected bone erosion (P = 0.0001).

Conclusion

Ultrasound PD joint inflammation is associated with disease activity and is correlated with DAS28. In contrast, GS joint inflammation is associated with structural damage and is correlated with ultrasound‐detected bone erosion.
Psychostimulant use disorder and the heart
Authors: Duflou Johan
Published: July 2019

Psychostimulants are a diverse range of substances that encompass cocaine and the phenylethylamines, the latter including the amphetamines, cathinones and some ‘novel psychoactive substances’. This paper examines the range of pathophysiological processes, clinical presentations and treatment options involving the heart and cardiovascular system both in the acute setting and where long‐term effects of psychostimulant use have affected the cardiovascular system. A common feature of these drugs is their effect on the cardiovascular system, where their major action is that of sympathomimetic amines with short‐ and long‐term stimulation of the adrenergic system and consequent effects on blood pressure, cardiac modelling, atherogenesis and cellular calcium signalling. Cocaine additionally exhibits a variety of prothrombotic effects, effects on inflammatory mediators and alterations in myocardial gene expression. Persistent psychostimulant use results in progressive cardiovascular pathology, largely in the form of accelerated atherosclerosis, hypertension and myocardial ischaemia. Abstinence results in at least partial reversal of pathology. To a large extent, an assumption is made that treatment protocols used for cocaine‐associated cardiovascular pathology apply to the amphetamines and other phenylethylamines, but there appears to be little research in this area, despite acknowledgement that cocaine and the better‐known amphetamines have different modes of action.
Protectionism under Trump: The China Shock, Deplorables, and the First White President
Authors: Noland Marcus
Published: July 2019

This paper uses USA county‐level electoral data to examine the 2016 turn to protectionism. The hypothesis that support for protectionism was purely a response to globalization is rejected. Exposure to trade competition encouraged a shift to the Republican candidate, but this effect is mediated by race, diversity, education, and age. If the turn toward protectionism is due to economic dislocation, then public policy interventions could mitigate the impact and support the re‐establishment of a political consensus for open trade. If, however, the drivers are identity or cultural values, then the scope for constructive policy intervention is unclear.
Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone‐only pill
Authors: Palacios Santiago , Colli Enrico , Regidor Pedro‐Antonio
Published: July 2019

Introduction

Approximately 100 million women currently use combined oral contraceptives. Combined oral contraceptives use is associated with increased risk of venous thromboembolic events and cardiovascular disease. Progestin‐only pills do not increase the risk of venous thromboembolic events, stroke and myocardial infarction but are associated with a poor cycle control. A novel estrogen‐free pill containing only drospirenone (DRSP) was developed to improve bleeding pattern, tolerability and acceptance without increasing venous thromboembolic events risks in contraception.

Material and methods

Two prospective, multicenter Phase III studies in healthy women aged 18‐45 years were performed to demonstrate the efficacy and safety of a drospirenone‐only pill in a regimen of 24 days of 4 mg of drospirenone tablets followed by 4 days of placebo. A total of 1571 women (14 329 exposure cycles) were analyzed: 713 patients in the 13‐cycle study 1 with 7638 exposure cycles and 858 patients in the 9‐cycle study 2 with 6691 exposure cycles. The primary endpoint was the overall Pearl index, calculated for each study separately, and for both pooled. As main secondary efficacy endpoint, the “method failure Pearl index” including all pregnancies during “perfect medication cycles” was evaluated. EudraCT registration numbers: 2010‐021787‐15 & 2011‐002396‐42.

Results

Calculations on pooled studies 1 and 2 with 1571 patients gave an overall Pearl index (based on 14 329 cycles) of 0.7258 (95% CI 0.3133 to 1.4301). No single case of deep vein thrombosis or pulmonary embolism and only one case of hyperkalemia were reported. Additional information such as laboratory parameters, body mass index, bodyweight, heart rate and blood pressure showed no statistically significant changes due to the treatment.

Conclusions

This is the first report of a new drospirenone‐only oral contraceptive providing clinical efficacy similar to combined oral contraceptives, with a good safety profile, and favorable cycle control.
Optimising the number of cores for magnetic resonance imaging‐guided targeted and systematic transperineal prostate biopsy
Authors: Hansen Nienke L. , Barrett Tristan , Lloyd Thomas , Warren Anne , Samel Christina , Bratt Ola , Kastner Christof
Published: July 2019

Objectives

To assess cancer detection rates of different target‐dependent transperineal magnetic resonance (MR)/ultrasonography (US) fusion‐guided biopsy templates with reduced number of systematic cores.

Patients and Methods

Single‐centre outcome of transperineal MR/US fusion‐guided biopsies of 487 men with a single target MR imaging (MRI) lesion, prospectively collected between 2012 and 2016. All men underwent transperineal targeted biopsy (TB) with two cores, followed by 18–24 systematic sector biopsies (SB) using the Ginsburg protocol. Gleason score ≥7 prostate cancer detection rates for two‐core TB, four‐core extended TB (eTB), 10‐ to 20‐core saturation TB (sTB) including cores from sectors adjacent to the target, and 14 core ipsilateral TB (iTB) were compared to combined TB+SB.

Results

Cancer was detected in 345 men and Gleason score 7–10 cancer in 211 men. TB alone detected 67%, eTB 76%, sTB 91% and iTB 91% of these Gleason score 7–10 cancers. In the subgroup of 33 men (7% of cohort) with an anterior >0.5 mL highly suspicious MRI lesion and a prostate volume ≤45 mL, four‐core eTB detected 31 of 32 cancers (97%) and all 26 Gleason score 7–10 cancers.

Conclusion

sTB detected Gleason score 7–10 cancer in 25% more of the men than a two‐core TB approach, and in almost as many men (91%) as the 20–26‐core combined TB+SB, while needing only 10–20 cores. A four‐core extended TB may suffice for large, highly suspicious anterior lesions in small or slightly enlarged prostates.
Surgical repair of traumatic cloaca: a modified technique
Authors: Zhou X. , Chen W. , Lin J. , Xu J. , Zheng S.
Published: July 2019

Aim

A modified repair technique for traumatic cloaca caused by obstetric anal sphincter injury was evaluated, and its feasibility and functional outcome were investigated.

Methods

A retrospective review of 23 consecutively enrolled patients diagnosed with traumatic cloaca who underwent the modified repair technique between September 2010 and August 2018 was performed. Demographic, clinical feature, operative and follow‐up data were recorded.

Results

The patients diagnosed with traumatic cloaca who underwent surgical repair after obstetric anal sphincter injury had a median time from obstetric injury of 24 (12–35) years. The median preoperative Wexner faecal incontinence score was 16 (14–17). The postoperative hospital stay was 6 (6–7) days. The median postoperative Wexner faecal incontinence score decreased to 2 (2–3). The anal resting pressure increased from 9.00 (5.25–11.50) mmHg to 56.00 (55.00–65.75) mmHg (P < 0.01) and the anal squeeze pressure increased from 29.00 (22.50–33.20) mmHg to 110.00 (96.20–121.50) mmHg (P < 0.01) at 2 months after the repair. Sixteen patients completed the Faecal Incontinence Quality of Life Scale questionnaire, and there were significant improvements 1 year after surgical repair in lifestyle (3.10 [2.60–3.70] vs 2.60 [1.90–3.00], P < 0.01), coping/behaviour (3.38 [2.57–3.44] vs 2.33 [1.89–3.00], P < 0.01), depression/self‐perception (3.11 [2.27–3.44] vs 2.33 [1.89–3.00], P < 0.01) and embarrassment (3.33 [2.75–3.67] vs 2.33 [2.33–3.00], P < 0.01). No patient presented rectovaginal fistula postoperatively within the median follow‐up period of 24 (12–48) months.

Conclusions

The modified repair technique for traumatic cloaca is feasible and achieves good functional outcomes and improved life quality.
2‐deoxy D‐glucose treatment does not elicit a hair growth response in alopecia areata
Authors: Sundberg John P. , Silva Kathleen A. , Kennedy Victoria E. , Wilson John J. , Gott Nicholas E. , Sundberg Beth A. , Roopenian Derry C.
Published: July 2019

2‐deoxy D‐glucose (2DG) was tested for efficacy in treating alopecia areata using the C3H/HeJ skin graft model. 2DG has proven to be efficacious in treatment of various mouse models of autoimmunity with minimal serious side effects noted. This agent has been shown to normalize abnormally activated T‐cell populations while also preventing cell surface expression of NKG2D; key factors defining alopecia areata disease progression. Daily oral ingestion of 2DG via drinking water to mice with patchy or diffuse alopecia areata for 16 weeks failed to prevent expansion of alopecia or cause regrowth of hair in treated mice. Histologically, there were no differences between treated and control groups. These results indicate that, while 2DG is effective for some autoimmune diseases, it was not efficacious for the cell‐mediated autoimmune mouse disease, alopecia areata.
Vitamin D differentially regulates colon stem cells in patient‐derived normal and tumor organoids
Authors: Fernández‐Barral Asunción , Costales‐Carrera Alba , Buira Sandra P. , Jung Peter , Ferrer‐Mayorga Gemma , Larriba María Jesús , Bustamante‐Madrid Pilar , Domínguez Orlando , Real Francisco X. , Guerra‐Pastrián Laura , Lafarga Miguel , García‐Olmo Damián , Cantero Ramón , Del Peso Luis , Batlle Eduard , Rojo Federico , Muñoz Alberto , Barbáchano Antonio
Published: July 2019

Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25‐dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids, calcitriol upregulates stemness‐related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7, and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness‐related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.