bluuebunny/crossref_metadata_2025 huggingface dataset:
The Safety and Effectiveness of High-Dose Propranolol as a Treatment for Challenging Behaviors in Individuals With Autism Spectrum Disorders
Authors: London Eric B. , Yoo J. Helen , Fethke Eric D. , Zimmerman-Bier Barbie
Published: March 2020

Purpose/Background

Individuals with autism spectrum disorders present with social communication deficits and a rigid adherence to sameness. Along with these symptoms, many individuals also present with severe challenging behaviors that place themselves as well as their families and communities at risk for injury. For these individuals, new and effective treatments are acutely needed. Propranolol has been used worldwide for over 50 years. Its primary indication is for hypertension, but there is evidence that, at higher doses, propranolol inhibits rage and anger through its effects on the central nervous system. This effect has been demonstrated in a variety of neuropsychiatric disorders.

Methods/Procedures

Here, we present 46 retrospective analyses of clinical cases that were followed by a psychiatrist. Propranolol was prescribed as an add-on to the patients' existing medications. The doses ranged from 120 to 960 mg per day (mean = 462 mg).

Findings/Results

Thirty-nine (85%) of 46 patients were found to be much improved or very much improved on the physician-rated Clinical Global Impression Improvement scale. There were few side effects noted, with only 2 subjects unable to tolerate the propranolol.

Implications/Conclusions

It appears that high-dose propranolol can be given safely with minimal adverse cardiovascular problems, provided that close clinical monitoring is maintained. A more rigorous clinical trial is needed to elucidate and verify its clinical utility, clinical practice parameters, and the effects of propranolol as a monotherapy versus as an add-on to the patient's existing medication regimen.
Does Treatment Response With Antidementia Drugs After 6 Months in Alzheimer's Disease Predict Long-term Treatment Outcome?
Authors: Horikoshi Sho , Kunii Yasuto , Matsumoto Junya , Gotoh Daisuke , Miura Itaru , Yabe Hirooki
Published: March 2020

Background

Alzheimer's disease (AD) is a chronic, progressive disorder that causes declines in cognitive and physical functions. This condition places severe burdens on families and caregivers. Delaying progressive declines in cognitive function and reducing their burden are thus important. Relationships between early treatment response and subsequent outcomes of schizophrenia and major depressive disorder have been reported. We thus aimed to investigate the relationships between treatment response to antidementia drugs in AD after 6 months (M) and subsequent outcomes.

Methods

Eligible individuals comprised 194 patients diagnosed with presumed AD. Of these, 110 patients who received antidementia drugs for the first time and were assessed using the Mini-Mental State Examination (MMSE) at 6 M, 12 M, and 24 M were categorized as responders (n = 84) or nonresponders (n = 26). Responders were defined as showing a change in MMSE after 6 M the same as or lower than that in the natural course according to previously reported data.

Results

No significant differences in baseline characteristics (age, sex, education, or comorbidities) were seen between groups. Mean MMSE score at baseline was significantly lower in responders (18.0) than in nonresponders (20.7; P = 0.008). Mean change from baseline MMSE was significantly smaller in responders than in nonresponders at both 12 M (−0.46 vs −2.5; P = 0.04) and 24 M (−0.78 vs −4.4; P = 0.001).

Conclusions

Treatment response with antidementia drugs after 6 M predicted better outcomes at 12 M and 24 M. Treatment response should be assessed every 6 M, and treatment should be reconsidered accordingly.
Pharmacokinetics and Pharmacodynamics of the Dual Orexin Receptor Antagonist Daridorexant in Japanese and Caucasian Subjects
Authors: Muehlan Clemens , Zuiker Rob , Peeters Pierre , Rowles Racheal , Dingemanse Jasper
Published: March 2020

Purpose/Background

Daridorexant is a dual orexin receptor antagonist in development for the treatment of sleep disorders. Thus far, it has not yet been studied in Japanese subjects. Study objectives were to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of single- and multiple-dose administration of daridorexant in healthy Caucasian and Japanese subjects.

Methods/Procedures

This was a double-blind, placebo-controlled, randomized study. Subjects received once-daily doses of daridorexant (25 or 50 mg) or placebo for 5 days. Pharmacokinetics and safety were investigated using standard assessments. To assess PD effects, a battery of tests (saccadic peak velocity, body sway, adaptive tracking performance, and visual analog scales for alertness, mood, and calmness), known to be sensitive to sleep-promoting drugs was used.

Findings/Results

On day 1, PK variables were similar between Caucasian and Japanese subjects. On day 5, slight accumulation occurred in Japanese but not in Caucasian subjects, resulting in a higher maximum concentration (1403 vs 1006 ng/mL) and area under the curve (8256 vs 6306 ng·h/mL) at a dose of 50 mg, whereas values for time to maximum concentration and half-life were similar. Daridorexant dose-dependently reduced vigilance, attention, visuomotor coordination, and postural stability. Pharmacokinetic effects were detectable within 1 hour after drug administration and returned to baseline 4 to 8 hours postdose. Overall, Japanese showed slightly larger PD effects and reported more adverse events than Caucasians. The most frequently reported were somnolence, fatigue, and headache. Changes in other safety assessments were unremarkable.

Implications/Conclusions

The PK, PD, and safety profile of daridorexant were similar in Japanese and Caucasian subjects.
Toward a Long-Term Artificial Lung
Authors: Arens Jutta , Grottke Oliver , Haverich Axel , Maier Lars S. , Schmitz-Rode Thomas , Steinseifer Ulrich , Wendel H.P. , Rossaint Rolf
Published: March 2020

Only a very small portion of end-stage organ failures can be treated by transplantation because of the shortage of donor organs. Although artificial long-term organ support such as ventricular assist devices provide therapeutic options serving as a bridge-to-transplantation or destination therapy for end-stage heart failure, suitable long-term artificial lung systems are still at an early stage of development. Although a short-term use of an extracorporeal lung support is feasible today, the currently available technical solutions do not permit the long-term use of lung replacement systems in terms of an implantable artificial lung. This is currently limited by a variety of factors: biocompatibility problems lead to clot formation within the system, especially in areas with unphysiological flow conditions. In addition, proteins, cells, and fibrin are deposited on the membranes, decreasing gas exchange performance and thus, limiting long-term use. Coordinated basic and translational scientific research to solve these problems is therefore necessary to enable the long-term use and implantation of an artificial lung. Strategies for improving the biocompatibility of foreign surfaces, for new anticoagulation regimes, for optimization of gas and blood flow, and for miniaturization of these systems must be found. These strategies must be validated byin vitroandin vivotests, which remain to be developed. In addition, the influence of long-term support on the pathophysiology must be considered. These challenges require well-connected interdisciplinary teams from the natural and material sciences, engineering, and medicine, which take the necessary steps toward the development of an artificial implantable lung.
Nonsurgical Management of Acute Appendicitis in Sickle Cell Disease
Authors: Sahib Sarah , Hanna Mark , Miller Scott T.
Published: March 2020

A 9-year-old child with sickle cell disease (sickle beta zero thalassemia) was diagnosed to have acute appendicitis during a hospitalization for pain, acute chest syndrome, and exacerbation of asthma. Because of his high surgical risk, his appendicitis was treated nonsurgically, successfully deferring his appendectomy. He remains well after 1 year. This approach should be considered at least in other sickle cell patients with appendicitis, and perhaps other high-risk populations, if not all children with appendicitis.
Complexity Leadership
Authors: Porter-O'Grady Tim
Published: March 2020

In this 21st-century postdigital age, deeper and more relevant understandings of both structure and process are critical in laying the foundations for the success of human enterprises and systems for the foreseeable future. Leadership of these complex, networked initiatives and environments will require a fundamentally different understanding and tool sets essential to the well-designed, linked, and integrated undertaking of the human enterprise. This is no less true of the unfolding health care networks now becoming the substantive framework for the delivery of health care services in the foreseeable future. This article explicates the essentials of this new model for leadership.
Challenges and Opportunities in Population Health
Authors: Denke Nancy J. , Winkleblack Laura K.
Published: March 2020

The school nurse role parallels the growing complexity of health care, education, and the social needs of youth in the United States. The complex and chaotic environment of the school setting requires leaders to be flexible and to have the ability to recognize and tackle the ever-changing needs of this environment. School nurses are in a prime position to enact change and drive the culture of the community, giving it purpose, while allowing its members to have a focus on their work. Nurses, as complexity leaders, are positioned to understand that change is a continual process that stems from collaboration, complex systems thinking, and innovation mindsets.
Antarcticimicrobium sediminis gen. nov., sp. nov., isolated from Antarctic intertidal sediment, transfer of Ruegeria lutea to Antarcticimicrobium gen. nov. as Antarcticimicrobium luteum comb. nov.
Authors: Zhang Shan , Liu Wei-Xiong , Liu Ning-Hua , He Xiao-Yan , Su Hai-Nan , Li Chun-Yang , Zhang Yu-Zhong , Song Xiao-Yan , Zhang Xi-Ying
Published: March 2020

A Gram-stain-negative, aerobic, non-flagellated and rod- or ovoid-shaped bacterium, designated as strain S4J41T, was isolated from Antarctic intertidal sediment. The isolate grew at 0–37 °C and with 0.5–10 % (w/v) NaCl. It reduced nitrate to nitrite and hydrolysed Tween 80 and gelatin. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain S4J41T constituted a distinct phylogenetic line within the family

Rhodobacteraceae

and was closely related with some species in the genera

Ruegeria

,

Phaeobacter

,

Pseudopuniceibacterium

,

Sulfitobacter

,

Puniceibacterium

and

Poseidonocella

with 98.6–95.7 % 16S rRNA gene sequence similarities. The major cellular fatty acids were C16 : 0, summed feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c) and C18 : 0 and the major polar lipids were phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol, phosphatidylethanolamine and one unidentified aminolipid. The sole respiratory quinone was Q-10. The genomic DNA G+C content of strain S4J41T was 60.3 mol%. Based on the phylogenetic, chemotaxonomic and phenotypic data obtained in this study, strain S4J41T is considered to represent a novel species in a new genus within the family

Rhodobacteraceae

, for which the name Antarcticimicrobium sediminis gen. nov., sp. nov. is proposed. The type strain is S4J41T (=MCCC 1K03508T=KCTC 62793T). Moreover, the transfer of

Ruegeria lutea

Kim et al. 2019 to Antarcticimicrobium gen. nov. as Antarcticimicrobium luteum comb. nov. (type strain 318-1T=JCM 30927T=KCTC 72105T) is also proposed.
Efficient Dual-Negative Selection for Bacterial Genome Editing
Authors: Cianfanelli Francesca Romana , Cunrath Olivier , Bumann Dirk
Published: March 2020

We describe a versatile method for chromosomal gene editing based on classical consecutive single-crossovers. The method exploits rapid plasmid construction using Gibson assembly, a convenientE. colidonor strain, and efficient dual-negative selection for improved suicide vector resolution. We used this method to generatein framedeletions, insertions and point mutations inSalmonella entericawith limited hands-on time. Similar strategies allowed efficient gene editing also inPseudomonas aeruginosaand multi-drug-resistant (MDR)Escherichia coliclinical isolates.
Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia
Authors: Kim Minsoo , Haney Jillian R. , Zhang Pan , Hernandez Leanna M. , Wang Lee-kai , Perez-Cano Laura , Loohuis Loes M. Olde , de la Torre-Ubieta Luis , Gandal Michael J.
Published: March 2020

The most significant common variant association for schizophrenia (SCZ) reflects increased expression of the complement component 4A (C4A). Yet, it remains unclear howC4Ainteracts with other SCZ risk genes and whether the complement system is more broadly implicated in SCZ pathogenesis. Here, we integrate several existing, large-scale genetic and transcriptomic datasets to interrogate the functional role of the complement system andC4Ain the human brain. Surprisingly, we find no significant genetic enrichment among known complement system genes for SCZ. Conversely, brain co-expression network analyses usingC4Aas a seed gene revealed that genes down-regulated whenC4Aexpression increased exhibit strong and specific genetic enrichment for SCZ risk. This convergent genomic signal reflected neuronal, synaptic processes and was sexually dimorphic and most prominent in frontal cortical brain regions. Overall, these results indicate that synaptic pathways—rather than the complement system—are the driving force conferring SCZ risk.
Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes
Authors: He Fei , Sullender Colin , Zhu Hanlin , Williamson Michael R. , Li Xue , Zhao Zhengtuo , Jones Theresa A. , Xie Chong , Dunn Andrew K. , Luan Lan
Published: March 2020

Neurovascular coupling, the close spatial and temporal relationship between neural activity and hemodynamics, is disrupted in pathological brain states. To understand the altered neurovascular relationship in brain disorders, longitudinal, simultaneous mapping of neural activity and hemodynamics is critical yet challenging to achieve. Here, we employ a multimodal neural platform in a mouse model of stroke and realize long-term, spatially-resolved tracking of intracortical neural activity and cerebral blood flow in the same brain regions. We observe a pronounced neurovascular dissociation that occurs immediately after small-scale strokes, becomes the most severe a few days after, lasts into chronic periods, and varies with the level of ischemia. Neuronal deficits extend spatiotemporally whereas restoration of cerebral blood flow occurs sooner and reaches a higher relative value. Our findings reveal the neurovascular impact of mini-strokes and inform the limitation of neuroimaging techniques that infer neural activity from hemodynamic responses.
The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation
Authors: El-Merahbi Rabih , Viera Jonathan Trujillo , Valdes Angel Loza , Kolczynska Katarzyna , Reuter Saskia , Löffler Mona C. , Erk Manuela , Ade Carsten P. , Karwen Till , Mayer Alexander E. , Eilers Martin , Sumara Grzegorz
Published: March 2020

Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.
An associated evaluation methodology of initial stress level of coal-rock masses in steeply inclined coal seams, Urumchi coal field, China
Authors: Shan Pengfei , Lai Xingping
Published: March 2020

Purpose

This paper aims to present an associated methodology to evaluate the initial stress of coal-rock masses in steeply inclined coal seams.

Design/methodology/approach

On the basis of the real-time monitoring data in the field, the corresponding analytical analysis is carried out in consideration of the characteristics of topography and geology, so as to deduce the value of the initial stress in the study area and also give the analytical model of the initial stress field.

Findings

The authors identified feasibility of the initial stress level of coal-rock masses in steeply inclined coal seams, and revealed that exact acquisition on the displacement of surrounding rock was feasible to analyze the initial stress level of coal-rock masses by the back analytical method in the steeply inclined coal seams as a two-dimensional plane problem.

Originality/value

The calculation results including vertical stress, minimum horizontal principal stress and shearing stress were 7.057, 8.085 and 0.057 MPa, respectively. The KJ743 coal mine initial stress monitoring system was used to collect real-time initial stress data, which were used to check the accuracy of the analytical back results. The value of the vertical stress varied from 6.8 to 7.0 MPa, which is slightly smaller than the result of the back calculation. The minimum principal horizontal stress varied from 7.6 to 8.4 MPa, which is similar to the result of the back calculation.
Career adaptability of South Korean engineering students
Authors: Park Sunyoung , Park Su Yeong
Published: March 2020

Purpose

The purpose of this study is to examine the role of mastery goal orientation, support for career development, career decision-making self-efficacy and engineering interest in career adaptability for engineering students.

Design/methodology/approach

Data were collected from 307 Korean engineering students from two universities. Structural equation modeling was used to analyze data and examine the relationships among the variables.

Findings

The results indicated that the level of mastery of goal orientation and support for career development significantly affected career decision-making self-efficacy. Engineering students’ career decision-making self-efficacy also positively influenced their engineering interests and career adaptability. Finally, the students’ engineering interest positively affected their career adaptability.

Originality/value

This study demonstrated that important factors for career planning and development need to be successively considered during the career choice process by linking it to career decision-making self-efficacy, engineering interest and career adaptability (career choice action), in consecutive order.
How BIM systems affect maintaining IBS building
Authors: Ismail Zul-Atfi
Published: March 2020

Purpose

The purpose of this paper is to discuss the system approaches and their application for managing IBS building in the context of Malaysian maintenance practice. Currently, the maintenance management method has affected the efficiency of the complex and high-rise industrialised building system (IBS) building maintenance management in Malaysia. Many issues such as poor service delivery, limited budgets, less competent staff and defect repetition emerged because of the usage of conventional method applications (paper-based form). The data revealed that the practice of maintenance management for complex and high-rise IBS buildings needs to be digitalised.

Design/methodology/approach

This qualitative research was carried out by conducting literature review and semi-structured interviews. Eight major maintenance organisations were selected based on a conventional method of practice in managing maintenance for complex and high-rise IBS buildings. The computerised system was developed using a data flow diagram and coding. Subsequently, the prototype system was tested.

Findings

By having this prototype system, the defect diagnosis and decision-making process become easier, faster and cost-effective in facilitating the maintenance assessment, defect diagnosis and control in relation to IBS building structure components.

Originality/value

In conclusion, the prototype system may improve the effectiveness of maintenance management practices for IBS building structure components in reducing defect design risks such as design calculation error to provide high-quality IBS building structure components for a safe and healthy environment.
Post-occupancy evaluation of University of Uyo buildings
Authors: Ikediashi Dubem , Udo Godfrey , Ofoegbu Maureen
Published: March 2020

Purpose

This study aims to evaluate the performance of buildings in the University of Uyo using the post-occupancy evaluation (POE) technique.

Design/methodology/approach

A quantitative questionnaire survey is adopted in which 333 copies of a validated questionnaire are administered to academic, administrative and maintenance staff and some students who occupy four buildings used for the survey. However, 124 valid responses are received giving a response rate of 37per cent. Data collected are analysed using descriptive and inferential statistical tools while the Kruskal Wallis chi-square (χ2) test is used to analyse hypotheses postulated for the study.

Findings

Findings reveal that the General Administration (GA) building has high ratings in five technical performance criteria of ambient level of sound in offices, the integrity of materials used for walls, and correctness of stair risers, threads in the building quality of lighting and quantity of lighting. Findings on the functional performance of GA building show that cleaning, friendliness, parking space, landscaping and indoor climate are the top five rated. Findings also reveal that lack of awareness about POE is a top-rated barrier, followed by a lack of orientation of stakeholders and a lack of adequately trained staff.

Originality/value

The study contributes to the body of knowledge on POE, particularly in universities by conducting an empirical evaluation of both technical and functional performance of the University of Uyo buildings. Besides, it establishes a set of factors that significantly hinder the implementation of POEs in universities. From a practice perspective, it provides valid feedback on which universities can build upon to improve conditions of their facilities and ultimately bolster the conducive environment for teaching and learning.
Training, productivity and performance: lessons from a chilean retailer
Authors: Rexworthy Jane
Published: March 2020

Purpose

A project to improve productivity in one of the largest retail firms in Latin America demonstrates how a tailor-made training intervention can improve workers’ performance and how — and by how much — investing in soft-skills can lead to productivity gains.

Design/methodology/approach

Individual-level longitudinal information gathered from the firm.

Findings

The training intervention was shown to have a positive and significant effect on both store-level sales and transactions per worker. This result was confirmed by a cost/benefit analysis. This provides clear evidence that productivity can be boosted with a high quality, well-designed and optimally-delivered training programme targeted to increase socio-emotional skills. This assertion has been corroborated by an empirical analysis of the project carried out by specialists from the Inter-American Development Bank and the Department of Economics, University of Maryland.

Originality/value

The project is one of the first to be subject to a detailed analysis to provide evidence of the causal impact of training on direct productivity measures.
Negative memorable experience: North American and British Airbnb guests’ perspectives
Authors: Sthapit Erose , Björk Peter , Jiménez Barreto Jano
Published: March 2020

Purpose

This paper aims to explore the components of a negative memorable Airbnb experience.

Design/methodology/approach

Two studies of North American and British nationals were conducted online using an open-ended survey questionnaire with photo-elicitation via Amazon Mechanical Turk (MTurk). The grounded theory was used to analyse the collected data.

Findings

The findings of the current study are destination-specific and generalisation is limited. In addition, this study gathered data using an open-ended survey questionnaire with visual images (photo-elicitation technique) in MTurk. Moreover, the study participants were mainly Westerners.

Research limitations/implications

Airbnb could provide hosts with a service quality checklist to warrant quality assurance across listings. Hosts must be informed, guided and monitored so that service quality standards are fulfilled. In addition, hosts should be incentivised to write an honest and accurate description of their listing.

Practical implications

Airbnb can provide hosts with a service quality checklist to ensure standardisation and quality assurance across listings. Hosts must be informed, guided and monitored so that service quality standards are fulfilled. In addition, hosts might benefit from training or workshops on the role of hosting and service quality management.

Originality/value

This is one of the first studies to explore the components of a negative memorable experience in the context of Airbnb.
Enhancing hospitality and tourism graduate employability through the 2u2i program
Authors: Mohd Yusof Mohd Fadil , Wong Anthony , Ahmad Ghazali , Che Aziz Roslizawati , Hussain Kashif
Published: March 2020

Purpose

The purpose of this paper is to present the concept of 2u2i – two years attachment with university and two years attachment with industry – a new learning mode introduced by the Ministry of Education as a strategy to enhance the employability of university undergraduate degree students in Malaysia.

Design/methodology/approach

The new mode of undergraduate degree program requires the university and industry to collaborate on the design of the curriculum and development of student training programs. Based on a series of qualitative discussions, the paper draws on the perspectives of university administrators and selected practitioners from the hospitality and tourism industry who are interested in developing 2u2i curriculum and working together to enhance the overall employability of university graduates. The paper explains the issues and challenges in implementing the 2u2i program at a local public university as a case study in Malaysia.

Findings

The 2u2i program provides a significant opportunity for industry to collaborate with the university in enhancing competencies and relevant skills among degree graduates so that they are able to excel in the workplace. Some of the issues and challenges involve bureaucratic procedures, time constraints in developing the program with industry, delay in approval procedures of the program and extra costs highlighted in managing the program with industry. Despite several challenges relating to the implementation of the program, it is important for industry to collaborate with universities in designing relevant curriculum to augment the employability skills of university graduates in Malaysia.

Originality/value

This paper explores different strategies for engaging with industry practitioners so that they are able to work closely with the university in crafting academic curricula in the hospitality and tourism field. This is important because it enhances university graduate employability via a relevant curriculum based on input from the industry.
Using the Nondonor Distribution to Improve Communication and Inform Decision Making for Low LRs from Minor Contributors in Mixed DNA Profiles
Authors: Schuerman Curt , Kalafut Tim , Buchanan Clint , Sutton Joel , Bright Jo‐Anne
Published: March 2020

The reporting of a likelihood ratio (LR) calculated from probabilistic genotyping software has become more popular since 2015 and has allowed for the use of more complex mixtures at court. The meaning of “inconclusive” LRs and how to communicate the significance of low LRs at court is now important. We present a method here using the distribution of LRs obtained from nondonors. The nondonor distribution is useful for examining calibration and discrimination for profiles that have produced LRs less than about 104. In this paper, a range of mixed DNA profiles of varying quantity were constructed and the LR distribution considering the minor contributor for a number of nondonors was compared to the expectation given a calibrated system. It is demonstrated that conditioning genotypes should be used where reasonable given the background information to decrease the rate of nondonor LRs above 1. In all 17 cases examined, the LR for the minor donor was higher than the nondonor LRs, and in 12 of the 17 cases, the 99.9 percentile of the nondonor distribution was lower when appropriate conditioning information was used. The output of the tool is a graph that can show the position of the LR for the person of interest set against the nondonor LR distribution. This may assist communication between scientists and the court.
Oligopolistic equilibrium and financial constraints
Authors: Beviá Carmen , Corchón Luis C. , Yasuda Yosuke
Published: March 2020

We model a dynamic duopoly in which firms can potentially drive their rivals from the market. For some parameter values, the Cournot equilibrium outcome cannot be sustained in an infinitely repeated setting. In those cases, there is a Markov perfect equilibrium in mixed strategies in which one firm, eventually, will exit the market with probability one. Producer surplus in the maximum collusive outcome is greater under bankruptcy consideration, because the outcome that maximizes joint profits is skewed in favor of the more efficient firm. Consumer surplus and social welfare also increase in many cases, although those effects are generally ambiguous.
Factors related to rapid progression of non‐small cell lung cancer in Chinese patients treated using single‐agent immune checkpoint inhibitor treatment
Authors: Zhang Liang , Bai Lianwei , Liu Xianhong , Liu Ying , Li Shuang , Liu Jingjing , Zhang Shuang , Yang Changliang , Ren Xiubao , Cheng Ying
Published: March 2020

Background

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non‐small cell lung cancer (NSCLC). While rapid progression (RP) has been proposed as a non‐negligible pattern of response to ICIs, its definition and related factors remain unclear. This study aimed to develop a clinical definition of RP and to identify related factors.

Methods

We retrospectively evaluated Chinese patients who had received an ICI as second‐line or later treatment for locally advanced or metastatic NSCLC at a single center. We defined RP as radiological progression at the first response assessment (<2 months after starting the ICI), as well as confirmation of progressive disease or cancer‐related death occurring at <3 months. The clinical outcomes were compared for patients with RP or non‐RP to identify prognostic factors.

Results

The study evaluated 74 eligible patients with detailed records regarding their ICI therapy, including 25 patients (33.8%) who had experienced RP. Relative to patients with non‐RP, patients with RP had significantly shorter median progression‐free survival (1.7 months [95% CI: 1.4–2.0 months] vs. 6.3 months [95% CI 5.2–7.3 months], P < 0.001; hazard ratio: 0.14, 95% CI: 0.08–0.25) and significantly shorter median overall survival (8.2 months [95% CI 3.0–13.4 months] vs. 22.6 months [95% CI 17.0–28.1 months], P < 0.001; hazard ratio: 0.27, 95% CI: 0.15–0.49). Multivariate analysis revealed that RP was independently predicted by the presence of ≥3 metastatic sites (P = 0.039) and a neutrophil‐to‐lymphocyte ratio of ≥3 (P = 0.044).

Conclusions

Among NSCLC patients, RP was a common response to ICI monotherapy and was associated with dramatically reduced progression‐free and overall survival. Care is needed when selecting ICI monotherapy for these patients, especially if they have ≥3 metastatic sites or a neutrophil‐to‐lymphocyte ratio of ≥3.

Key points

Significant findings of the study: Patients with rapid progression after immune checkpoint inhibitor monotherapy had poor survival outcomes. The number of metastatic sites and the neutrophil‐to‐lymphocyte ratio may independently predict treatment response in this setting.What this study adds: This is the first study to evaluate rapid progression after second‐line or later single‐agent immunotherapy in a Chinese population. Our findings may help establish effective immunotherapy strategies for NSCLC.
viewshed3d: An r package for quantifying 3D visibility using terrestrial lidar data
Authors: Lecigne Bastien , Eitel Jan U. H. , Rachlow Janet L.
Published: March 2020

Visual information affects animal behaviour and fitness in diverse ways, but a lack of suitable methods to quantify visibility in three‐dimensional (3D) environments limits applications of the concept of visibility in ecological research.

The viewshed3d r package is dedicated to quantifying the visual environment from a single location or from a cumulation of viewpoints based on 3D point clouds acquired with terrestrial laser scanning. We present the entire workflow required to prepare the data and perform the visibility analyses in viewshed3d.

This approach can help unlock the potential contributions of viewshed analyses to the emerging subdiscipline of ‘viewshed ecology’.
Adolescent nicotine induces depressive and anxiogenic effects through ERK 1‐2 and Akt‐GSK‐3 pathways and neuronal dysregulation in the nucleus accumbens
Authors: Hudson Roger , Green Matthew , Wright Daniel J. , Renard Justine , Jobson Christina E.L. , Jung Tony , Rushlow Walter , Laviolette Steven R.
Published: March 2020

Long‐term tobacco dependence typically develops during adolescence and neurodevelopmental nicotine exposure is associated with affective disturbances that manifest as a variety of neuropsychiatric comorbidities in clinical and preclinical studies, including mood and anxiety‐related disorders. The nucleus accumbens shell (NASh) is critically involved in regulating emotional processing, and both molecular and neuronal disturbances in this structure are associated with mood and anxiety‐related pathologies. In the present study, we used a rodent model of adolescent neurodevelopmental nicotine exposure to examine the expression of several molecular biomarkers associated with mood/anxiety‐related phenotypes. We report that nicotine exposure during adolescence (but not adulthood) induces profound upregulation of the ERK 1‐2 and Akt‐GSK‐3 signalling pathways directly within the NASh, as well as downregulation of local D1R expression that persists into adulthood. These adaptations were accompanied by decreases in τ, α, β, and γ‐band oscillatory states, hyperactive medium spiny neuron activity with depressed bursting rates, and anxiety and depressive‐like behavioural abnormalities. Pharmacologically targeting these molecular and neuronal adaptations revealed that selective inhibition of local ERK 1‐2 and Akt‐GSK‐3 signalling cascades rescued nicotine‐induced high‐γ‐band oscillatory signatures and phasic bursting rates in the NASh, suggesting that they are involved in mediating adolescent nicotine‐induced depressive and anxiety‐like neuropathological trajectories.
Extended ex vivo normothermic perfusion for preservation of vascularized composite allografts
Authors: Fahradyan Vahe , Said Sayf Al‐deen , Ordenana Carlos , Dalla Pozza Edoardo , Frautschi Russell , Duraes Eliana F. R. , Madajka‐Niemeyer Maria , Papay Frank A. , Rampazzo Antonio , Bassiri Gharb Bahar
Published: March 2020

Ischemia and reperfusion injury remains a significant limiting factor for the successful revascularization of amputated extremities. Ex vivo normothermic perfusion is a novel approach to prolong the viability of the amputated limbs by maintaining physiologic cellular metabolism. This study aimed to evaluate the outcomes of extended ex vivo normothermic limb perfusion (EVNLP) in preserving the viability of amputated limbs for over 24 hours. A total of 10 porcine forelimbs underwent EVNLP. Limbs were perfused using an oxygenated colloid solution at 38°C containing washed RBCs. Five forelimbs (Group A) were perfused for 12 hours and the following 5 (Group B) until the vascular resistance increased. Contralateral forelimbs in each group were preserved at 4°C as a cold storage control group. Limb viability was compared between the 2 groups through assessment of muscle contractility, compartment pressure, tissue oxygen saturation, indocyanine green (ICG) angiography and thermography. EVNLP was performed for 12 hours in group A and up to 44 hours (24‐44 hours) in group B. The final weight increase (−1.28 ± 8.59% vs. 7.28 ± 15.05%, P = .548) and compartment pressure (16.50 ± 8.60 vs. 24.00 ± 9.10) (P = .151) were not significantly different between the two groups. Final myoglobin and CK mean values in group A and B were: 875.0 ± 325.8 ng/mL (A) versus 1133.8 ± 537.7 ng/mL (B) (P = .056) and 53 344.0 ± 16 603.0 U/L versus 64 333.3 ± 32 481.8 U/L (P = .286). Tissue oxygen saturation was stable until the end in both groups. Infra‐red thermography and ICG‐angiography detected variations of peripheral limb perfusion. Our results suggest that extended normothermic preservation of amputated limbs is feasible and that the outcomes of prolonged EVNLP (>24 hours) are not significantly different from short EVNLP (12 hours).
Endemic Burkitt lymphoma – an aggressive childhood cancer linked to Plasmodium falciparum exposure, but not to exposure to other malaria parasites
Authors: Quintana Maria del Pilar , Smith‐Togobo Cecilia , Moormann Ann , Hviid Lars
Published: March 2020

Burkitt lymphoma (BL) is an aggressive non‐Hodgkin lymphoma. The prevalence of BL is ten‐fold higher in areas with stable transmission of Plasmodium falciparum malaria, where it is the most common childhood cancer, and is referred to as endemic BL (eBL). In addition to its association with exposure to P. falciparum infection, eBL is strongly associated with Epstein–Barr virus (EBV) infection (>90%). This is in contrast to BL as it occurs outside P. falciparum‐endemic areas (sporadic BL), where only a minority of the tumours are EBV‐positive. Although the striking geographical overlap in the distribution of eBL and P. falciparum was noted shortly after the first detailed description of eBL in 1958, the molecular details of the interaction between malaria and eBL remain unresolved. It is furthermore unexplained why exposure to P. falciparum appears to be essentially a prerequisite to the development of eBL, whereas other types of malaria parasites that infect humans have no impact. In this brief review, we summarize how malaria exposure may precipitate the malignant transformation of a B‐cell clone that leads to eBL, and propose an explanation for why P. falciparum uniquely has this capacity.
Adult height in patients with childhood‐onset inflammatory bowel disease: a nationwide population‐based cohort study
Authors: Mouratidou Natalia , Malmborg Petter , Sachs Michael C. , Askling Johan , Ekbom Anders , Neovius Martin , Smedby Karin E. , Sävendahl Lars , Ludvigsson Jonas F. , Olén Ola
Published: March 2020

Background

Growth retardation is well described in childhood‐onset inflammatory bowel disease (IBD).

Aims

To study if childhood‐onset IBD is associated with reduced final adult height.

Methods

We identified 4201 individuals diagnosed with childhood‐onset IBD 1990‐2014 (Crohn's disease: n = 1640; ulcerative colitis: n = 2201 and IBD‐unclassified = 360) in the Swedish National Patient Register.

Results

Patients with IBD attained a lower adult height compared to reference individuals (adjusted mean height difference [AMHD] −0.9 cm [95% CI −1.1 to −0.7]) and to their healthy siblings (AMHD −0.8 cm [−1.0 to −0.6]). Patients with Crohn’s disease (CD) were slightly shorter than patients with ulcerative colitis (UC; −1.3 cm vs −0.6 cm). Lower adult height was more often seen in patients with pre‐pubertal disease onset (AMHD −1.6 cm [−2.0 to −1.2]), and in patients with a more severe disease course (AMHD −1.9 cm, [−2.4 to −1.4]). Some 5.0% of CD and 4.3% of UC patients were classified as growth retarded vs 2.5% of matched reference individuals (OR 2.42 [95% CI 1.85‐3.17] and 1.74 [1.36‐2.22] respectively).

Conclusion

Patients with childhood‐onset IBD on average attain a slightly lower adult height than their healthy peers. Adult height was more reduced in patients with pre‐pubertal onset of disease and in those with a more severe disease course.
Modelling NAFLD disease burden in four Asian regions—2019‐2030
Authors: Estes Chris , Chan Henry L. Y. , Chien Rong N. , Chuang Wan‐Long , Fung James , Goh George Boon-Bee , Hu Tsung H. , Huang Jee‐Fu , Jang Byoung K. , Jun Dae W. , Kao Jia H. , Lee Jin‐Woo , Lin Han‐Chieh , Razavi‐Shearer Kathryn , Seto Wai‐Kay , Wong Grace L. ‐H. , Wong Vincent W. ‐S. , Razavi Homie
Published: March 2020

Background

Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) account for an increasing proportion of liver disease in the Asia‐Pacific region. Many areas in the region are experiencing epidemics of metabolic syndrome among rapidly ageing populations.

Aims

To estimate using modelling the growth in NAFLD populations, including cases with significant fibrosis that are most likely to experience advanced liver disease and related mortality.

Methods

A disease progression model was used to summarise and project fibrosis progression among the NAFLD populations of Hong Kong, Singapore, South Korea and Taiwan. For each area, changes in the adult prevalence of obesity was used to extrapolate long‐term trends in NAFLD incidence.

Results

In the areas studied, prevalent NAFLD cases were projected to increase 6%‐20% during 2019‐2030, while prevalent NASH cases increase 20%‐35%. Incident cases of hepatocellular carcinoma are projected to increase by 65%‐85%, while incident decompensated cirrhosis cases increase 65%‐100% by 2030. Likewise, NAFLD‐related mortality is projected to increase between 65% and 100% from 2019 to 2030. NAFLD disease burden is expected to increase alongside rising trends in metabolic syndrome and obesity among populations in the region. This leads to more cases of advanced liver disease and associated mortality.

Conclusions

Preventing the growth of diabetic and obese populations will be a key factor in reducing ongoing increases in NAFLD‐related disease burden in the Asia‐Pacific region.
Gonadal hormone‐independent sex differences in GABAA receptor activation in rat embryonic hypothalamic neurons
Authors: Mir Franco R. , Wilson Carlos , Cabrera Zapata Lucas E. , Aguayo Luis G. , Cambiasso María Julia
Published: March 2020

Background and Purpose

GABAA receptor functions are dependent on subunit composition, and, through their activation, GABA can exert trophic actions in immature neurons. Although several sex differences in GABA‐mediated responses are known to be dependent on gonadal hormones, few studies have dealt with sex differences detected before the critical period of brain masculinisation. In this study, we assessed GABAA receptor functionality in sexually segregated neurons before brain hormonal masculinisation.

Experimental Approach

Ventromedial hypothalamic neurons were obtained from embryonic day 16 rat brains and grown in vitro for 2 days. Calcium imaging and electrophysiology recordings were carried out to assess GABAA receptor functional parameters.

Key Results

GABAA receptor activation elicited calcium entry in immature hypothalamic neurons mainly through L‐type voltage‐dependent calcium channels. Nifedipine blocked calcium entry more efficiently in male than in female neurons. There were more male than female neurons responding to GABA, and they needed more time to return to resting levels. Pharmacological characterisation revealed that propofol enhanced GABAA‐mediated currents and blunted GABA‐mediated calcium entry more efficiently in female neurons than in males. Testosterone treatment did not erase such sex differences. These data suggest sex differences in the expression of GABAA receptor subtypes.

Conclusion and Implications

GABA‐mediated responses are sexually dimorphic even in the absence of gonadal hormone influence, suggesting genetically biased differences. These results highlight the importance of GABAA receptors in hypothalamic neurons even before hormonal masculinisation of the brain.
Socratic reductionism in ethics
Authors: Smyth Nicholas
Published: March 2020

In this paper, I clarify and defend a provocative hypothesis offered by Bernard Williams, namely, that modern people are much more likely to speak in terms of master‐concepts like “good” or “right,” and correspondingly less likely to think and speak in the pluralistic terms favored by certain Ancient societies. By conducting a close reading of the Platonic dialogues Charmides and Laches, I show that the figure of Socrates plays a key historical role in this conceptual shift. Once we understand that our narrow, reductionist focus on “thin” ethical concepts is a contingent historical development, we are, I claim, in a much better position to evaluate it.
Statin treatment and accrual of covert cerebral ischaemia on neuroimaging: a systematic review and meta‐analysis of randomized trials
Authors: Katsanos A. H. , Lioutas V.‐A. , Charidimou A. , Catanese L. , Ng K. K. H. , Perera K. , de Sa Boasquevisque D. , Tsivgoulis G. , Smith E. E. , Sharma M. , Selim M. H. , Shoamanesh A.
Published: March 2020

Background and purpose

Prevention of ischaemic stroke and cardiovascular events is an established benefit of statin therapy, but the effects of statin treatment on the accrual of magnetic resonance imaging (MRI) markers of ischaemic cerebral injury remain unknown. A systematic review was performed to identify all studies that randomized patients with cardiovascular risk factors to statin treatment and assessed the effect of statin treatment on covert infarcts (asymptomatic, evident only on neuroimaging) and white matter hyperintensity (WMH) accrual on MRI.

Methods

A systematic review in MEDLINE and Scopus from inception to 23 October 2019 was performed. A random‐effects model was used to calculate the pooled estimates of the crude risk ratios and standardized mean differences.

Results

Data from three randomized controlled trials (1430 participants) were included evaluating the effect of rosuvastatin (10 mg/day) in 668 hypertensive patients older than 60 years of age over 5 years, pravastatin (40 mg/day) in 554 elderly people more than 70 years of age over 3 years and simvastatin (20 mg/day) in 208 patients with asymptomatic middle cerebral artery stenosis over 2 years. Patients randomized to statin treatment had decreased accrual of new covert infarcts (risk ratio 0.63, 95% confidence interval 0.46–0.88) during a mean follow‐up of 2–6 years. Only one study reported WMH decreased volume change in patients randomized to statin treatment compared to patients randomized to non‐statin treatment (standardized mean difference −1.17; 95% confidence interval −1.33, −1.00).

Conclusion

Our findings suggest that, in addition to stroke prevention, statin treatment can reduce the accrual of covert MRI markers of ischaemic cerebral injury.