bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality Assurance of PBPK Modeling Platforms and Guidance on Building, Evaluating, Verifying and Applying PBPK Models Prudently under the Umbrella of Qualification: Why, When, What, How and By Whom?
Authors: Frechen Sebastian , Rostami-Hodjegan Amin
Published: April 2022

Modeling and simulation emerges as a fundamental asset of drug development. Mechanistic modeling builds upon its strength to integrate various data to represent a detailed structural knowledge of a physiological and biological system and is capable of informing numerous drug development and regulatory decisions via extrapolations outside clinically studied scenarios. Herein, physiologically based pharmacokinetic (PBPK) modeling is the fastest growing branch, and its use for particular applications is already expected or explicitly recommended by regulatory agencies. Therefore, appropriate applications of PBPK necessitates trust in the predictive capability of the tool, the underlying software platform, and related models. That has triggered a discussion on concepts of ensuring credibility of model-based derived conclusions. Questions like ‘why’, ‘when’, ‘what’, ‘how’ and ‘by whom’ remain open. We seek for harmonization of recent ideas, perceptions, and related terminology. First, we provide an overview on quality assurance of PBPK platforms with the two following concepts. Platform validation: ensuring software integrity, security, traceability, correctness of mathematical models and accuracy of algorithms. Platform qualification: demonstrating the predictive capability of a PBPK platform within a particular context of use. Second, we provide guidance on executing dedicated PBPK studies. A step-by-step framework focuses on the definition of the question of interest, the context of use, the assessment of impact and risk, the definition of the modeling strategy, the evaluation of the platform, performing model development including model building, evaluation and verification, the evaluation of applicability to address the question, and the model application under the umbrella of a qualified platform.
Dynamic path learning in decision trees using contextual bandits
Authors: Ju Weiyu , Yuan Dong , Bao Wei , Ge Liming , Zhou Bing Bing
Published: April 2022

We present a novel online decision-making solution, where the optimal path of a given decision tree is dynamically found based on the contextual bandits analysis. At each round, the learner finds a path in the decision tree by making a sequence of decisions following the tree structure and receives an outcome when a terminal node is reached. At each decision node, the environment information is observed to hint on which child node to visit, resulting in a better outcome. The objective is to learn the context-specific optimal decision for each decision node to maximize the accumulated outcome. In this paper, we propose Dynamic Path Identifier (DPI), a learning algorithm where the contextual bandit is applied to every decision node, and the observed outcome is used as the reward of the previous decisions of the same round. The technical difficulty of DPI is the high exploration challenge caused by the width (i.e., the number of paths) of the tree as well as the large context space. We mathematically prove that DPI’s regret per round approached zero as the number of the rounds approaches infinity. We also prove that the regret is not a function of the number of paths in the tree. Numerical evaluations are provided to complement the theoretical analysis.
Organic Cation Transporter-Mediated Accumulation of Quinolinium Salts in the LV Myocardium of Rodents
Authors: Grievink Hilbert , Shamni Ofer , Krajewski Seweryn , Steczek Łukasz , Gründemann Dirk , Mishani Eyal , Abourbeh Galith
Published: April 2022

Purpose

Quaternary ammonium salts have demonstrated marked accumulation in the left ventricular (LV) myocardium of rodents and swine. To investigate the mechanism underlying this uptake, the present study examined the interaction of [18F]fluoroethylquinolinium ([18F]FEtQ) with the family of organic cation transporters (OCTs).

Procedures

The cellular uptake of [18F]FEtQ into HEK293 cells, expressing human OCT1, -2, or -3 (HEK293-hOCT), and its inhibition by corticosterone was evaluated in vitro. The inhibitory effect of decynium 22 (D 22) in vivo was also studied, using PET/CT of HEK293-hOCT tumor-bearing mice. Furthermore, the distribution kinetics of [18F]FEtQ were determined in rats, with and without pre-administration of corticosterone, and following administration to a non-human primate (NHP).

Results

The accumulation of [18F]FEtQ in HEK293-hOCT cells was 15–20-fold higher than in control cells and could be inhibited by corticosterone. in vivo, the uptake of [18F]FEtQ in the LV myocardium of corticosterone-treated rats was significantly reduced compared to that of untreated animals. Similarly, following administration of D 22 to HEK293-hOCT tumor-bearing mice, the peak tumor uptake of [18F]FEtQ was reduced by 40–45 % compared to baseline. Contrary to the distinct accumulation of [18F]FEtQ in the LV myocardium of rats, no cardiac uptake was observed following its administration to a NHP.

Conclusions

The quinolinium salt derivative [18F]FEtQ interacts with the family of OCTs, and this interaction could account, at least in part, for the increased uptake in the LV myocardium of rodents. Nonetheless, its low affinity for hOCT3 and the results of PET/CT imaging in a NHP indicate a limited clinical applicability as a radiopharmaceutical for cardiac and/or OCT imaging.
Transfersomal eosin topical delivery assisted by fractional CO2 laser for photodynamic treatment of palmar hyperhidrosis: case study
Authors: Fadeel Doaa A. Abdel , Fadel Maha , Tawfik Abeer , Omar Yasser
Published: April 2022

Hyperhidrosis is a condition in which the cholinergic receptors on the eccrine glands are overstimulated, resulting in excessive sweating. It is considered a serious cosmetic and psychological problem that affects the patient’s quality of life. Searching for novel treatment modalities is required to minimize the side effects and to attain better patient satisfaction.

Photodynamic therapy (PDT), using eosin as a photosensitizer, is developed as a promising modality of the treatment of palmar and axillary hyperhidrosis. In this study, we treated six cases suffering palmar hyperhidrosis by applying the fractional CO2 laser prior to PDT session. For PDT, a hydrogel of eosin loaded in a transfersomes as a nano-delivery carrier was applied for 5 min, followed by irradiation by intense pulsed light (IPL). The prepared transfersomes loaded by eosin were spherical in shape with encapsulation efficiency of 33 ± 3.5%, particle size 305.5 ± 5.7 nm, average zeta potential of − 54 ± 7.6 mV with 80 ± 4% of the loaded eosin was released after 3 h. Two cases achieved 90% improvement after four sessions, three patients needed six sessions to show 75% improvement, while one patient showed only 25% improvement after six sessions. This resulted in shortening the time of PS application and decreasing the number of sessions required to achieve acceptable improvement. More clinical studies on large number of patients are required to optimize the results.

Graphical abstract
Prediction of post-stroke cognitive impairment by Montreal Cognitive Assessment (MoCA) performances in acute stroke: comparison of three normative datasets
Authors: Salvadori Emilia , Cova Ilaria , Mele Francesco , Pomati Simone , Pantoni Leonardo
Published: April 2022

Background

Cognitive assessment in acute stroke is relevant for identifying patients at risk of persistent post-stroke cognitive impairment (PSCI). Despite preliminary evidence on MoCA accuracy, there is no consensus on its optimal score in the acute stroke setting to predict PSCI.

Aims

(1) To explore whether the application of different normative datasets to MoCA scores obtained in the acute stroke setting results in variable frequency of patients defined as cognitively impaired; (2) to assess whether the normality cut-offs provided by three normative datasets predict PSCI at 6–9 months; (3) to calculate alternative MoCA cut-offs able to predict PSCI.

Methods

Consecutive stroke patients were reassessed at 6–9 months with extensive neuropsychological and functional batteries for PSCI determination.

Results

Out of 207 enrolled patients, 118 (57%) were followed-up (mean 7.4 ± 1.7 months), and 77 of them (65%) received a PSCI diagnosis. The application of the normality thresholds provided by the 3 normative datasets yielded to variable (from 28.5% to 41%) rates of patients having an impaired MoCA performance, and to an inadequate accuracy in predicting PSCI, maximizing specificity instead of sensitivity. In ROC analyses, a MoCA score of 22.82, adjusted according to the most recent normative dataset, achieved a good diagnostic accuracy in predicting PSCI.

Conclusions

The classification of acute stroke patients as normal/impaired based on MoCA thresholds proposed by general population normative datasets underestimated patients at risk of persistent PSCI. We calculated a new adjusted MoCA score predictive of PSCI in acute stroke patients to be further tested in larger studies.
Variation in the prevalence of different forms of bullying victimisation among adolescents and their associations with family, peer and school connectedness: a population-based study in 40 lower and middle income to high-income countries (LMIC-HICs)
Authors: Biswas Tuhin , Thomas Hannah J. , Scott James G. , Munir Kerim , Baxter Janeen , Huda M. Mamun , Renzaho Andre M.N. , Cross Donna , Ahmed Helal Uddin , Mahumud Rashidul Alam , Mamun Abdullah A
Published: April 2022

This study aimed to estimate the prevalence of different forms of bullying victimization experiences and their association with family functioning, peer relationships and school connectedness among adolescents across 40 lower and middle income to high-income countries (LMIC-HICs). Data were drawn from the Health Behaviour in School-Aged Children (HBSC) school-based survey of adolescents aged 11–15 years, between 2013 and 2014. We estimated the weighted prevalence by categorising experiences into traditional bullying victimization only, cyberbullying victimization only, and combined traditional and cyberbullying victimization, at country and country income classification. We used multinominal logistic regression models to estimate the adjusted association with the form of bullying victimization by demographic characteristics, family functioning, peer relationships and school connectedness. Overall, 8.0% reported traditional bullying victimization only (8.8% males, 7.4% females), 2.3% of adolescents reported cyberbullying victimization only (2.1% males, 2.2% females), and 1.7% reported combined traditional and cyber bullying victimization (1.7% males, 1.8% females). All three forms of bullying victimization during adolescence were significantly associated with poor family functioning, poor peer relations and poor school connectedness. A consistent finding is that traditional bullying victimization is considerably more common among adolescents across both LMICs and HICs than cyberbullying victimization. This study also demonstrated that a significant proportion of adolescent’s experience victimization in both forms. Positive family functioning, strong peer relationships and greater school connectedness are associated with a lower risk of both forms of bullying victimization.
Adulteration detection technologies used for halal/kosher food products: an overview
Authors: Mortas Mustafa , Awad Nour , Ayvaz Huseyin
Published: April 2022

In the Islamic and Jewish religions, there are various restrictions that should be followed in order for food products to be acceptable. Some food items like pork or dog meat are banned to be consumed by the followers of the mentioned religions. However, illegally, some food producers in various countries use either the meat or the fat of the banned animals during food production without being mentioned in the label on the final products, and this considers as food adulteration. Nowadays, halal or kosher labeled food products have a high economic value, therefore deceiving the consumers by producing adulterated food is an illegal business that could make large gains. On the other hand, there is an insistent need from the consumers for getting reliable products that comply with their conditions. One of the main challenges is that the detection of food adulteration and the presence of any of the banned ingredients is usually unnoticeable and cannot be determined by the naked eye. As a result, scientists strove to develop very sensitive and precise analytical techniques. The most widely utilized techniques for the detection and determination of halal/kosher food adulterations can be listed as High-Pressure Liquid Chromatography (HPLC), Capillary Electrophoresis (CE), Gas Chromatography (GC), Electronic Nose (EN), Polymerase Chain Reaction (PCR), Enzyme-linked Immuno Sorbent Assay (ELISA), Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR), Near-infrared (NIR) Spectroscopy, Laser-induced Breakdown Spectroscopy (LIBS), Fluorescent Light Spectroscopy, Fourier Transform Infrared (FTIR) Spectroscopy and Raman Spectroscopy (RS). All of the above-mentioned techniques were evaluated in terms of their detection capabilities, equipment and analysis costs, accuracy, mobility, and needed sample volume. As a result, the main purposes of the present review are to identify the most often used detection approaches and to get a better knowledge of the existing halal/kosher detection methods from a literature perspective.
Early Maize (Zea mays) in the North American Central Plains: The Microbotanical Evidence
Authors: Adair Mary J. , Duncan Neil A. , Young Danielle N. , Bozarth Steven R. , Lusteck Robert K.
Published: April 2022

Artifacts, including ceramics, ground stone, and soil samples, as well as dental calculus, recovered from sites in the eastern North American central Plains were submitted to multiple laboratories for analysis of microbotanical remains. Direct accelerator mass spectrometer (AMS) dates of 361–197 cal BC provide evidence for the earliest use of maize (Zea maysssp.mays) in this region. Squash (Cucurbitasp.), wild rice (cf.Zizaniaspp.), and palm (Arecaceae sp.) microremains were also found. This research adds to the growing evidence of the importance of microbotanical analysis in documenting plant use and in the identification of early maize. The combined data on early maize from the eastern Plains adds to our understanding of the timing and dispersal of this crop out of the American Southwest. Alternative explanations for the adoption and early use of maize by eastern central Plains communities include its value as a secondary resource, as an addition to an existing farming strategy, or as a component of Middle Woodland rituals.
A Simple Theory of Acting Together
Authors: GILBERT MARGARET
Published: April 2022

I argue for an account of acting together that has a particular notion of joint commitment at its core. The account presented offers a compact explanation of four significant aspects of acting together as this is ordinarily understood: the parties have pertinent obligations to one another; each needs the concurrence of the rest with his or her untimely exit from the joint activity; an appropriate collective goal is sufficient to motivate the parties; and the parties may have personal goals contrary to the collective goal. I argue that the simplicity of the account coupled with its explanatory power argue for it in face of concerns that it takes us beyond the concepts we need to explain what it is for an individual to act alone. Indeed, there is reason to invoke joint commitment in many contexts other than acting together in which more than one person is involved. I conclude by noting that the joint commitment account of acting together plausibly accounts for the apparently transformative nature of doing things with others, citing its connection with a sense of togetherness, solidarity, and unity, as in the phrase ‘There is no I in team’.
Use of ultraviolet light in graduate medical education to assess confidence among residents and fellows in handwashing instruction
Authors: Aouthmany Shaza , Mehalik Haley , Bailey Morgan , Pei Mitchell , Syed Sameer , Brickman Kristopher , Morrison Kayla , Khuder Sadik
Published: April 2022

Background:

Coronavirus disease 2019 (COVID-19) has made it imperative to focus on strategies to improve hand hygiene to minimize threats of viral transmission in hospitals.

Objective:

We investigated the potential of using ultraviolet (UV) light as a visual tool in hand-hygiene education to bring awareness of individual handwashing effectiveness to healthcare workers.

Methods:

In 2020, 117 individuals participated in the simulation and completed surveys on proper handwashing technique. Of these, 114 were first-year residents and fellows. Surveys of confidence in hand hygiene were obtained before and after formal hand-hygiene education utilizing UV light with Glo Germ lotion. The UV light and Glo Germ lotion were used to identify deficiencies in individual handwashing technique.

Results:

With a total response rate of 97.4%, first-year residents and fellows demonstrated a significant decrease in handwashing confidence in pre- and posteducation surveys. Study participants who had had formal hand-hygiene training in the previous 3 years also indicated confidence in hand hygiene similar to those who had not had previous hand-hygiene training. Conclusions: Overall, resident interns and fellows may have falsely elevated their hand-hygiene confidence levels. However, conclusions regarding the confidence of residents and fellows individually could not be made due to sample size. Many healthcare personnel practice improper handwashing techniques, which may be improved with education and training that includes UV light.
Comparison of aerosol mitigation strategies and aerosol persistence in dental environments
Authors: Choudhary Shruti , Durkin Michael J. , Stoeckel Daniel C. , Steinkamp Heidi M. , Thornhill Martin H. , Lockhart Peter B. , Babcock Hilary M. , Kwon Jennie H. , Liang Stephen Y. , Biswas Pratim
Published: April 2022

Objective:

To determine the impact of various aerosol mitigation interventions and to establish duration of aerosol persistence in a variety of dental clinic configurations.

Methods:

We performed aerosol measurement studies in endodontic, orthodontic, periodontic, pediatric, and general dentistry clinics. We used an optical aerosol spectrometer and wearable particulate matter sensors to measure real-time aerosol concentration from the vantage point of the dentist during routine care in a variety of clinic configurations (eg, open bay, single room, partitioned operatories). We compared the impact of aerosol mitigation strategies (eg, ventilation and high-volume evacuation (HVE), and prevalence of particulate matter) in the dental clinic environment before, during, and after high-speed drilling, slow–speed drilling, and ultrasonic scaling procedures.

Results:

Conical and ISOVAC HVE were superior to standard-tip evacuation for aerosol-generating procedures. When aerosols were detected in the environment, they were rapidly dispersed within minutes of completing the aerosol-generating procedure. Few aerosols were detected in dental clinics, regardless of configuration, when conical and ISOVAC HVE were used.

Conclusions:

Dentists should consider using conical or ISOVAC HVE rather than standard-tip evacuators to reduce aerosols generated during routine clinical practice. Furthermore, when such effective aerosol mitigation strategies are employed, dentists need not leave dental chairs fallow between patients because aerosols are rapidly dispersed.
Estimating the non-dimensional energy of vortex rings by modelling their roll-up
Authors: de Guyon Guillaume , Mulleners Karen
Published: April 2022

The non-dimensional energy of starting vortex rings typically converges to values around 0.33 when they are created by a piston-cylinder or a bluff body translating at a constant speed. To explore the limits of the universality of this value and to analyse the variations that occur outside of those limits, we present an alternative approach to the slug-flow model to predict the non-dimensional energy of a vortex ring. Our approach is based on the self-similar vortex sheet roll-up described by Pullin (J. Fluid Mech., vol. 88, 1978, pp. 401–430). We derive the vorticity distribution for the vortex core resulting from a spiralling shear layer roll-up and compute the associated non-dimensional energy. To demonstrate the validity of our model for vortex rings generated through circular nozzles and in the wake of disks, we consider different velocity profiles of the vortex generator that follow a power law with a variable time exponent

$m$

. Higher values of

$m$

indicate a more uniform vorticity distribution. For a constant velocity (

$m=0$

), our model yields a non-dimensional energy of

${{E}^{{*}}}=0.33$

. For a constant acceleration (

$m=1$

), we find

${{E}^{{*}}}=0.19$

. The limiting value

$m \rightarrow \infty$

corresponds to a uniform vorticity distribution and leads to

${{E}^{{*}}}=0.16$

, which is close to values found in the literature for Hill's spherical vortex. The radial diffusion of the vorticity within the vortex core results in the decrease of the non-dimensional energy. For a constant velocity, we obtain realistic vorticity distributions by radially diffusing the vorticity distribution of the Pullin spiral and predict a decrease of the non-dimensional energy from 0.33 to 0.28, in accordance with experimental results. Our proposed model offers a practical alternative to the existing slug flow model to predict the minimum non-dimensional energy of a vortex ring. The model is applicable to piston-generated and wake vortex rings and only requires the kinematics of the vortex generator as input.
Balance as a Pre-Estimation Test for Time Series Analysis
Authors: Pickup Mark , Kellstedt Paul M.
Published: April 2022

It is understood that ensuring equation balance is a necessary condition for a valid model of times series data. Yet, the definition of balance provided so far has been incomplete and there has not been a consistent understanding of exactly why balance is important or how it can be applied. The discussion to date has focused on the estimates produced by the general error correction model (GECM). In this paper, we go beyond the GECM and beyond model estimates. We treat equation balance as a theoretical matter, not merely an empirical one, and describe how to use the concept of balance to test theoretical propositions before longitudinal data have been gathered. We explain how equation balance can be used to check if your theoretical or empirical model is either wrong or incomplete in a way that will prevent a meaningful interpretation of the model. We also raise the issue of “
$I(0)$
balance” and its importance.
‘Win-win’ contested: negotiating the privatisation of Africa's Freedom Railway with the ‘Chinese of today’
Authors: Zajontz Tim
Published: April 2022

As infrastructure development has become a key ingredient in Africa–China relations, the role of African governments in co-determining the design, funding and governance of the continent's infrastructures has come under close scrutiny. This article sheds light on the rehabilitation of a symbol of Sino–African friendship: the Tanzania–Zambia Railway Authority (TAZARA). Employing Jessop's strategic-relational approach, it is shown that the strategies of the shareholding governments in the negotiations with a Chinese consortium were informed by strategic learning from previous railway privatisations, corresponding cost–benefit analyses and reflection about Chinese commercial interests. Zambia's indebtedness and Tanzania's autocratic developmental state under President Magufuli formed crucial elements of the structural context in which the fate of Africa's Freedom Railway was negotiated. The article transcends both crudely structuralist accounts of a supposedly all-powerful China and voluntarist conceptions of African agency that are void of structure. Assessing (African) agency requires analytical sensitivity towards the dialectical interaction between specific strategic capacities and strategically selective political–economic contexts.
Hidden Identities, Forgotten Histories: Female Provincial Touring Artists in Britain, 1887–1900
Authors: Ince Bernard
Published: April 2022

Provincial touring companies of the late Victorian period, comprising mostly unknown actors and actresses, have received minimal scholarly attention until recently. The sheer number of ‘on-the-road’ artists who were employed in such enterprises from the late nineteenth century onwards increased to such an extent that to establish a framework for their individual and collective study presents significant challenges. This article addresses this problem by proposing a method, grounded in genealogy, that records the male and/or female artists of a given touring company over its full term without selective bias in order to establish a cohort of subjects for further examination. It tracks the touring companies of actor-manager Lawrence Daly, an individual unheard of today, between 1887 and 1900, the year of his death. One hundred and twenty-five female artists employed by Daly during this period are recovered, and their careers, family histories, and personal identities are subjected to statistical analysis. The conclusions drawn here not only contribute to the better understanding of the social history of non-elite female provincial artists of the late nineteenth century, but also afford the opportunity to shine a light on figures whose names, lives, and achievements are long forgotten. Further, a case is made for the method as the basis for a wide-ranging database of provincial touring companies and artists. Bernard Ince is an independent theatre historian who has contributed several articles on Victorian and Edwardian theatre to New Theatre Quarterly.
Deleuze, Beckett, and the Art of Multiplicity
Authors: Wilmer S. E.
Published: April 2022

The relationship between Gilles Deleuze and Samuel Beckett has excited many scholars and continues to be of major interest today. This article explores the Deleuzian concept of multiplicity by considering quantitative and qualitative multiplicities in Beckett’s work. In differentiating between these two types, Deleuze and Félix Guattari indicate that extensive or quantitative multiplicities are essentially numerical and can be counted and represented in space. This form of multiplicity is seen in Beckett’s use of various lists of items such as Molloy counting his sucking stones or Watt considering how to dispose of Mr Knott’s food. Qualitative multiplicities, by contrast, cannot be counted because they differ in kind from one another. They are represented in duration and are here observed in the minorization of language in How It Is, among other examples. S. E. Wilmer is Professor Emeritus of Drama at Trinity College in Dublin. His most recent publications include Performing Statelessness in Europe (Palgrave Macmillan, 2018) and (with co-editor Radek Przedpełski) Deleuze, Guattari, and the Art of Multiplicity (Edinburgh University Press, 2020). He is currently co-editing the Palgrave Handbook of Theatre and Migration.
Outbreak of delta variant SARS-CoV-2 virus on a psychogeriatric ward in Helsinki, Finland, August 2021: two-dose vaccination reduces mortality and disease severity amongst the elderly
Authors: Malik Adnan , Lehtola Laura , Isosomppi Sanna , Smura Teemu , Saarenheimo Jaana , Anttila Veli-Jukka , Särelä Eeva
Published: April 2022

We describe an outbreak of delta variant SARS-CoV-2 on a psychogeriatric ward of elderly patients. Retrospectively collected data was analysed using Fisher's exact test to assess the association between patients’ vaccination status and infection rates, severity of disease and mortality. Vaccination with two doses was shown to reduce severity of disease (5% vs. 75%, p < 0.001) and mortality (5% vs. 50%, p < 0.018) amongst an elderly inpatient population during an outbreak of delta variant SARS-CoV-2. Vaccination should be encouraged in elderly care institutions. Furthermore, adequate vaccination in elderly care institutions is an important consideration in current booster (third/fourth) dose schedules.
The impact of alcohol control policy on pneumonia mortality in Lithuania: an interrupted time-series analysis
Authors: Zafar Anush , Rehm Jürgen , Feng Xinyang , Jiang Huan , Kim Kawon Victoria , Manthey Jakob , Radišauskas Ričardas , Štelemėkas Mindaugas , Petkevičienė Janina , Tran Alexander , Lange Shannon
Published: April 2022

Despite the growing body of evidence suggesting that alcohol consumption is associated with an increased risk of and poorer treatment outcomes from pneumonia, little is known about the association between alcohol control policy and pneumonia mortality. As such, this study aimed to assess the impact of three alcohol control policies legislated in 2008, 2017 and 2018 in Lithuania on sex-specific pneumonia mortality rates among individuals 15+ years of age. An interrupted time-series analysis using a generalised additive mixed model was performed for each policy. Of the three policies, only the 2008 policy resulted in a significant slope change (i.e. decline) in pneumonia mortality rates among males; no significant slope change was observed among females. The low R2 values for all sex-specific models suggest that other external factors are likely also influencing the sex-specific pneumonia mortality rates in Lithuania. Overall, the findings from this study suggest alcohol control policy's targeting affordability may be an effective way to reduce pneumonia mortality rates, among males in particular. However, further research is needed to fully explore their impact.
Frontal EEG asymmetry moderates the relation between borderline personality disorder features and feelings of social rejection in adolescents
Authors: Stead Victoria E. , Schmidt Louis A. , Crowley Michael J. , Dyce Lisa , Hall Geoffrey B. , Van Lieshout Ryan J. , Boylan Khrista
Published: April 2022

Although associations among borderline personality disorder (BPD), social rejection, and frontal EEG alpha asymmetry scores (FAA, a neural correlate of emotion regulation and approach-withdrawal motivations) have been explored in different studies, relatively little work has examined these relations during adolescence in the same study. We examined whether FAA moderated the relation between BPD features and rejection sensitivity following a validated social exclusion paradigm, Cyberball. A mixed, clinical-community sample of 64 adolescents (females = 62.5%;Mage = 14.45 years;SD= 1.6; range = 11-17 years) completed psychodiagnostic interviews and a self-report measure of BPD (Time 1). Approximately two weeks later (Time 2), participants completed a resting EEG recording followed by Cyberball. FAA moderated the relation between BPD features and overall feelings of rejection following Cyberball: individuals with greater relative left FAA had the highest and lowest feelings of social rejection depending on whether they had high and low BPD feature scores, respectively. Results remained after controlling for age, sex, gender, depression, and BPD diagnosis. These results suggest that FAA may moderate the relation between BPD features and social rejection, and that left frontal brain activity at rest may be differentially associated with those feelings in BPD. Findings are discussed in terms of the link between left frontal brain activity in the regulation and dysregulation of social approach behaviors, characteristic of BPD.
Should the government subsidize innovation or automation?
Authors: Chu Angus C. , Cozzi Guido , Furukawa Yuichi , Liao Chih-Hsing
Published: April 2022

This study introduces automation into a Schumpeterian growth model to explore the effects of R&D and automation subsidies. R&D subsidy increases innovation and growth but decreases the share of automated industries and the degree of capital intensity in the aggregate production function. Automation subsidy has the opposite effects on these macroeconomic variables. Calibrating the model to US data, we find that raising R&D subsidy increases the welfare of high-skill workers but decreases the welfare of low-skill workers and capital owners, whereas increasing automation subsidy increases the welfare of high-skill workers and capital owners but decreases the welfare of low-skill workers. Therefore, whether the government should subsidize innovation or automation depends on how it evaluates the welfare gains and losses of different agents in the economy.
Caregivers’ provision of sweetened fruit-flavoured drinks to young children: importance of perceived product attributes and differences by socio-demographic and behavioural characteristics
Authors: Choi Yoon Y , Jensen Melissa L , Fleming-Milici Frances , Harris Jennifer L
Published: April 2022

Objective:

Drinks containing added sugar and/or non-nutritive sweeteners are not recommended for children under 6 years. Yet, most young children consume these products. The current study examined factors associated with caregivers’ provision of sweetened drinks to their young child.

Design:

Caregivers reported frequency of providing sweetened fruit-flavoured drinks (fruit drinks and flavoured water) and unsweetened juices (100 % juice and juice/water blends) to their 1- to 5-year-old child in the past month and perceived importance of product attributes (healthfulness, product claims and other characteristics), other drinks provided, reading the nutrition facts panel and socio-demographic characteristics. A partial proportional odds model measured the relationship between these factors and frequency of providing sweetened fruit-flavoured drinks.

Setting:

Online cross-sectional survey.

Participants:

U.S. caregivers (n 1763) with a young child (ages 1–5).

Results:

The majority (74 %) of caregivers provided sweetened fruit-flavoured drinks to their child in the past month; 26 % provided them daily. Provision frequency was positively associated with some drink attributes, including perceived healthfulness, vitamin C claims and box/pouch packaging; child requests and serving other sweetened drinks and juice/water blends. Provision frequency was negatively associated with perceived importance of ‘no/less sugar’ and ‘all natural’ claims. Reading nutrition facts panels, serving water to their child and child’s age were not significant.

Conclusion:

Misunderstanding of product healthfulness and other marketing attributes contribute to frequent provision of sweetened drinks to young children. Public health efforts to address common misperceptions, including counter marketing, may raise awareness among caregivers about the harms of providing sweetened drinks to young children.
Update Achalasie
Authors: Fetzner Ulrich Klaus , Trujillo Martha , Dimopoulos Ioannis , Hoffmann Marc Frederic , Berlth Felix , Mann Carolina , Grimminger Peter , Gerdes Berthold
Published: April 2022

Zusammenfassung. Die neurodegenerative Erkrankung Achalasie (veraltet: «Kardiaspasmus») stellt nach der Refluxerkrankung die zweithäufigste funktionelle Erkrankung des Ösophagus dar. Sie ist mit einem extrem hohen Leidensdruck für die Patienten verbunden. Pathophysiologisch handelt es sich um eine Kombination aus fehlender schluckreflektorischer Relaxation am Mageneingang und gestörter Peristaltik der tubulären Speiseröhre. Goldstandard in der Diagnostik ist die hochauflösende Manometrie. Die Erkrankung ist nicht heilbar, das therapeutisch Spektrum umfasst medikamentöse, endoskopisch-interventionelle und operative Verfahren.
Diagnostik und Therapie der gastroösophagealen Reflux-Krankheit im Kindesalter
Authors: Frongia Giovanni , Fetzner Ulrich Klaus , Vuille-dit-Bille Raphael Nicolas , Holland-Cunz Stefan Gerhard
Published: April 2022

Zusammenfassung. Bei Kindern mit gastroösophagealer Refluxkrankheit (GERD) sollen stets sämtliche konservativen und operativen Therapiemöglichkeiten gegeneinander abgewogen und eine individuelle, dem Patienten angepasste Lösung gefunden werden. Bei der Entscheidungsfindung soll ein interdisziplinäres Team die Patienten und deren Eltern beraten. Hierbei sollte möglichst frühzeitig ein Kinderchirurg miteinbezogen werden, um Möglichkeit, Vor- und Nachteile einer chirurgischen Intervention sowie den optimalen Zeitpunkt ebendieser frühzeitig zu besprechen. Entgegen der gegebenenfalls unbegründeten Befürchtung nicht operativer Disziplinen ist eine Fundoplicatio zur gezielten chirurgischen GERD-Therapie im Kindesalter meist komplikationsarm durchzuführen und in gründlich selektierten Fällen mit einem positiven Outcome verbunden. Die Erfüllung der hierfür entscheidenden Voraussetzungen ist eng an die Kenntnis der pädiatrischen Besonderheiten bezüglich Symptomatik, Diagnostik und Therapie, die Wahl der optimalen Operationstechniken und an eine langfristig gesicherte Nachsorge geknüpft. Die Eckpunkte dieser pädiatrischen Besonderheiten werden hier ausführlich erläutert.
Minimalinvasive Ösophagektomie für maligne Tumore der Speiseröhre
Authors: Berlth Felix , Hadzijusufovic Edin , Mann Carolina , Fetzner Ulrich Klaus , Grimminger Peter
Published: April 2022

Zusammenfassung. Die Ösophagektomie mit Magenhochzug und intrathorakaler oder zervikaler Ösophagogastrostomie stellt den Standardeingriff zur kurativen Behandlung von malignen Erkrankungen der Speiseröhre und des ösophagogastralen Überganges dar. Der Eingriff besitzt durch den Zugang zu zwei oder drei Körperhöhlen (Abdomen, Thorax, Hals) ein hohes Mass an Invasivität, was die Verwendung von minimalinvasiven Techniken zur Minimierung des Operationstraumas nahelegt. Auf der anderen Seite bedarf der Eingriff aufgrund der technischen Komplexität einer relevanten Lernkurve, insbesondere bei minimalinvasiver Operation. Mittlerweile stehen mit der konventionellen Laparoskopie/Thorakoskopie sowie der Robotic zwei unterschiedliche minimalinvasive Verfahren für die Ösophagektomie zur Verfügung, die sich in Behandlungszentren bereits bewährt und etabliert haben. Vorteile für den Patienten bestehen in reduzierter postoperativer Komplikation, insbesondere pulmonal sowie reduziertem postoperativen Schmerz. Die chirurgisch onkologische Radikalität der minimalinvasiven Verfahren ist mit der Radikalität offener und kombiniert minimalinvasiv/offener Verfahren mindestens gleichwertig, wobei Langzeitergebnisse hinsichtlich des Überlebens aus kontrollierten randomisierten Studien hier noch ausstehen. Die robotische Operationstechnologie hat sich in der vergangenen Dekade in der Chirurgie etabliert und die Ösophagektomie bietet eine sinnvolle Anwendungsmöglichkeit. Durch stetige Weiterentwicklung wird mit einem hohen Stellenwert der robotischen Chirurgie in Zukunft gerechnet. Hinsichtlich der onkologischen Ösophagusresektion wertet die laufende ROBOT-2-Studie mögliche Vorteile der robotischen Verfahrens gegenüber dem konventionell laparoskopisch/thorakoskopischen Verfahren aus.
Akute Erkrankungen des Ösophagus – Ösophagitis
Authors: Gerdes Christoph , Neesse Albrecht
Published: April 2022

Zusammenfassung. Eine Entzündung der Speiseröhre kann durch Reflux im Sinne einer erosiven Ösophagitis, eine infektiöse oder medikamentöse Genese oder durch eine immunvermittelte Reaktion auf Allergene verursacht sein. Zudem kann eine Bestrahlung eine Ösophagitis auslösen. Selten ist sie Teil einer systemischen Erkrankung wie zum Beispiel Morbus Crohn [1, 2]. Symptome umfassen Sodbrennen, retrosternale Schmerzen, Dysphagie, Steckenbleiben von Nahrung, Odynophagie und Foetor ex ore [3]. Komplikationen wie Blutungen, Stenosen und Strikturen können die Folge sein. Die Diagnostik umfasst die Anamnese inklusive der Medikamentenanamnese, die körperliche Untersuchung mit besonderem Augenmerk auf orale Manifestationen und als wichtigstes diagnostisches Mittel die flexible hochauflösende Endoskopie. Bei der Endoskopie wird der makroskopische Befund beurteilt, in welchem sich häufig Ulzera und Erosionen darstellen, sowie Biopsien und mikrobiologische Proben gewonnen.
Biased Witnesses: Crystal Thermal Records May Give Conflicting Accounts of Magma Cooling
Authors: Culha C. , Keller T. , Suckale J.
Published: April 2022

Crystals retain an imprint of the dynamic changes within a magma reservoir and hence contain invaluable information about the evolving conditions inside volcanic plumbing systems. However, instead of telling a single, simple story, they comprise overprinted evidence of numerous processes relating to temperature, pressure and composition that drive crystal precipitation and dissolution in magmatic systems. To decipher these different elements in the story that crystals tell, we attempt to identify the observational signatures of a simple, yet ubiquitous process: crystal precipitation and dissolution during magma cooling. To isolate this process in a complex magmatic system with intricate dynamic feedbacks, we assume that synthetic crystals precipitate and dissolve rapidly in response to deviations from thermodynamic equilibrium. In our crystalline‐scale simulations, synthetic crystals drag along the cooler‐than‐ambient melt in which they precipitated and can drive a temperature‐dependent, crystal‐driven convection. We analyze the non‐dimensional conditions for this coupled convection and record the heterogeneous thermal histories that synthetic crystals in this flow regime experience. We show that many synthetic crystals dissolve, loosing their thermal record of the convection. Based on our findings, we suggest that heterogeneity in the thermal history of crystals is more indicative of local, crystal‐scale processes than the overall, system‐wide cooling trend.
Understanding the Importance of Salt Marshes
Authors: Xin Pei , Wilson Alicia , Ge Zhenming , Santos Isaac
Published: April 2022

Hydrological processes affect plant ecology and the biogeochemical exchange between salt marshes and the sea.
Community Science Builds a Seismic Network in Haiti
Authors: Samuels Fionna
Published: April 2022

Small, inexpensive seismometers are capable of sharing high-quality data in real time—and were put to the test during an August 2021 earthquake.
Effect of natural and commercially produced juices on colour stability of microhybrid and nanohybrid composites
Authors: Meshki Razieh , Rashidi Marjan
Published: April 2022

Objective

This study aims to evaluate the discoloration rate of two types of composites, microhybrid and nanohybrid, after exposure to natural and commercially-produced juices.

Materials and methods

In this experimental study, 90 disc-shaped specimens with a thickness of 2 mm and a diameter of 10 mm were taken from two composites, microhybrid P4 (Kerr-ITALY) and nanohybrid Filtek Z250XT (3M-ESPE-USA) (two groups of 45). Then, the samples of each group were divided into five subgroups of nine and were immersed for 10 days for 4 h in five solutions of commercially-produced orange juice, natural orange juice, commercially-produced pomegranate juice, natural pomegranate juice, and distilled water (control group). The colour of the samples was measured by a reflective spectrophotometer using the CLEl*a*b colour space at baseline and after discoloration.

Result

The independent t-test showed that the mean discoloration rate (∆E) of nanohybrid composite exposed to commercially-produced orange juice, natural pomegranate juice, and commercially-produced pomegranate juice was significantly higher than microhybrid composite (P < 0.01). In addition, the test found that the highest discoloration rate of the nanohybrid composite was related to the effect of commercially-produced orange juice (∆E = 13.03) and the highest discoloration rate of microhybrid composite was related to the effect of natural pomegranate juice (∆E = 4.79).

Conclusion

According to the results, it seems that microhybrid composites are more resistant to discoloration than nanohybrid composites. According to the results, consumption of dyed drinks, particularly natural pomegranate juice, commercially-produced orange juice, and commercially-produced pomegranate juice, is not recommended in the first few days after composite restoration.
Adding bendamustine to melphalan before ASCT improves CR rate in myeloma vs. melphalan alone: A randomized phase-2 trial
Authors: Farag Sarah , Bacher Ulrike , Jeker Barbara , Legros Myriam , Rhyner Gaelle , Lüthi Jean-Marc , Schardt Julian , Zander Thilo , Daskalakis Michael , Mansouri Behrouz , Manz Chantal , Pabst Thomas
Published: April 2022

Definite cure remains exceptional in myeloma patients even after high-dose chemotherapy (HDCT) with melphalan (Mel) and autologous stem cell transplantation (ASCT). Thus, improving efficacy of HDCT in MM remains an unresolved issue. This randomized phase II trial compared standard 200 mg/m2 Mel HDCT to experimental HDCT with 200 mg/m2 bendamustine, given both at days −4 and −3, combined with 100 mg/m2 melphalan at days −2 and −1 (BenMel) before ASCT as first-line consolidation in myeloma patients. The primary endpoint aimed to identify at least a 15% improvement in the complete remission rate (stringent CR + CR) after HDCT with BenMel compared with Mel alone. A total of 120 MM patients were 1:1 randomized. The rate of sCR/CR after ASCT was higher in BenMel than in Mel treated patients (70.0% vs. 51.7%; p = 0.039). Three patients in the BenMel group (5.0%) had reversible acute renal insufficiency compared with none in Mel patients. Minimal residual disease negativity (<10-5) by flow cytometry was observed in 26 (45.6%) BenMel patients and 22 (37.9%) in the Mel group (p = 0.375). Our data suggest that BenMel HDCT is safe and improves the sCR/CR rate compared with standard Mel alone.
Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic
Authors: Tontsch-Grunt Ulrike , Traexler Paula-Elena , Baum Anke , Musa Hanny , Marzin Kristell , Wang Shaonan , Trapani Francesca , Engelhardt Harald , Solca Flavio
Published: April 2022

Background

BET inhibitors have been tested in several clinical trials where, despite encouraging preclinical results, substantial clinical benefit in monotherapy remains limited. This work illustrates the translational challenges and reports new data around the novel BET inhibitor, BI 894999. At clinically achievable concentrations, mechanistic studies were carried out to study pathway modulation and rational drug combinations.

Methods

BRD-NUT fusions are oncogenic drivers in NUT carcinoma (NC). The effects of BI 894999 on proliferation, chromatin binding and pathway modulation were studied in NC in vitro. These studies were complemented by efficacy studies either as a single agent or in combination with the clinical p300/CBP inhibitor CCS1477.

Results

Based on the modelling of preclinical and clinical data, we proposed and implemented a new clinical scheduling regimen. This led to plasma levels sufficient to fully dislodge BRD-NUT from chromatin and to sustained and pronounced pharmacodynamic (PD) modulation of HEXIM1 and HIST2H2BF. Platelet counts in patient blood samples were improved compared to previous schedules. Rational combination studies of BI 894999 performed at clinically meaningful concentrations led to tumour regressions in all NC xenograft models tested.

Conclusions

BI 894999 holds significant potential as a combination drug and CCS1477 p300/CBP inhibitor is a promising partner for future clinical trials.