bluuebunny/crossref_metadata_2025 huggingface dataset:
Low‐copy transgene detection using nested digital polymerase chain reaction for gene‐doping control
Authors: Tozaki Teruaki , Ohnuma Aoi , Hamilton Natasha A. , Kikuchi Mio , Ishige Taichiro , Kakoi Hironaga , Hirota Kei‐ichi , Kusano Kanichi , Nagata Shun‐ichi
Published: October 2021

Gene doping is prohibited for fair competition in human and horse sports. One style of gene doping is the administration of an exogeneous gene, called a transgene, to postnatal humans and horses. Although many transgene detection methods based on quantitative polymerase chain reaction (PCR), including real‐time PCR and digital PCR, have been recently developed, it remains difficult to reliably detect low‐copy transgenes. In this study, we developed and validated a nested digital PCR method to specifically detect low‐copy transgenes. The nested digital PCR consists of (1) preamplification using conventional PCR and (2) droplet digital PCR detection using a hydrolysis probe. Using 5, 10, 20, 60 and 120 transgene copies as template, 496.0, 1089.7, 1820.7, 4313.3 and 7840.0 copies per microlitre, respectively, were detected using our nested digital PCR. Although high concentrations of phenol, proteinase K, ethanol, EDTA, heparin and genomic DNA all inhibited preamplification, their effects on the digital PCR detection were limited. Once preamplification was successful, even substitution of bases within the primers and probes had minimal effects on transgene detection. The nested digital PCR developed in this study successfully detected low‐copy transgenes and can be used to perform a qualitative test, indicating its usefulness in the prevention of false positives and false negatives in gene‐doping detection.
E‐Cadherin restricts mast cell degranulation in mice
Authors: Klewer Theres , Bakic Ljubica , Müller‐Reichert Thomas , Kiewisz Robert , Jessberger Gregor , Kiessling Nadine , Roers Axel , Jessberger Rolf
Published: October 2021

Crosslinking of FcεRI‐bound IgE triggers the release of a large number of biologically active, potentially anaphylactic compounds by mast cells. FcεRI activation ought to be well‐controlled to restrict adverse activation. As mast cells are embedded in tissues, adhesion molecules may contribute to limiting premature activation. Here, we report that E‐Cadherin serves that purpose. Having confirmed that cultured mast cells express E‐Cadherin, a mast‐cell‐specific E‐Cadherin deficiency, Mcpt5‐Cre E‐Cdhfl/fl mice, was used to analyze mast cell degranulation in vitro and in vivo. Cultured peritoneal mast cells from Mcpt5‐Cre E‐Cdhfl/fl mice were normal with respect to many parameters but showed much‐enhanced degranulation in three independent assays. Soluble E‐Cadherin reduced the degranulation of control cells. The release of some newly synthesized inflammatory cytokines was decreased by E‐Cadherin deficiency. Compared to controls, Mcpt5‐Cre E‐Cdhfl/fl mice reacted much stronger to IgE‐dependent stimuli, developing anaphylactic shock. We suggest E‐Cadherin‐mediated tissue interactions restrict mast cell degranulation to prevent their precocious activation.
Study on the wear of spiral drum cutting coal containing rock
Authors: Liu Hongmei
Published: October 2021

Significant load fluctuations are encountered when cutting the coal rock using the shearer spiral drum, causing excessive drum wear. Thus, a coupling discrete element model of coal‐rock was developed, and the discrete element method and multi‐body dynamics were used to build a two‐way coupling simulation model of coal rock drum cutting. The drum wear was analyzed, along with the pick and spiral blade wear positions. The results have shown that the pick wear is primarily concentrated at the pick tip and the shaft shoulder, while the outer spiral blade edge blade is generally worn near the pick root. The maximum wear depth obtained in the simulation was 0.00316 mm. The tangential cumulative energy of the drum and the normal cumulative energy were 1.794e5 and 7.819e4 J, respectively. The friction wear of the drum was more prominent compared to the impact wear. By using a single factor method, the relationship between the drum rotational speed, traction speed, rock firmness coefficient, cutting depth, and spiral blade angle, and drum wear was obtained. Finally, it was concluded that the study at hand provides a quick and straightforward way to study drum wear law.
ResectVol: A tool to automatically segment and characterize lacunas in brain images
Authors: Casseb Raphael F. , de Campos Brunno M. , Morita‐Sherman Marcia , Morsi Amr , Kondylis Efstathios , Bingaman William E. , Jones Stephen E. , Jehi Lara , Cendes Fernando
Published: October 2021

Objective

To assess and validate the performance of a new tool developed for segmenting and characterizing lacunas in postoperative MR images of epilepsy patients.

Methods

A MATLAB‐based pipeline was implemented using SPM12 to produce the 3D mask of the surgical lacuna and estimate its volume. To validate its performance, we compared the manual and automatic lacuna segmentations obtained from 51 MRI scans of epilepsy patients who underwent temporal lobe resections.

Results

The code is consolidated as a tool named ResectVol, which can be run via a graphical user interface or command line. The automatic and manual segmentation comparison resulted in a median Dice similarity coefficient of 0.77 (interquartile range: 0.71‐0.81).

Significance

Epilepsy surgery is the treatment of choice for pharmacoresistant focal epilepsies, and despite the extensive literature on the subject, we still cannot predict surgical outcomes accurately. As the volume and location of the resected tissue are fundamentally relevant to this prediction, researchers commonly perform a manual segmentation of the lacuna, which presents human bias and does not provide detailed information about the structures removed. In this study, we introduce ResectVol, a user‐friendly, fully automatic tool to accomplish these tasks. This capability enables more advanced analytical techniques applied to surgical outcomes prediction, such as machine‐learning algorithms, by facilitating coregistration of the resected area and preoperative findings with other imaging modalities such as PET, SPECT, and functional MRI ResectVol is freely available at https://www.lniunicamp.com/resectvol.
E. coli and the etiology of human PBC: Antimitochondrial antibodies and spreading determinants
Authors: Yang Yao , Choi Jinjung , Chen Ying , Invernizzi Pietro , Yang Guoxiang , Zhang Weici , Shao Ti‐hong , Jordan Frank , Nemeria Natalia S. , Coppel Ross L. , Ridgway William M. , Kurth Mark , Ansari Aftab A. , Leung Patrick S.C. , Gershwin M. Eric
Published: October 2021

Background and Aims

The increased frequency of urinary tract infections in patients with primary biliary cholangitis (PBC) and the cross‐reactivity between the lipoyl domains (LD) of human pyruvate dehydrogenase complex (hPDC‐E2) and Escherichia coli PDC‐E2 (ePDC‐E2) have long suggested a role of E. coli in causality of PBC. This issue, however, has remained speculative. We hypothesized that by generating specific constructs of human and E. coli PDC‐E2, we would be able to assess the specificity of autoantibody responses and define whether exposure to E. coli in susceptible hosts is the basis for the antimitochondrial antibody (AMA) response.

Approach and Results

Importantly, the reactivity of hPDC‐E2 LD (hPDC‐E2LD) affinity‐purified antibodies against hPDC‐E2LD could only be removed by prior absorption with hPDC‐E2LD and not ePDC‐E2, suggesting the presence of unique human PDC‐E2 epitopes distinct from E. coli PDC‐E2. To identify the autoepitope(s) present in hPDC‐E2LD, a more detailed study using a variety of PDC‐E2 constructs was tested, including the effect of lipoic acid (LA) on ePDC‐E2 conformation and AMA recognition. Individual recombinant ePDCE2 LD domains LD1, LD2 and LD3 did not react with either AMA or antibodies to LA (anti‐LA), but in contrast, anti‐LA was readily reactive against purified recombinant LD1, LD2, and LD3 expressed in tandem (LP); such reactivity increased when LP was precultured with LA. Moreover, when the three LD (LD1, LD2, LD3) domains were expressed in tandem in pET28a or when LD1 was expressed in another plasmid pGEX, they were lipoylated and reactive to PBC sera.

Conclusions

In conclusion, our data are consistent with an exposure to E. coli that elicits specific antibody to ePDC‐E2 resulting in determinant spreading and the classic autoantibody to hPDC‐E2LD. We argue this is the first step to development of human PBC.
Privatization, Deregulation, and Capital Accumulation
Authors: Glomm Gerhard , Méndez Fabio
Published: October 2021

In this paper, we study how the privatization and deregulation of intermediate goods industries influence capital accumulation. Our model is solved under three alternative scenarios: (i) the intermediate sector is composed of a public monopoly under government control; (ii) the intermediate sector is dominated by a private monopoly; and (iii) the intermediate sector is competitive. The comparison of these models suggests that the income benefits of state‐to‐market transitions are mostly due to increased competition on the deregulated market and that the privatization of state enterprises is not likely to generate significant changes in the economy when the public monopoly is replaced by a private monopoly. We find that elimination of monopoly rights can increase aggregate income significantly.
When Less Is More: Optimal Patent Breadth under the Threat of Patent Validity Challenges
Authors: Yiannaka Amalia
Published: October 2021

This article determines the optimal breadth of patent protection for a drastic process innovation when the innovator faces the likelihood of a direct patent validity challenge by a third party and potential entry and infringement by a competitor who provides a technologically equivalent process. The effect of the innovator's patent breadth decision on the entrant's incentive to generate a competing process and on the entrant's ability to enter the market is also examined. Analytical results show that the greater the patent breadth, the smaller the entrant's incentive to develop a non‐infringing process and the optimal flow of research and development spending. However, when patent breadth can be used to deter entry, the incumbent always prefers to deter entry by choosing the smallest patent breadth possible that could achieve entry deterrence. In addition, when entry cannot be deterred, it is never optimal for the incumbent to claim the maximum patent breadth possible.
Research Choice and Finance in University Bioscience
Authors: Buccola Steven , Ervin David , Yang Hui
Published: October 2021

Academic bioscience's rising importance for downstream technology and growing private sector relationships have evoked substantial policy attention. We contribute to the scrutiny by asking how university bioscientists design and finance their research, with particular attention to the mutuality of research portfolio choice and funding success. The analysis requires consideration of other major influences on academic science, including scientific norms, human capital, and institutional environment. Drawing on a national survey of university bioscientists, we find that public financial support encourages more basic investigation and private support encourages more applied investigation. Yet downstream research is only moderately more excludable than upstream. Once research basicness and other program factors are accounted for, neither the next public nor the next private dollar brings significantly more excludable laboratory discoveries. Public money is attracted to applied and excludable research, and private and public funding crowd each other out at the margin. Professional norms have substantial impacts on the research pursued and financing obtained.
An integrative multilevel review of thriving at work: Assessing progress and promise
Authors: Goh Zen , Eva Nathan , Kiazad Kohyar , Jack Gavin A. , De Cieri Helen , Spreitzer Gretchen M.
Published: October 2021

Thriving at work is a notable construct given its role in individual health and developmental outcomes. According to the Socially Embedded Model of Thriving (SEMT), individuals thrive at work when embedded in environments that support agentic behaviors and can self‐sustain this state through positive spirals of agentic behaviors, resources, and thriving. The SEMT is inherently multilevel, yet there are two unarticulated but critical multilevel issues in existing scholarship: a paucity of research reflecting these multilevel features of the SEMT and an incipient multilevel conceptualization of thriving that has little theoretical justification. As a catalyst for progress, we present an integrative review drawing from the SEMT and other supplementary theoretical perspectives to define a multilevel conceptualization of thriving at work. Through this lens, we organize, synthesize, and evaluate the body of evidence, integrating the multilevel view of thriving within established scholarship. To substantiate our framework theoretically, we articulate how lower level processes unfold to develop higher level collective manifestations of thriving at work. We identify opportunities for theoretical and empirical advancement, coupled with specific, actionable recommendations, to deepen a multilevel conceptualization of thriving. Altogether, we advance thriving at work as a multilevel construct meaningful at three levels—individuals, dyads, and collectives.
The cross‐level moderating effect of team task support on the nonlinear relationship between proactive personality and employee reflective learning
Authors: Yang Huadong , van der Heijden Beatrice , Shipton Helen , Wu Chiahuei
Published: October 2021

Reflective learning is a fundamental part of human learning and development and has attracted attention from management scholars as well as practitioners. In this study, we build on trait activation theory and investigate how proactive personality and team task support jointly influence employee reflective learning. Using a questionnaire survey, we collected data at two time points from 154 participants nested in 37 teams in five organizations in the United Kingdom. The results from multilevel analyses showed that proactive personality had a positive effect on reflective learning up to a certain point. Over and above this inflection point, this positive effect ceased to further increase. In addition, the nonlinear effect of proactive personality on reflective learning was much stronger when team task support was weak than when it was strong. The finding regarding the nonlinear relationship extends our understanding of the effect of proactive personality. The cross‐level moderating effect of team task support suggests a complementary perspective to appreciate the interactions between proactive personality and its relevant situational characteristics. Practitioners can use these findings to design effective intervention plans and facilitate employee reflective learning in specific settings and in workplace learning in general.
Polyurea Modified with 4‐Dihydropyrimidone‐2‐ketone Rings by Biginelli Reaction and its Boostered AIE Characteristic
Authors: Zhang Da , Zheng Jinxin , Zhang Pengfei , Zhao Ronghui , Chen Zhuo , Wang Meng , Deng Kuilin
Published: October 2021

In the synthesis of traditional AIE‐active polymers with conjugate or multi‐benzene system, the troublesome process is still faced such as consuming time, high temperature, catalysis, no water or vacuum, and so on. In this study, the polydihydropyrimidone derivatives (PDPMDs) with AIE properties are facilely synthesized by the introduction of 4‐dihydropyrimidone rings onto non‐AIE‐active intermediate polyureas (PUs) in Biginelli reaction. It is found that the unsymmetrical L‐lysine ethyl diisocyanate and butylenediamine played a very important role in the smooth preparation and fluorescence enhancement of PDPMDs. Compared with the intermediate PUs, the fluorescence of PDPMDs is significantly enhanced (35‐fold increase), which is mainly due to the intramolecular aggregation of dihydropyrimidone rings on PUs chains. At the same time, with the increase of the content of dihydropyrimidone rings, the fluorescence intensity of PDPMDs also increases, and the emission wavelength shows an obvious red shift. The fluorescence of PDPMDs also showed obvious dependence on excitation wavelength, which further reveals the clusterization‐triggering emission (CTE) mechanism. In summary, the strategy of endowing AIE properties to non‐AIE active polymer by introducing heterocycles into the backbone through multi‐component reaction provides useful guidance for AIE functionalization of other non‐AIE materials.
Reducing systematic errors due to deformation of organs at risk in radiotherapy
Authors: Rørtveit Øyvind Lunde , Hysing Liv Bolstad , Stordal Andreas Størksen , Pilskog Sara
Published: October 2021

Purpose

In radiotherapy (RT), the planning CT (pCT) is commonly used to plan the full RT‐course. Due to organ deformation and motion, the organ shapes seen at the pCT will not be identical to their shapes during RT. Any difference between the pCT organ shape and the organ's mean shape during RT will cause systematic errors. We propose to use statistical shrinkage estimation to reduce this error using only the pCT and the population mean shape computed from training data.

Methods

The method was evaluated for the rectum in a cohort of 37 prostate cancer patients that had a pCT and 7–10 treatment CTs with rectum delineations. Deformable registration was performed both within‐patient and between patients, resulting in point‐to‐point correspondence between all rectum shapes, which enabled us to compute a population mean rectum. Shrinkage estimates were found by combining the pCTs linearly with the population mean.

The method was trained and evaluated using leave‐one‐out cross validation. The shrinkage estimates and the patient mean shapes were compared geometrically using the Dice similarity index (DSI), Hausdorff distance (HD), and bidirectional local distance. Clinical dose/volume histograms, equivalent uniform dose (EUD) and minimum dose to the hottest 5% volume (D5%) were compared for the shrinkage estimate and the pCT.

Results

The method resulted in moderate but statistically significant increase in similarity to the patient mean shape over the pCT. On average, the HD was reduced from 15.6 to 13.4 mm, while the DSI was increased from 0.74 to 0.78. Significant reduction in the bias of volume estimates was found in the DVH‐range of 52.5–65 Gy, where the bias was reduced from −1.3 to −0.2 percentage points, but no significant improvement was found in EUD or D5%,

Conclusions

The results suggest that shrinkage estimation can reduce systematic errors due to organ deformations in RT. The method has potential to increase the accuracy in RT of deformable organs and can improve motion modeling.
Screening for von Willebrand disease does not impact posttonsillectomy bleeding in a low‐risk population
Authors: Digiandomenico Stefanie , Conley Stephen F. , Johnson Victoria P. , Christopherson Pamela A. , Haberichter Sandra L. , Zhang Jian , Simpson Pippa , Abshire Thomas C. , Montgomery Robert R. , Flood Veronica H.
Published: October 2021

Background

Bleeding is an important complication in children following tonsillectomy. Screening with coagulation tests prior to procedure is common to assess bleeding risk in the perioperative period, although ASH/ASPHO Choosing Wisely guidelines recommend against routine PT/PTT testing. Our aim was to compare von Willebrand factor antigen (VWF:Ag) and activity levels among patients with postoperative bleeding following tonsillectomy to evaluate for potential risk for bleeding.

Procedure

Eligible subjects were aged 0–18 without significant personal or family history of major bleeding. Postoperative bleeding diaries were collected and symptoms measured using a postoperative bleeding score. Plasma VWF levels were drawn at time of anesthesia administration.

Results

Postoperative bleeding occurred in 248 cases out of 1399 total subjects. Median VWF:Ag was 86 in patients with postoperative bleeding scores of 1–2, 86 for scores 3–4, 84 for scores 5–6, and 83 for scores >6, with no significant difference among groups (p = .98). Additionally, no difference was observed for subjects with multiple days of postoperative bleeding as compared to those with only 1 day of postoperative bleeding. Finally, no difference in VWF:Ag was observed for subjects whose first reported bleed occurred early in the postoperative course compared to those whose first reported bleed occurred later. VWF:Ag does not correlate with severity of bleeding, time of onset of first bleeding event, or recurrence of bleeding in healthy children with no personal or family history of bleeding who have postoperative bleeding following tonsillectomy.

Conclusions

This data does not support routine von Willebrand disease screening prior to tonsillectomy.
Long‐term health‐related quality of life in young childhood cancer survivors and their parents
Authors: Fardell Joanna E. , Wakefield Claire E. , De Abreu Lourenco Richard , Signorelli Christina , McCarthy Maria , McLoone Jordana , Osborn Michael , Gabriel Melissa , Anazodo Antoinette , Alvaro Frank , Lockwood Liane , Walwyn Thomas , Skeen Jane , Tillemans Ramon , Cohn Richard J. ,   ANZCHOG Survivorship Group
Published: October 2021

Purpose

Few studies have investigated the health‐related quality of life (HRQoL) of young childhood cancer survivors and their parents. This study describes parent and child cancer survivor HRQoL compared to population norms and identifies factors influencing child and parent HRQoL.

Methods

We recruited parents of survivors who were currently <16 years, and >5 years postdiagnosis. Parents reported on their child's HRQoL (Kidscreen‐10), and their own HRQoL (EQ‐5D‐5L). Parents rated their resilience and fear of cancer recurrence and listed their child's cancer‐related late effects.

Results

One hundred eighty‐two parents of survivors (mean age = 12.4 years old and 9.7 years postdiagnosis) participated. Parent‐reported child HRQoL was significantly lower than population norms (48.4 vs. 50.7, p < .009). Parents most commonly reported that their child experienced sadness and loneliness (18.1%). Experiencing more late effects and receiving treatments other than surgery were associated with worse child HRQoL. Parents’ average HRQoL was high (0.90) and no different to population norms. However 38.5% of parents reported HRQoL that was clinically meaningfully different from perfect health, and parents experienced more problems with anxiety/depression (43.4%) than population norms (24.7%, p < .0001). Worse child HRQoL, lower parent resilience, and higher fear of recurrence was associated with worse parent HRQoL.

Conclusions

Parents report that young survivors experience small but significant ongoing reductions in HRQoL. While overall mean levels of HRQoL were no different to population norms, a subset of parents reported HRQoL that was clinically meaningfully different from perfect health. Managing young survivors’ late effects and improving parents’ resilience through survivorship may improve HRQoL in long‐term survivorship.
Association between weight change and remission of type 2 diabetes: a retrospective cohort study in primary care
Authors: Dambha‐Miller Hajira , Hounkpatin Hilda , Stuart Beth , Farmer Andrew
Published: October 2021

The purpose of this study was to quantify the association between weight change and the likelihood of remission of type 2 diabetes in a population‐based cohort without intensive interventions.

We undertook a retrospective analysis of adults with type 2 diabetes registered across 150 primary care practices in Southern England, United Kingdom, within the electronic Care and Health Information Analytics (CHIA) database between 2013 and 2020. Stepwise mixed logistic models were constructed to examine the association between percentage weight change over five‐years, and the likelihood of remission in the subsequent two years using four categories: weight gain ≥2.5%; weight loss ≤2.5–5% or ≥5–10% or ≥10%.

The study cohort included 56,120 people with type 2 diabetes with a mean (SD) disease duration of 8.0 (6.7) years. In total, 17,035 (30.4%) had microvascular complications and 10,661 (19.0%) had macrovascular complications. A total of 19.4% (10,896) lost ≥10% of their baseline weight with 1646 (15.1%) of these achieving remission. Overall, those who lost ≥10% in weight had a significantly higher likelihood of remission in both unadjusted and adjusted models; RR 1.53 (95% CI 1.40–1.68); and RR 1.51 (95% CI 1.37–1.66), respectively. Remission was still achievable but less likely among younger men with a longer diabetes duration (≥5 years), higher baseline HbA1c level, or pre‐existing microvascular or macrovascular complications.

It was concluded weight loss of >10% is associated with remission of type 2 diabetes even among those with advanced disease and established microvascular or macrovascular complications. Our findings could motivate people with diabetes to lose weight in order to increase likelihood of remission. Copyright © 2021 John Wiley & Sons.
Synergistic effects of cellulose nanocrystals‐organic montmorillonite as hybrid nanofillers for enhancing mechanical, crystallization, and heat‐resistant properties of three‐dimensional printed poly(lactic acid) nanocomposites
Authors: Liu Hao , Zhang Bao , Zhou Laihong , Li Jinbo , Zhang Jiacheng , Chen Xiao , Xu Shunjian , He Hui
Published: October 2021

Cellulose nanocrystals (CNC)‐organic montmorillonite (OMMT) hybrid nanofillers were prepared, and their effects in reinforcing the performance of three‐dimensional (3D) printed poly(lactic acid) (PLA) nanocomposites were studied. The results indicated that the hybrid CNC‐OMMT nanofillers had a synergistic impact on enhancing the mechanical properties of PLA nanocomposites compared to either single nanofillers (CNC or OMMT). The dispersion of CNC‐OMMT in the PLA matrix was not only significantly improved, but also the hybrid nanofillers did not form pore defects in the nanocomposites. In terms of the crystallization performance, the multidimensional hybrid nanofillers acted as efficient heterogeneous‐nucleating agents and increased the PLA crystallization rate. Additionally, the incorporation of the hybrid nanofillers improved the heat resistance of the PLA nanocomposites when the printing platform temperature was adjusted to a temperature within the crystallization temperature range of PLA. The preparation of hybrid nanofillers based on existing nanomaterials and their incorporation into polymers creates a novel route for the development of high‐performance polymer nanocomposites.
Elevated acute phase proteins affect pharmacokinetics in COVID‐19 trials: Lessons from the CounterCOVID ‐ imatinib study
Authors: Bartelink Imke H. , Bet Pierre M. , Widmer Nicolas , Guidi Monia , Duijvelaar Erik , Grob Bram , Honeywell Richard , Evelo Amanda , Tielbeek Ivo P. E. , Snape Sue D. , Hamer Henrike , Decosterd Laurent A. , Jan Bogaard Harm , Aman Jurjan , Swart Eleonora L.
Published: October 2021

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID‐19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID‐19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax) and trough concentration (Ctrough) were 2.32‐fold (95% confidence interval [CI] 1.34–3.29), 2.31‐fold (95% CI 1.33–3.29), and 2.32‐fold (95% CI 1.11–3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID‐19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1‐acid glycoprotein (AAG) concentrations measured in patients with COVID‐19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG‐PK‐Model) gave an estimated mean (SD) prediction error (PE) of −20% (31%) for total and −7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID‐19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID‐19.
Efficacy of Persian medicine herbal formulations (capsules and decoction) compared to standard care in patients with COVID‐19, a multicenter open‐labeled, randomized, controlled clinical trial
Authors: Karimi Mehrdad , Zarei Azadeh , Soleymani Samaneh , Jamalimoghadamsiahkali Saeidreza , Asadi Asmaa , Shati Mohsen , Jafari Mohieddin , Rezadoost Hassan , Kordafshar Gholamreza , Naghizadeh Ayeh , Mardi Raefeh , Namiranian Parva , Khamechi Seyed Peyman , Ansari Narges , Adel Mehraban Mohammad Sadegh , Aliakbarzadeh Hananeh , Khanavi Mahnaz , Esmaealzadeh Niusha , Moravveji Alireza , Salahi Mehrdad , Khoi Maryam , Razzaghi Reza , Banafshe Hamid Reza , Alizadeh Mostafa , Akhbari Marzieh , Atharizadeh Mina , Izadikhah Akram , Elsagh Mahin , Hossein Zade Ghahnavieh Mahdi , Eghbalian Fatemeh , Vanai Azam , Izadi Hossein , Moravej Seyed Ali Al‐hadi , Jazayeri Seyede Ferdos , Bayat Houman , Emadi Koochak Hamid , Zargaran Arman
Published: October 2021

Persian medicine has recommended clinical experiences and proper herbal remedies for prevention and treatment of microbial infections and respiratory diseases. An open‐label, randomized, controlled, multicenter trial was conducted at five hospitals in Tehran and Isfahan provinces of Iran on 358 hospitalized adult patients. A total of 174 patients received standard care and 184 received herbal remedies (polyherbal decoction every 8 hr and two herbal capsules every 12 hr) plus standard care for 7 days. The primary clinical endpoint was the duration of hospital stay, and secondary outcomes were clinical improvement of symptoms based on self‐assessment questionnaire. Results demonstrated that these natural decoction and capsules treatment plus routine care significantly decreased duration of hospital dyspnea (3.291 day vs. 6.468 days), accelerated clinical improvement, and decreased symptoms such as dry cough, dyspnea, muscle pain, headache, fatigue, anorexia, chills, runny nose, sputum cough, and vertigo in the treatment group compared with standard‐care group. Significant effects of these polyherbal formulations on improving the symptoms of COVID‐19 could be incredibly promising for managing this pandemic with acceptable tolerability.
Study of a Selected Series of 3‐ and 4‐Arylcoumarins as Antifungal Agents against Dermatophytic Fungi: T. rubrum and T. mentagrophytes
Authors: Lopez Cisneros Carmen Lucía , Cazar Ramírez María Elena , Bailon‐Moscoso Natalia , Guardado Estela , Borges Fernanda , Uriarte Eugenio , Matos Maria João
Published: October 2021

The main etiological agents in dermatophytosis of human skin and nails are Trichophyton, in particular Trichophyton rubrum (T. rubrum) and Trichophyton mentagrophytes (T. mentagrophytes). A new series of twenty‐three 3‐ and 4‐arylcoumarins was synthesized and the antifungal activities against clinical isolates of T. rubrum and T. mentagrophytes were evaluated. Sixteen out of twenty‐three molecules exhibited antifungal activity against one or both fungi strains. In some cases, the activity against T. rubrum has been comparable to fluconazole, one of the standards, being 8‐methoxy‐3‐(4’‐nitrophenyl)coumarin (16) the best compound within this series (minimum inhibitory concentration, MIC=6.25 μg/mL). The preliminary structure‐activity relationship study showed that the antifungal activity depends on the position and nature of the substitution patterns. The cytotoxicity of eleven compounds on D‐384 (astrocytoma), A‐549 (lung cancer) and RKO (colorectal cancer) cell lines was also performed. With the aim of deeply understand the potential of these molecules as hits to develop new drugs, the theoretical absorption, distribution, metabolism and excretion (ADME) properties of the active compounds were calculated.
The Abelian Higgs model under a gauge invariant looking glass: exploiting new Ward identities for gauge invariant operators and the Equivalence Theorem
Authors: Dudal D. , Peruzzo G. , Sorella S. P.
Published: October 2021

Abstract

The content of two additional Ward identities exhibited by the U(1) Higgs model is exploited. These novel Ward identities can be derived only when a pair of local composite operators providing a gauge invariant setup for the Higgs particle and the massive vector boson is introduced in the theory from the beginning. Among the results obtained from the above mentioned Ward identities, we underline a new exact relationship between the stationary condition for the vacuum energy, the vanishing of the tadpoles and the vacuum expectation value of the gauge invariant scalar operator. We also present a characterization of the two-point correlation function of the composite operator corresponding to the vector boson in terms of the two-point function of the elementary gauge fields. Finally, a discussion on the connection between the cartesian and the polar parametrization of the complex scalar field is presented in the light of the Equivalence Theorem. The latter can in the current case be understood in the language of a constrained cohomology, which also allows to rewrite the action in terms of the aforementioned gauge invariant operators. We also comment on the diminished role of the global U(1) symmetry and its breaking.
Clinical Speech fMRI in Children and Adolescents
Authors: Krafft Hannah , Staudt Martin
Published: October 2021

Purpose

In patients with drug-resistant focal epilepsy, surgical resection is often the only treatment option to achieve long-term seizure control. Prior to brain surgery involving potential language areas, identification of hemispheric language dominance is crucial. Our group developed and validated a functional magnetic resonance imaging (fMRI) battery of four pediatric language tasks. The present study aimed at optimizing fMRI data acquisition and analysis using these tasks.

Methods

We retrospectively analyzed speech fMRI examinations of 114 neuropediatric patients (age range 5.8–17.8 years) who were examined prior to possible epilepsy surgery. In order to evaluate hemispheric language dominance, 1–4 language tasks (vowel identification task VIT, word-chain task WCT, beep-story task BST, synonym task SYT) were measured.

Results

Language dominance was classified using fMRI activation in the 13 validly lateralizing ROIs (VLR) in frontal, temporal and parietal lobes and cerebellum of the recent validation study from our group: 47/114 patients were classified as left-dominant, 34/114 as bilateral and 6/114 as right-dominant. In an attempt to enlarge the set of VLR, we then compared for each task agreement of these ROI activations with the classified language dominance. We found four additional task-specific ROIs showing concordant activation and activation in ≥ 10 sessions, which we termed validly lateralizing (VLRnew). The new VLRs were: for VIT the temporal language area and for SYT the middle frontal gyrus, the intraparietal sulcus and cerebellum. Finally, in order to find the optimal sequence of measuring the different tasks, we analyzed the success rates of single tasks and all possible task combinations. The sequence 1) VIT 2) WCT 3) BST 4) SYT was identified as the optimal sequence, yielding the highest chance to obtain reliable results even when the fMRI examination has to be stopped, e.g., due to lack of cooperation.

Conclusion

Our suggested task order together with the enlarged set of VLRnew may contribute to optimize pediatric speech fMRI in a clinical setting.
Paper-based aptamer-antibody biosensor for gluten detection in a deep eutectic solvent (DES)
Authors: Svigelj Rossella , Dossi Nicolò , Grazioli Cristian , Toniolo Rosanna
Published: October 2021

Paper has been widely employed as cheap material for the development of a great number of sensors such as pregnancy tests, strips to measure blood sugar, and COVID-19 rapid tests. The need for new low-cost analytical devices is growing, and consequently the use of these platforms will be extended to different assays, both for the final consumer and within laboratories. This work describes a paper-based electrochemical sensing platform that uses a paper disc conveniently modified with recognition molecules and a screen-printed carbon electrode (SPCE) to achieve the detection of gluten in a deep eutectic solvent (DES). This is the first method coupling a paper biosensor based on aptamers and antibodies with the DES ethaline. Ethaline proved to be an excellent extraction medium allowing the determination of very low gluten concentrations. The biosensor is appropriate for the determination of gluten with a limit of detection (LOD) of 0.2 mg L−1 of sample; it can detect gluten extracted in DES with a dynamic range between 0.2 and 20 mg L−1 and an intra-assay coefficient of 10.69%. This approach can be of great interest for highly gluten-sensitive people, who suffer from ingestion of gluten quantities well below the legal limit, which is 20 parts per million in foods labeled gluten-free and for which highly sensitive devices are essential.

Graphical abstract
Charcot-Marie-Tooth neuropathy score and ambulation index are both predictors of orthotic need for patients with CMT
Authors: Prada Valeria , Zuccarino Riccardo , Schenone Cristina , Mennella Giulia , Grandis Marina , Shy Michael E. , Schenone Angelo
Published: October 2021

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy with an estimated prevalence of 1 person affected on 2500. Frequent symptoms include distal weakness and muscle wasting, sensory loss, reduced deep tendon reflexes, and skeletal deformities, such as hammer toes and pes cavus. CMT is a progressive disease and patients’ needs change over their lifetime. In particular, ambulation aids are increasingly needed to maintain ambulation and reduce the risk of falls. We performed a retrospective analysis of medical records from 149 patients with confirmed CMT to evaluate patients ambulation needs related to the severity of their CMT as measured by the CMT Neuropathy Score (CMTNS) and Ambulation Index (AI). Most patients required some form of orthotics (86.6%). The CMTNS and AI scores both differed significantly between patients with no orthotics compared to those who wore insoles/inserts. The CMTNS and AI also differed significantly between patients wearing insoles and those with ankle foot orthotics (AFOs). CMTNS and the AI were valid predictors of the type and choice of the orthotics. Both the CMTNS and AI can be effective tools to aid in the correct choice of orthotics in patients affected by CMT.
Self vs. other, child vs. adult. An experimental comparison of valuation perspectives for valuation of EQ-5D-Y-3L health states
Authors: Lipman S. A. , Reckers-Droog V. T. , Karimi M. , Jakubczyk M. , Attema A. E.
Published: October 2021

Objectives

EQ-5D-Y-3L health states are valued by adults taking the perspective of a 10-year-old child. Compared to valuation of adult EQ-5D instruments, this entails two changes to the perspective: (i) child health states are valued instead of adult health states and: (ii) health states are valued for someone else instead of for oneself. Although earlier work has shown that these combined changes yield different values for child and adult health states that are otherwise equal, it currently remains unclear why. Hence, we aimed to disentangle the effects of both changes.

Methods

A sample of 205 students (mean age: 19.48) was surveyed. Each respondent completed visual analogue scale (VAS) and time trade-off (TTO) tasks for five EQ-5D-Y-3L states, using four randomly ordered perspectives: (i) self-adult (themselves), (ii) other-adult (someone their age), (iii) self-child (themselves as a 10-year-old), (iv) other-child (a child of 10 years old). We compared how each perspective impacted outcomes, precision and quality of EQ-5D-Y-3L valuation.

Results

Overall, differences between perspectives were consistent, with their direction being dependent on the health states and respondents. For VAS, the effect on outcomes of valuation depended on severity, but variance was higher in valuation with child perspectives. For TTO, we observed that EQ-5D-Y-3L states valued on behalf of others (i.e., children or adults) received higher valuations, but lower variances.

Conclusion

The use of a different perspective appears to yield systematic differences in EQ-5D-Y-3L valuation, with considerable heterogeneity between health states and respondents. This may explain mixed findings in earlier work.
Significance of chemotherapy-free interval and tumor regression grade in patients with recurrent esophageal squamous cell carcinoma receiving chemotherapy with fluorouracil and platinum after esophagectomy following preoperative chemotherapy
Authors: Okunaka Mashiro , Kotani Daisuke , Demachi Ken , Fujiwara Hisashi , Sakashita Shingo , Yoshino Takayuki , Fujita Takeo , Kojima Takashi
Published: October 2021

Background

In Japan, standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) includes preoperative chemotherapy with fluorouracil plus cisplatin followed by esophagectomy. However, its efficacy is unclear in patients with recurrent disease with < 6 months of chemotherapy-free interval (CFI) after preoperative chemotherapy followed by esophagectomy and in those with ≥ 6 months of CFI and poor pathological response to prior preoperative chemotherapy.

Method

We retrospectively evaluated the efficacy of fluorouracil plus platinum in patients with recurrent ESCC who received preoperative chemotherapy followed by curative esophagectomy.

Results

Among 105 patients with recurrent ESCC after preoperative chemotherapy followed by esophagectomy, a total of 55 patients received fluorouracil plus platinum for recurrent disease. Patients with a CFI < 6 months (n = 20) had significantly shorter overall survival (OS) (median, 7.1 vs 14.5 months, P = 0.008) compared with those with a CFI ≥ 6 months (n = 35). Multivariate analysis showed that OS was worse in patients with a CFI < 6 months or a tumor regression grade (TRG) ≤ 1a. Furthermore, in patients with a CFI ≥ 6 months, TRG ≤ 1a was associated with significantly shorter OS (11.1 months vs. not reached, P = 0.001).

Conclusion

Fluorouracil plus platinum was ineffective for recurrent ESCC in patients with a CFI < 6 months and in those with a CFI ≥ 6 months and a TRG ≤ 1a. Alternate regimens including nivolumab or pembrolizumab might be considered for the treatment for recurrence in these patients.
Can agriculture and conservation be compatible in a coastal wetland? Balancing stakeholders’ narratives and interactions in the management of El Hondo Natural Park, Spain
Authors: Ricart Sandra , Rico-Amorós Antonio M.
Published: October 2021

Coastal wetlands are among the most productive and valuable ecosystems worldwide, although one of the main factors affecting their survival is the coexistence between agriculture and conservation. This paper analyses the complex balance between agriculture and conservation coexistence in El Hondo Natural Park (Alicante, Spain) coastal wetland by examining stakeholders’ narratives, perceptions, and interactions. The aim is to highlight the concurrence between socio-economic progress and socio-environmental justice perspectives by identifying those driving factors motivating stakeholders’ conflicts while expanding stakeholders’ behaviour and interaction when discussing the current and future management of this socio-ecological system. Data were collected between April and June 2019 from semi-structured interviews and questionnaires to river basin authorities, regional governments, municipalities, irrigation communities, union farms, regional and local ecologist groups, and social movements; and scrutinized through qualitative data analysis and descriptive statistics. Stakeholders discussed the main driving factors identified through the local newspapers to motivating current conflicts and confronting perspectives in El Hondo Natural Park: (1) the origin and evolution of the coastal wetland, (2) the provision and value of ecosystem services, (3) the management of water scarcity and water quality standards, (4) the guarantee and management of public and private investment, and (5) consequences of a natural park declaration. Likewise, the triple-loop analysis of stakeholders’ representativeness, relevance and collaboration highlighted examples of stakeholders’ underrepresentation and power imbalance, a negative assessment of the stakeholders’ actions, and how agreements are based on both stakeholders’ predisposition to collaborate and affinity.
Relationships between empirical damage and direct/indirect costs for the assessment of seismic loss scenarios
Authors: Di Ludovico Marco , De Martino Giuseppina , Prota Andrea , Manfredi Gaetano , Dolce Mauro
Published: October 2021

The definition of relationships between damage and losses is a crucial aspect for the prediction of seismic effects and the development of reliable models to define risk maps, loss scenarios and mitigation strategies. The paper focuses on the analysis of post-earthquake empirical data to define relationships between buildings’ damage expressed as usability rating or as global damage state and the associated costs for repair (i.e. direct costs) or for population assistance (i.e. a part of total indirect costs). The analysis refers to the data collected on residential buildings damaged by 2009 L'Aquila earthquake. For different usability rating or damage states, the paper presents the costs expressed in terms of percentage with respect to the reference unit cost of a new building (%Cr and %Ca for repair and population assistance costs, respectively). In particular, the costs analysis refers to undamaged, lightly or severely damaged buildings classified according to usability rating (i.e. A, B-C or E according to Italian classification) or to five different global Damage States (DSs). DSs comply with European Macroseismic Scale (EMS-98) and derive from literature available matrices properly defined to convert empirical damage to structural and non-structural components into building global damage. The %Cr probability density functions and relevant statistics derive from the analysis of actual data of post-earthquake reconstruction process, while, to determine those related to %Ca, a deep analysis of population assistance types, person/month assistance cost for each assistance form, and a methodology to associate such costs to each building are herein presented and discussed. Finally, the paper presents a relationship calibrated on empirical data to directly correlate repair costs on a building with assistance costs to their occupants. The relationships between empirical damage and direct and indirect costs herein presented are of paramount importance because they allow reliable loss scenarios to be defined by simply using literature fragility curves (defined according to empirical or mechanical approaches) aimed at evaluating the probability of exceeding different usability rating or damage states of existing buildings.