bluuebunny/crossref_metadata_2025 huggingface dataset:
Punctuated equilibrium as the default mode of evolution of large populations on fitness landscapes dominated by saddle points in the weak-mutation limit
Authors: Bakhtin Yuri , Katsnelson Mikhail I. , Wolf Yuri I. , Koonin Eugene V.
Published: July 2020

Punctuated equilibrium is a mode of evolution in which phenetic change occurs in rapid bursts that are separated by much longer intervals of stasis during which mutations accumulate but no major phenotypic change occurs. Punctuated equilibrium has been originally proposed within the framework of paleobiology, to explain the lack of transitional forms that is typical of the fossil record. Theoretically, punctuated equilibrium has been linked to self-organized criticality (SOC), a model in which the size of ‘avalanches’ in an evolving system is power-law distributed, resulting in increasing rarity of major events. We show here that, under the weak-mutation limit, a large population would spend most of the time in stasis in the vicinity of saddle points in the fitness landscape. The periods of stasis are punctuated by fast transitions, in lnNetime (Ne, effective population size), when a new beneficial mutation is fixed in the evolving population, which moves to a different saddle, or on much rarer occasions, from a saddle to a local peak. Thus, punctuated equilibrium is the default mode of evolution under a simple model that does not involve SOC or other special conditions.

Significance

The gradual character of evolution is a key feature of the Darwinian worldview. However, macroevolutionary events are often thought to occur in a non-gradualist manner, in a regime known as punctuated equilibrium, whereby extended periods of evolutionary stasis are punctuated by rapid transitions between states. Here we analyze a mathematical model of population evolution on fitness landscapes and show that, for a large population in the weak-mutation limit, the process of adaptive evolution consists of extended periods of stasis, which the population spends around saddle points on the landscape, interrupted by rapid transitions to new saddle points when a beneficial mutation is fixed. Thus, punctuated equilibrium appears to be the default regime of biological evolution.
In silico comparative genomics of SARS-CoV-2 to determine the source and diversity of the pathogen in Bangladesh
Authors: Shishir Tushar Ahmed , Naser Iftekhar Bin , Faruque Shah M.
Published: July 2020

The COVID19 pandemic caused by SARS-CoV-2 virus has severely affected most countries of the world including Bangladesh. We conducted comparative analysis of publicly available whole-genome sequences of 64 SARS-CoV-2 isolates in Bangladesh and 371 isolates from another 27 countries to predict possible transmission routes of COVID19 to Bangladesh and genomic variations among the viruses. Phylogenetic analysis indicated that the pathogen was imported in Bangladesh from multiple countries. The viruses found in the southern district of Chattogram were closely related to strains from Saudi Arabia whereas those in Dhaka were similar to that of United Kingdom and France. The 64 SARS-CoV-2 sequences from Bangladesh belonged to three clusters. Compared to the ancestral SARS-CoV-2 sequence reported from China, the isolates in Bangladesh had a total of 180 mutations in the coding region of the genome, and 110 of these were missense. Among these, 99 missense mutations (90%) were predicted to destabilize protein structures. Remarkably, a mutation that leads to an I300F change in the nsp2 protein and a mutation leading to D614G change in the spike protein were prevalent in SARS-CoV-2 genomic sequences, and might have influenced the epidemiological properties of the virus in Bangladesh.
Vesicle Navigation of Microtubule Ends Distinguished by A Single Rate-Constant Model
Authors: Gramlich M.W. , Gómez S. Balseiro , Tabei S. M. Ali , Parkes M. , Yogev S.
Published: July 2020

Axonal motor driven cargo utilizes the microtubule cytoskeleton in order to direct cargo, such as presynaptic vesicle precursors, to where they are needed. This transport requires vesicles to travel up to microns in distance. It has recently been observed that finite microtubule lengths can act as roadblocks inhibiting vesicles and increasing the time required for transport. Vesicles reach the end of a microtubule and pause until they can navigate to a neighboring microtubule in order to continue transport. The mechanism by which axonal vesicles navigate the end of a microtubule in order to continue mobility is unknown. In this manuscript we model experimentally observed vesicle pausing at microtubule ends inC. elegans. We show that a single rate-constant model reproduces the time vesicles pause at MT-ends. This model is based on the time a vesicle must detach from its current microtubule and re-attach to a neighboring microtubule. We show that vesicle pause times are different for anterograde and retrograde motion, suggesting that vesicles utilize different proteins at plus and minus end sites. Last, we show that vesicles do not likely utilize a tug-of-war like mechanism and reverse direction in order to navigate microtubule ends.
Crystal structure, Hirshfeld surface analysis and DFT studies of (E)-2-{[(3-chloro-4-methylphenyl)imino]methyl}-4-methylphenol
Authors: Faizi Md. Serajul Haque , Cinar Emine Berrin , Aydin Alev Sema , Agar Erbil , Dege Necmi , Mashrai Ashraf
Published: July 2020

The title compound, C15H14ClNO, was synthesized by condensation reaction of 2-hydroxy-5-methylbenzaldehyde and 3-chloro-4-methylaniline, and crystallizes in the monoclinic space group P21/c. The 3-chlorobenzene ring is inclined to the phenol ring by 9.38 (11)°. The configuration about the C=N bond is E and an intramolecular O—H...N hydrogen bond forms an S(6) ring motif. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the packing arrangement are from H...H (43.8%) and C...H/H...C (26.7%) interactions. The density functional theory (DFT) optimized structure at the B3LYP/ 6–311 G(d,p) level is compared with the experimentally determined molecular structure and the HOMO–LUMO energy gap is provided.
DL-Piperidinium-2-carboxylate bis(hydrogen peroxide): unusual hydrogen-bonded peroxide chains
Authors: Navasardyan Mger A. , Grishanov Dmitry A. , Prikhodchenko Petr V. , Churakov Andrei V.
Published: July 2020

The title compound, C6H11NO2·2H2O2, is the richest (by molar ratio) in hydrogen peroxide among the peroxosolvates of aliphatic α-amino acids. The asymmetric unit contains a zwitterionic pipecolinic acid molecule and two hydrogen peroxide molecules. The two crystallographically independent hydrogen peroxide molecules form a different number of hydrogen bonds: one forms two as donor and two as acceptor ([2,2] mode) and the other forms two as donor and one as acceptor ([2,1] mode). The latter hydrogen peroxide molecule forms infinite hydrogen-bonded hydroperoxo chains running along the c-axis direction, which is unusual for aliphatic α-amino acid peroxosolvates.
Reentry guidance by accelerated fractional-order particle swarm optimization method
Authors: Sana Khurram Shahzad , Hu Weiduo
Published: July 2020

Purpose

The aim of this study is to design a guidance method to generate a smoother and feasible gliding reentry trajectory, a highly constrained problem by formalizing the control variables profile.

Design/methodology/approach

A novel accelerated fractional-order particle swarm optimization (FAPSO) method is proposed for velocity updates to design the guidance method for gliding reentry flight vehicles with fixed final energy.

Findings

By using the common aero vehicle as a test case for the simulation purpose, it is found that during the initial phase of the longitudinal guidance, there are oscillations in the state parameters which cause to violate the path constraints. For the glide phase of the longitudinal guidance, the path constraints have higher values because of the increase in the atmosphere density.

Research limitations/implications

The violation in the path constraints may compromise the flight vehicle safety, whereas the enforcement assures the flight safety by flying it within the reentry corridor.

Originality/value

An oscillation suppression scheme is proposed by using the FAPSO method during the initial phase of the reentry flight, which smooths the trajectory and enforces the path constraints partially. To enforce the path constraints strictly in the glide phase, ultimately, another scheme by using the FAPSO method is proposed. The simulation results show that the proposed algorithm is efficient to achieve better convergence and accuracy for nominal as well as dispersed conditions.
Changes in industrial network logics: the case of the Japanese retail industry
Authors: Hara Yoritoshi
Published: July 2020

Purpose

This study aims to examine changes in “network logics” that refer to cognitive views socially accepted by actors about the network. These logics provide organizations with templates on how to act in business networks. This study investigates the causes and processes of network logic changes and the phases in the changes.

Design/methodology/approach

This study relies on content analysis using text data from newspaper articles on global retailers entering the Japanese retail industry. Three different logics were found to describe the actions of the retailers. Two of the logics are related to institutional and strategic logics including network logics, while the third is associated with institutional works that mean actions to create, maintain and disrupt institutions.

Findings

With regard to transitions in network logics in the Japanese retail industry, the analysis identified four phases: politicization, reflection, establishment and evaluation. Changes in regulative and normative logics were resulted from institutional works of the global retailers into the Japanese market. The findings also include empirical description about how network changes progress through interactions among business actors. Additionally, compared to the regulative and normative logics, it would be difficult to influence the cultural-cognitive logics.

Originality/value

Business networks often transform with changes in network logics. This study contributes to the literature on industrial network changes by exploring the interactions between macro-level structural states and micro-level events in network logic transitions.
Dermoscopic clues of palmoplantar hyperkeratotic eczema and palmoplantar psoriasis: A prospective, comparative study of 90 patients
Authors: Çetinarslan Tubanur , Türel Ermertcan Aylin , Temiz Peyker
Published: July 2020

Diagnosis can be difficult in isolated palmar and plantar lesions in patients with psoriasis and eczema. The purpose of our study is to compare the dermoscopic findings in patients with palmoplantar psoriasis and palmoplantar hyperkeratotic eczema. This prospective, comparative study included 90 patients histopathologically diagnosed with eczema or psoriasis (35 psoriasis and 55 eczema). The age range was 18–75 years. The most common vessel type was dot vessel in psoriasis. Red globular ring vessels were seen in five patients with psoriasis, but not in any with eczema (P = 0.007). The most common vascular distribution pattern was regular in psoriasis (40%). Patchy vascular pattern was significant in eczema. The most common background color was light red in psoriasis (48.6%) (P < 0.001). Brownish‐orange globules were observed in 25.7% of patients with eczema and 5.7% in patients with psoriasis (P = 0.02). There is only one study in the published work about dermoscopy of palmoplantar psoriasis and eczema. In our study, yellow crusts, patchy scale distribution, patchy vascular pattern, yellow scale color, dull red background color and brownish‐orange globules were significant in patients with palmoplantar eczema. On the other hand, patients with psoriasis had light red background color, regular vascular distribution pattern and white scale color. We observed globule structures with a pale center and dark peripheral rim only in patients with eczema, which was not identified in previous studies. This globule structure may be a new finding in eczema.
Resveratrol ameliorates thymus senescence changes in D‐galactose induced mice
Authors: Wei Ting‐ting , Li Meng‐jie , Guo Li , Xie Yan‐dong , Chen Wen‐hui , Sun Yun , Liu Guo‐hong , Ding Yi , Chai Yu‐rong
Published: July 2020

The thymic microenvironment plays an important role in the development of T cells. A decrease of thymic epithelial cells is the main cause of age‐related thymic atrophy or degeneration. Resveratrol (RSV), a phytoalexin produced from plants, has been shown to inhibit the adverse effects of dietary obesity on the structure and function of the thymus. D‐Galactose (D‐gal) can induce accelerated aging in mice. In the present study, young mice (2 months old) were injected with D‐gal (120 mg/kg/day) for 8 consecutive weeks to construct an accelerated aging model. Compared with normal control mice, the thymus epithelium of the D‐gal treated mice had structural changes, the number of senescent cells increased, the number of CD4+ T cells decreased, and CD8+ T cells increased. After RSV administration by gavage for 6 weeks, it was found that RSV improved the surface phenotypes of D‐gal treated mice, and recovered thymus function by maintaining the ratio of CD4+ to CD8+ cells. It also indicated that RSV enhanced the cell proliferation and inhibited cell senescence. Increased autoimmune regulator (Aire) expression was present in the RSV treated mice. The lymphotoxin‐beta receptor (LTβR) expression also increased. These findings suggested that RSV intake could restore the alterations caused by D‐gal treatment in the thymus via stimulation of Aire expression.
Alteration in miRNAs expression in paediatric acute lymphocyticleukaemia: Insight into patients' therapeutic response
Authors: El‐maadawy Eman A. , Bakry Rania M. , Moussa Mohamed M. , El‐Naby SobhyHasab , Talaat Roba M.
Published: July 2020

MicroRNAs (miRNAs) revealed themselves as potential tumour markers and play a significant role in the pathogenesis and progression of acute lymphocytic leukaemia (ALL). This work is designed to investigate the expression of miR‐21, miR‐26, miR‐148a, miR‐133b and miR‐24 in paediatric ALL patients in response to treatment. The expression of miRNAs was determined by quantitative reverse transcriptase–polymerase chain reaction (qRT–‐PCR) in 43 paediatric ALL patients (33 treatment responders and 10 non‐responders) compared to 42 healthy controls. miR‐21, miR‐148a, and miR‐24 were found to be significantly (P < .05, P < .01, P < .05; respectively) up‐regulated in ALL patients compared to controls. No statistically significant differences in expression levels of miR‐26a and miR133b were detected in both groups. Concerning treatment, responders are found to have a decreased level of miR‐24 compared to non‐responder patients. A significant increase (P < .01) in miR‐24 expression level in relapsed patients compared to non‐relapsed ones was found. Positive correlations were detected between miR‐148a and miR‐24 (r = .347; P < .05) and between miR‐26a and miR‐24 (r = .353; P < .05) in ALL group. The highest sensitivity (72%) and specificity (81%) among miRNAs were detected in miR‐24 at a cut‐off value of 2.928. Taken together, the up‐regulation of tumour suppressor miRNA(miR‐148a) concur with the up‐regulation of oncomiR (miR‐21) might provide a new era that could help in disease management strategy. The reduction of oncomiR‐24 is one of the promising effects of treatment. A larger prospective study is highly recommended to confirm our findings.
The Heritability of Palatal Rugae Morphology Among Siblings*†
Authors: Chong Jun Ai , Syed Mohamed Alizae Marny Fadzlin , Marizan Nor Murshida , Pau Allan
Published: July 2020

Although there is clinical applicability of the palatal rugae as an identification tool in forensic odontology, controversy exists whether the palatal rugae patterns are stable or variable. The greater the genetic component, the higher the probability that palatal rugae patterns are stable. The aim of this study was to compare the palatal rugae morphology between full siblings and the proportion of variability due to genetic component. This cross‐sectional study was conducted on digital models of 162 siblings aged 15–30 years old. The palatal rugae patterns were assessed with Thomas and Kotze (1983) classification using Geomagic Studio software (3D Systems, Rock Hill, SC). The palatal rugae morphology between siblings showed significantly similar characteristics for total number of left rugae (p = 0.001), left primary rugae (p = 0.017), secondary rugae for right (p = 0.024) and left sides (p = 0.001), right straight rugae (p = 0.010), and right convergent rugae (p = 0.005) accounting for at least 6.25%‐12.8% of the variability due to heredity. Despite the similarities found, the palatal rugae patterns showed significant differences between siblings of at least 46.9% (p = 0.001). Zero heritability was found in 9 of the 14 rugae patterns. Meanwhile, total number of rugae, primary, backward, and convergent rugae showed moderate heritability (h2 > 0.3) and total number of secondary rugae showed high heritability (h2 > 0.6). In conclusion, despite the individuality characteristics, an appreciable hereditary component is observed with significant similarities found between sibling pairs and the palatal rugae patterns were both environmentally and genetically influenced.
Analysis of insects colonised on human corpses during autopsy in Riyadh, Saudi Arabia
Authors: Mashaly Ashraf , Al‐Khalifa Mohammed , Al‐Qahtni Abdulmani , Alshehri Adel
Published: July 2020

In medicolegal cases, an analysis of the presence of insects on human bodies may have potential legal significance. This study investigates the presence of insects on human bodies during autopsies in legal medicine. It was implemented in Riyadh, Saudi Arabia. Nine cadavers were examined, respectively, from four cases of homicide, two cases of burning, one suicide, one accident and one case of neglect. Insects associated with the human corpses were carefully collected and identified using valid taxonomic keys. Three of the cadavers were of children with ages ranging from seven months to nine years. In seven cases decomposition had occurred outdoors while in two cases it was indoors. Overall, eleven different species of insects were identified. Six of the cases exhibited species from five families within Diptera (Calliphoridae, Muscidae, Ulidiidae, Tachinidae and Sarcophagidae), specifically Chrysomya albiceps (Wiedemann), Musca domestica (Linnaeus), Tachinidae sp. (Bigot), Physiphora alceae (Preyssler) and Sarcophaga dux (Thompson). Six of the cadavers hosted beetles, which were identified as Dermestes maculatus (DeGeer), D. frischii (Kugelann), Necrobia rufipes (Fabricius), Nitidula bipunctata (Linnaeus), Pimelia interjecta (Solier) and Latridiidae sp. (Erichson). Moreover, the suicide corpse was colonised by more fly species than the other corpses, while the beetles colonised the homicide and accident corpses more than the other corpses. Analysis of the diversity of insects on human corpses may lead to advances in the understanding of forensic entomology and more sophisticated estimates of the minimum post‐mortem interval.
Lung cancer and intraocular metastasis in gestation: Clinical experiences of a rare case
Authors: Lin Lin , Sun Jing , Wang Jie
Published: July 2020

Lung cancer in pregnancy combined with intraocular metastasis rarely occurs and has a poor prognosis. Here, we report an extremely rare case of a 31‐year‐old non‐smoking pregnant female who was diagnosed with lung adenocarcinoma with multiple metastasis including choroidal metastasis. Whole exon sequencing was performed but no appropriate therapeutic target was identified. The patient received standard pemetrexed plus carboplatin for first‐line treatment after delivery. Ophthalmic treatment including transpupillary thermotherapy and intravitreal ranibizumab injections were administered and the patient responded very well to treatment. Her visual acuity was restored, indicating systemic therapy combined with ophthalmic treatment was an appropriate choice of therapy.

Key points

Significant findings of the study

The case reported here of a pregnant female diagnosed with lung cancer with choroidal metastasis highlights the aggressive characteristics of the disease.

What this study adds

Systemic therapy in combination with ocular therapy is an appropriate choice of treatment.
Enhancing Rescue in Chapter 11: Lessons from Reform Efforts in the United Kingdom
Authors: Landry Robert J.
Published: July 2020

This is a dynamic time for insolvency law. Many jurisdictions have made or are considering reforms to their insolvency regimes. The United Kingdom has proposed a new standalone restructuring mechanism that incorporates many attributes of Chapter 11, including a cross‐class cram down and the absolute priority rule. A distinctive feature of the UK proposal is the infusion of judicial discretion permitting courts to deviate from the absolute priority rule. This discretion is not permitted in the United States. This judicial discretion addresses a key problem with the application of the absolute priority rule in the United States—it may serve as an impediment to reorganization. This impediment is exacerbated by the recent U.S. Supreme Court decision, Czyzewski v. Jevic Holding Corp., which impacts the effective use of Chapter 11 rescue tools. This article explores the absolute priority rule, the problems associated with it, and the effect of Jevic in the United States. Drawing on the UK reform proposal, I argue that the United States should implement reforms that infuse judicial discretion into the application of the absolute priority rule. Doing so will facilitate the underlying policy goal of rescuing the company in Chapter 11 and also promote a broader policy goal of rescuing the business.
Squeezing linkLine: Rethinking Recoupment in Price Squeeze Cases
Authors: Kennedy Patrick
Published: July 2020

The Supreme Court's decision in Pacific Bell Telephone Co. v. linkLine Communications, Inc. removed an important tool from competition regulators’ arsenals. Not only did the Court express skepticism about the existence of a price squeeze cause of action, but it also applied the economically mismatched predatory pricing test to price squeeze cases. Unfortunately, the lack of clarity on linkLine's reach also caused significant confusion in the lower courts. Examining these issues, this article clarifies the distinction between price squeeze and predatory pricing claims, and argues that the second step of the predatory pricing test, probability of recoupment, is inappropriate for price squeeze cases and should either be dropped from the test or replaced with a presumption of recoupment.
Abnormal laboratory findings and plasma concentration monitoring of lopinavir and ritonavir in COVID‐19
Authors: Batteux Benjamin , Bodeau Sandra , Gras‐Champel Valérie , Liabeuf Sophie , Lanoix Jean‐Philippe , Schmit Jean‐Luc , Andréjak Claire , Zerbib Yoann , Haye Guillaume , Masmoudi Kamel , Lemaire‐Hurtel Anne‐Sophie , Bennis Youssef
Published: July 2020

It is not known whether the adverse events (AEs) associated with the administration of lopinavir and ritonavir (LPV/r) in the treatment of COVID‐19 are concentration‐dependent. In a retrospective study of 65 patients treated with LPV/r and therapeutic drug monitoring (TDM) for severe forms of COVID‐19 (median age: 67; males: 41 [63.1%]), 33 (50.8%) displayed a grade ≥2 increase in plasma levels of hepatobiliary markers, lipase and/or triglycerides. A causal relationship between LPV/r and the AE was suspected in 9 of the 65 patients (13.8%). At 400 mg b.i.d., the plasma trough concentrations of LPV/r were high and showed marked interindividual variability (median [interquartile range]: 16,600 [11,430–20,842] ng/ml for lopinavir and 501 [247–891] ng/ml for ritonavir). The trough lopinavir concentration was negatively correlated with body mass index, while the trough ritonavir concentration was positively correlated with age and negatively correlated with prothrombin activity. However, the occurrence of abnormal laboratory values was not associated with higher trough plasma concentrations of LPV/r. Further studies will be needed to determine the value of TDM in LPV/r‐treated patients with COVID‐19.
Mapping the construct and measurement of medication literacy: A scoping review
Authors: Pantuzza Laís Lessa Neiva , do Nascimento Elizabeth , Botelho Stephanie Ferreira , Martins Maria Auxiliadora Parreiras , de Souza Groia Veloso Ronara Camila , do Nascimento Mariana Martins Gonzaga , Vieira Liliana Batista , Reis Adriano Max Moreira
Published: July 2020

Aim

To systematically review the literature on definitions, tools and factors associated with medication literacy.

Methods

We searched on Medline, Lilacs, Cochrane, CINAHL, PsycINFO, Embase, Scopus, Web of Science, databases of theses/dissertations and the references of the selected studies. The screening was carried out by two independent researchers. Observational, experimental or methodological studies were eligible for inclusion. The tools were critically analysed and evaluated regarding the dimensions and statements on medication literacy.

Results

Thirty‐five studies were included. Most were conducted in China and the United States, included adults and were published after 2010. Different terms were identified for literacy in the context of medication use and the most frequently used was “medication literacy”. Its definition varied, but “medication literacy” was generally defined as the individual ability to understand and act on medication‐related information. Twelve tools were identified. Most included only functional and numerical dimensions of literacy. No instrument covered all the essential statements on medication literacy. The tools had essential limitations in their development and measurement characteristics. Factors associated with medication literacy varied among studies, but the most frequent were age, education and inappropriate self‐medication.

Conclusion

“Medication literacy” is the recommended term for literacy in the context of medication use. Different definitions were identified, and the most comprehensive was the one proposed by Pouliot in 2018. The tools did not cover all the essential literacy skills for medication use and focused only on functional e numeracy domains. Sociodemographic characteristics and inappropriate self‐medication were the most common factors associated with medication literacy.
Physiologically based pharmacokinetic modelling of lisinopril in children: A case story of angiotensin converting enzyme inhibitors
Authors: Xie Feifan , Van Bocxlaer Jan , Vermeulen An
Published: July 2020

Aims

Lisinopril is an angiotensin converting enzyme inhibitor to treat hypertension. It shows complex pharmacokinetics (PK), and its PK behaviour in paediatric populations is not well characterized. The aim of this study was to develop a physiologically based PK (PBPK) model for lisinopril to describe the drug's PK in children.

Methods

The PBPK model development was performed in a step‐wise manner. An adult model was initially developed to characterize lisinopril's disposition and absorption and verified using literature data. Subsequently, the adult PBPK model was extrapolated to the paediatric population (0.5–18 years old) by accounting for age‐dependent physiological and anatomical changes. Model performance was evaluated by comparing the PK profiles and drug exposures of observedvspredicted data.

Results

The disposition of lisinopril was well described by a minimal PBPK model—an effective strategy to capture the biphasic elimination of the drug. The absorption of lisinopril was described by the intestinal peptide transporter‐mediated uptake. The adult model adequately described the literature data with predictions within a twofold range of clinical observations. Good model predictivity was also observed in children older than 6 years of age. The model overpredicted the drug exposure in children under 6 years, probably due to not incorporating the actual, unknown ontogeny of the intestinal peptide transporter.

Conclusions

The PBPK model predicted the PK of lisinopril in adults and children above 6 years of age well. Model refinement in children under 6 years warrants future informative ontogeny data of the intestinal peptide transporter.
Stevens–Johnson syndrome associated with TS‐1 in a patient with gastric cancer: A case report
Authors: Wang Kaichun , Gu Chao , Hu Daode
Published: July 2020

TS‐1, an effective anticancer drug that consists of tegafur, gimeracil and oteracil, has been increasingly used for the treatment of many types of cancer. However, few studies investigate its cutaneous adverse reactions. Here, we report a female patient with gastric cancer treated with TS‐1 after a gastrectomy, who then developed Stevens–Johnson syndrome, a cutaneous and potentially life‐threatening adverse reaction. This is the first case report about a Grade IV toxic reaction associated with TS‐1. The patient presented with systemic symptoms of erythematous macules, vesicle formation, erosions, binocular ptosis and oedema of the lower eyelid conjunctiva. After 3 weeks of hospitalization with drug treatment and discontinuation of TS‐1, her symptoms were fully relieved and did not recur because the chemotherapy regimen was adjusted to modified FOLFOX6. According to the comprehensive analysis and the score of both the Naranjo assessment scale and algorithm of drug causality for epidermal necrolysis, we have drawn the preliminary conclusion that this is TS‐1‐induced Stevens–Johnson syndrome.
Would they trust it? An exploration of psychosocial and environmental factors affecting prescriber acceptance of computerised dose‐recommendation software
Authors: Carland Jane E. , Elhage Tania , Baysari Melissa T. , Stocker Sophie L. , Marriott Deborah J.E. , Taylor Natalie , Day Richard O.
Published: July 2020

Aims

Dose‐prediction software can optimise vancomycin therapy, improving therapeutic drug monitoring processes and reducing drug toxicity. Success of software in hospitals may be dependent on prescriber uptake of software recommendations. This study aimed to identify the perceived psychosocial and environmental barriers and facilitators to prescriber acceptance of dose‐prediction software.

Methods

Semi‐structured interviews, incorporating prescribing scenarios, were undertaken with 17 prescribers. Participants were asked to prescribe the next maintenance dose of vancomycin for a scenario(s) and then asked if they would accept a recommendation provided by a dose‐prediction software. Interviews further explored opinions of dose‐prediction software. Interview transcripts were analysed using an inductive approach to identify themes and the Theoretical Domains Framework was used to synthesise barriers and facilitators to software acceptance.

Results

When presented with software recommendations, half of the participants were comfortable with accepting the recommendation. Key barriers to acceptance of software recommendations aligned with 2 Theoretical Domains Framework domains: Knowledge (uncertainty of software capability) and Beliefs about Consequences (perceived impact of software on clinical outcomes and workload). Key facilitators aligned with 2 domains: Beliefs about Consequences (improved efficiency) and Social Influences (influence of peers). A novel domain, Trust, was identified as influential.

Conclusion

Prescribers reported barriers to acceptance of dose‐prediction software aligned with limited understanding of, and scepticism about, software capabilities, as well as concerns about clinical outcomes. Identification of key barriers and facilitators to acceptance provides essential information to design of implementation strategies to support the introduction of this intervention into the workplace.
Molecular dynamics simulations provide molecular insights into the role of HLA‐B51 in Behçet's disease pathogenesis
Authors: Gur Mert , Golcuk Mert , Gul Ahmet , Erman Burak
Published: July 2020

Behçet's disease is an inflammatory disorder of unknown etiology. Genetic tendency has an important role in its pathogenesis, and HLA‐B51, a class I MHC antigen, has been recognized as the strongest susceptibility factor for Behçet's disease. Despite the confirmation of the association of HLA‐B51 with Behçet's disease in different populations, its pathogenic mechanisms remain elusive. HLA‐B51 differs in only two amino acids from HLA‐B52, other split antigen of HLA‐B5, which is not associated with Behçet's disease. These two amino acids are located in the B pocket of the antigen‐binding groove, which occupies the second amino acids of the bound peptides. To understand the nature of the HLA–peptide interactions, differences in structure and dynamics of two HLA alleles were investigated by molecular dynamics simulations using YAYDGKDYI, LPRSTVINI, and IPYQDLPHL peptides. For HLA‐B51, all bound peptides fluctuated to larger extent than HLA‐B52. Free energy profiles of unbinding process for YAYDGKDYI by steered molecular dynamics simulations showed that unbinding from HLA‐B52 results in greater free energy differences than HLA‐B51. These results suggest the possibility of an instability of HLA‐B51 associated with the repertoire of peptides, and this finding may provide significant insight to its pathogenic role in Behçet's disease.
Proposing novel MDM2 inhibitors: Combined physics‐driven high‐throughput virtual screening and in vitro studies
Authors: Aydin Gulsah , Paksoy Maide Nur , Orhan Müge Didem , Avsar Timucin , Yurtsever Mine , Durdagi Serdar
Published: July 2020

The mouse double minute 2 (MDM2) protein acts as a negative regulator of the p53 tumor suppressor. It directly binds to the N terminus of p53 and promotes p53 ubiquitination and degradation. Since the most common p53‐suppressing mechanisms involve the MDM2, proposing novel inhibitors has been the focus of many in silico and also experimental studies. Thus, here we screened around 500,000 small organic molecules from Enamine database at the binding pocket of this oncogenic target. The screening was achieved systematically with starting from the high‐throughput virtual screening method followed by more sophisticated docking approaches. The initial high number of screened molecules was reduced to 100 hits which then were studied extensively for their therapeutic activity and pharmacokinetic properties using binary QSAR models. The structural and dynamical profiles of the selected molecules at the binding pocket of the target were studied thoroughly by all‐atom molecular dynamics simulations. The free energy of the binding of the hit molecules was estimated by the MM/GBSA method. Based on docking simulations, binary QSAR model results, and free energy calculations, 11 compounds (E1–E11) were selected for in vitro studies. HUVEC vascular endothelium, colon cancer, and breast cancer cell lines were used for testing the binding affinities of the identified hits and for further cellular effects on human cancer cell. Based on in vitro studies, six compounds (E1, E2, E5, E6, E9, and E11) in breast cancer cell lines and six compounds (E1, E2, E5, E6, E8, and E10) in colon cancer cell lines were found as active. Our results showed that these compounds inhibit proliferation and lead to apoptosis.
Behaviour management or institutionalised repression? Children’s experiences of physical restraint in custody
Authors: Shenton Felicity , Smith Roger
Published: July 2020

This article reports on a study of children's experiences of being physically restrained by staff in a range of custodial settings. The research was carried out in collaboration with a team of young researchers, and generated rich and insightful accounts of children's experiences of legitimised violence in the form of ‘restraint’. These lead us to reflect on whether this is a normal and justifiable feature of custody, or as oppressive and unacceptable to the extent that it represents a form of brutalisation, and an unnecessary, unjustifiable and repressive form of control, where the rights of children are routinely transgressed.
Defining appropriateness criteria for endoscopic sinus surgery in the management of adult dental implant patients with incidental maxillary sinus findings on conebeam computed tomography
Authors: Amin Nikul , Walker Abigail , Alobid Isam , Anari Shahram , Bast Florian , Bhalla Rajiv K. , Cathcart Russell , Harries Philip G. , Hathorn Iain , Philpott Carl M. , Ramakrishnan Yujay , Stew Benjamin , Surda Pavol , Ting Fiona , Hopkins Claire
Published: July 2020

Objectives

Conebeam computed tomography (CBCT) imaging is commonly requested by dental implant surgeons, preoperatively, for patients being considered for dental implants. Incidental maxillary sinus findings often result in otolaryngology (ENT) referral for further assessment.

CBCT findings include transient and benign mucosal changes that may not require any intervention and therefore unnecessarily delay implant surgery.

We aim to define appropriateness criteria for ESS in the management of adult dental implant patients with incidental maxillary sinus findings on CBCT and provide guidance to both dental implant and ENT surgeons.

Design

The RAND/UCLA appropriateness methodology was used to develop and define the appropriateness criteria.

Setting

A virtual panel of 13 international experts in ESS.

Participants

The expert panel completed two rounds of a modified Delphi ranking process for nine clinical scenarios, considering various factors affecting decision‐making processes.

Main outcome measures

To define appropriateness criteria for ESS in adult dental implant patients who have incidental maxillary sinus findings on CBCT.

Results

Patients with clinical symptoms and endoscopic findings of chronic rhinosinusitis together with an obstructed ostiomeatal complex (OMC) and concentric mucosal thickening of the ipsilateral maxillary sinus or pansinusitis were deemed appropriate candidates for ESS prior to their dental implant. ESS was not appropriate in asymptomatic patients with a patent OMC and mucosal thickening isolated to floor of the ipsilateral maxillary sinus.

For uncertain scenarios, further discussion between dental implant and ENT surgeon should be considered.

Conclusions

This study has developed and reported a list of appropriateness criteria to offer ESS in adult dental implant patients with incidental maxillary sinus findings on CBCT.
Is that a pibu or a pibo? Children with reading and language deficits show difficulties in learning and overnight consolidation of phonologically similar pseudowords
Authors: Malins Jeffrey G. , Landi Nicole , Ryherd Kayleigh , Frijters Jan C. , Magnuson James S. , Rueckl Jay G. , Pugh Kenneth R. , Sevcik Rose , Morris Robin
Published: July 2020

Word learning is critical for the development of reading and language comprehension skills. Although previous studies have indicated that word learning is compromised in children with reading disability (RD) or developmental language disorder (DLD), it is less clear how word learning difficulties manifest in children with comorbid RD and DLD. Furthermore, it is unclear whether word learning deficits in RD or DLD include difficulties with offline consolidation of newly learned words. In the current study, we employed an artificial lexicon learning paradigm with an overnight design to investigate how typically developing (TD) children (N = 25), children with only RD (N = 93), and children with both RD and DLD (N = 34) learned and remembered a set of phonologically similar pseudowords. Results showed that compared to TD children, children with RD exhibited: (i) slower growth in discrimination accuracy for cohort item pairs sharing an onset (e.g. pibu‐pibo), but not for rhyming item pairs (e.g. pibu‐dibu); and (ii) lower discrimination accuracy for both cohort and rhyme item pairs on Day 2, even when accounting for differences in Day 1 learning. Moreover, children with comorbid RD and DLD showed learning and retention deficits that extended to unrelated item pairs that were phonologically dissimilar (e.g. pibu‐tupa), suggestive of broader impairments compared to children with only RD. These findings provide insights into the specific learning deficits underlying RD and DLD and motivate future research concerning how children use phonological similarity to guide the organization of new word knowledge.
The influence of an acute bout of moderate‐intensity cycling exercise on sensorimotor integration
Authors: Brown Katlyn E. , Neva Jason L. , Mang Cameron S. , Chau Briana , Chiu Larissa K. , Francisco Beatrice A. , Staines William R. , Boyd Lara A.
Published: July 2020

Acute cycling exercise can modulate motor cortical circuitry in the non‐exercised upper‐limb. Within the primary motor cortex, measures of intracortical inhibition are reduced and intracortical facilitation is enhanced following acute exercise. Further, acute cycling exercise decreases interhemispheric inhibition between the motor cortices and lowers cerebellar‐to‐motor cortex inhibition. Yet, investigations into the effects of acute exercise on sensorimotor integration, referring to the transfer of incoming afferent information from the primary somatosensory cortex to motor cortex, are lacking. The current work addresses this gap in knowledge with two experimental sessions. In the first session, we tested the exercise‐induced changes in somatosensory and motor excitability by assessing somatosensory (SEP) and motor evoked potentials (MEPs). In the second session, we explored the effects of acute cycling exercise on short‐ (SAI) and long‐latency afferent inhibition (LAI), and afferent facilitation. In both experimental sessions, neurophysiological measures were obtained from the non‐exercised upper‐limb muscle, tested at two time points pre‐exercise separated by a 25‐min period of rest. Next, a 25‐min bout of moderate‐intensity lower‐limb cycling was performed with measures assessed at two time points post‐exercise. Acute lower‐limb cycling increased LAI, without modulation of SAI or afferent facilitation. Further, there were no exercise‐induced changes to SEP or MEP amplitudes. Together, these results suggest that acute exercise has unique effects on sensorimotor integration, which are not accompanied by concurrent changes in somatosensory or motor cortical excitability.
Asymmetric distribution of pallial‐expressed genes in zebrafish (Danio rerio)
Authors: Messina Andrea , Boiti Alessandra , Vallortigara Giorgio
Published: July 2020

The left and right distribution of a set of twenty‐six genes in the zebrafish pallium was examined by RT‐qPCR experiments. The analysis comprised four general pallial markers (eomesa, emx2, emx3 and prox1); eight genes, dapper1, htr3a, htr3b, htr4, id2, ndr2, pkcβ and lmo4, that have been described as asymmetric distributed in the brain of mammals (human and mouse); six genes, arrb2, auts2, baiap2, fez1, gap43 and robo1, asymmetrically distributed in the mammalian cortex, that have been associated with autism in humans; and, eight genes, baz1b, fzd9, limk1, tubgcp5, cyfip1, grik1a, nipa1 and nipa2, which have been associated with developmental dyscalculia, a brain disability linked to brain laterality in humans. We found a leftward bias in the expression of 10 genes (dapper1, htr3a, htr3b, htr4, id2, ndr2, pkcß, auts2, baiap2 and grik1a) and a rightward bias for 5 genes (lmo4, arrb2, fez1, gap43, robo1) in agreement with the data reported in mammals. We also found a rightward lateralization for nipa1 and nipa2, whereas the remaining genes (eomesa, emx2, emx3, prox1, baz1b, cyfip1, fzd9, limk1 and tubgpc5) were bilaterally distributed. These findings suggest a basic homology in the asymmetric expression of several pallial vertebrate genes.
Workplace Policies and Perinatal Depressive Symptoms Among Low‐Income Single and Partnered Working Mothers
Authors: Newkirk Katie , Perry‐Jenkins Maureen , Laws Holly B. , Hien Michelle
Published: July 2020

Objective

This study examined associations between workplace policies and maternal depression in the context of mothers' relationship status and job characteristics.

Background

The associations between workplace policies and postpartum depressive symptoms may differ based on contextual factors that have received little attention in the literature. In this study, these questions are addressed in an understudied sample of low‐income working mothers.

Method

Participants included 95 employed, low‐income mothers who were recruited from prenatal classes in southern New England. Mothers' self‐reported data was collected at five time points from the third trimester of pregnancy through 12 months postpartum. Multilevel structural equation modeling was used to test all study hypotheses.

Results

Length of parental leave and negative spillover interacted to predict levels of depressive symptoms, such that longer leave mattered more in the context of high spillover. A moderated mediation was found, whereby schedule flexibility related to less of an increase in depressive symptoms for single mothers, whereas partnered mothers with greater schedule flexibility experienced an increase in spillover, with no net benefit to depression.

Conclusion

Contextual factors, such as mothers' relationship status and the level of spillover on the job, can influence whether and how much different types of workplace policies can benefit maternal postpartum mental health.

Implications

Employers also may ease the transition back to work after parental leave by taking steps to minimize negative work‐to‐family spillover for new mothers. More work needs to be done to enable partnered mothers to experience the mental health benefits of schedule flexibility policies.
Association between dietary patterns and prognosis of hepatocellular carcinoma in the Guangdong liver cancer cohort study
Authors: Luo Yun , Zhang Yao‐jun , Zhang Dao‐ming , Yishake Dinuerguli , Liu Zhao‐yan , Chen Min‐shan , Wang Fan , Zhou Zhong‐guo , Long Jing‐an , Zhong Rong‐huan , Chen Si , Lu Xiao‐ting , Li Shu‐yi , He Tong‐tong , Luo Yan , Fang Ai‐ping , Zhu Hui‐lian
Published: July 2020

Aim

Adherence to dietary recommendations has been linked to a reduced risk of developing hepatocellular carcinoma (HCC) and dying of chronic liver disease. However, its role in the prognosis of HCC is still unclear. We prospectively investigated the association of two dietary quality indices, the Chinese Healthy Eating Index (CHEI) and the Healthy Eating Index‐2015 (HEI‐2015), with all‐cause and HCC‐specific mortality in a large prospective cohort of HCC survivors.

Methods

We included 887 patients with newly diagnosed, previously untreated HCC enrolled in the Guangdong Liver Cancer Cohort (GLCC) between September 2013 and April 2017 in the analysis. CHEI and HEI‐2015 scores were calculated based on the dietary intake in the year before diagnosis of HCC. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for each index.

Results

During a median follow‐up of 797 days, 389 deaths were identified, including 347 from HCC. Higher CHEI scores, reflecting favorable adherence to the 2016 Dietary Guidelines for Chinese, were associated with a lower risk of all‐cause mortality (T3 vs. T1: HR = 0.75, 95% CI: 0.58–0.98) and HCC‐specific mortality (T3 vs. T1: HR = 0.74, 95% CI: 0.56–0.98). Non‐significant, inverse associations of HEI‐2015 score with all‐cause mortality (T3 vs. T1: HR = 0.86, 95% CI: 0.67–1.11) and HCC‐specific mortality (T3 vs. T1: HR = 0.93, 95% CI: 0.71–1.21) were suggested.

Conclusions

Our findings suggest that better adherence to the 2016 Dietary Guidelines for Chinese may reduce the risk of all‐cause and HCC‐specific mortality in patients with HCC.