bluuebunny/crossref_metadata_2025 huggingface dataset:
The effectiveness of early colchicine administration in patients over 60 years old with high risk of developing severe pulmonary complications associated with coronavirus pneumonia SARS-CoV-2 (COVID-19): study protocol for an investigator-driven randomized controlled clinical trial in primary health care—COLCHICOVID study
Authors: Estebanez Elena Bustamante , Alconero Lucía Lavín , Fernández Beatriz Josa , Marguello Monica Gozalo , Caro Juan Carlos López , Vallejo Jonathan Diez , Sampedro Marta Fernandez , Cacho Pedro Muñoz , Espiga Carlos Richard , Saiz María Mar García
Published: September 2021

Background

There is no strong evidence that any drug is beneficial either for the treatment of SARS-CoV-2 disease or for post-exposure prophylaxis. Therefore, clinical research is crucial to generate results and evaluate strategies against COVID-19. Primary care (PC) centers, the first level of care in the health system, are in a favorable position to carry out clinical trials (CD), as they work with a large volume of patients with varied profiles (from acute to chronic pathologies). During the COVID-19 pandemic, the need for hospital admission and mortality is higher in people > 60 years. Therefore, this is a target population to try to reduce the serious complications and lethality of COVID pneumonia and to avoid overloading the hospital system. Given the pharmacological properties of colchicine (anti-inflammatory and anti-fibrotic, possible inhibition of viral replication, and inhibitory effect on coagulation activation), early treatment with colchicine may reduce the rate of death and serious pulmonary complications from COVID-19 in vulnerable patients.

Methods

The COLCHICOVID study is a randomized, multicenter, controlled, open-label parallel group (2:1 ratio), phase III clinical trial to investigate the efficacy of early administration of colchicine in reducing the development of severe pulmonary complications associated with COVID-19 infection in patients over 60 years of age with at-risk comorbidities.

Discussion

This is a pragmatic clinical trial, adapted to usual clinical practice.

The demonstration that early administration of colchicine has clinical effectiveness in reducing the complications of SARS-CoV-2 infection in a population highly susceptible may mitigate the health crisis and prevent the collapse of the health system in the successive waves of the coronavirus pandemic. In addition, colchicine is a well-known medicine, simple to use in the primary care setting and with a low cost for the health system.

Trial registration

ClinicalTrials.govNCT04416334. Registered on 4 June 2020. Protocol version: v 3.0, dated 22 September 2020.
Postpartum Early EMDR therapy Intervention (PERCEIVE) study for women after a traumatic birth experience: study protocol for a randomized controlled trial
Authors: Hendrix Y. M. G. A. , van Dongen K. S. M. , de Jongh A. , van Pampus M. G.
Published: September 2021

Background

Up to 33% of women develop symptoms of posttraumatic stress disorder (PTSD) after a traumatic birth experience. Negative and traumatic childbirth experiences can also lead to fear of childbirth, avoiding or negatively influencing a subsequent pregnancy, mother-infant bonding problems, problems with breastfeeding, depression and reduced quality of life. For PTSD in general, eye movement desensitization and reprocessing (EMDR) therapy has proven to be effective. However, little is known about the preventive effects of early intervention EMDR therapy in women after a traumatic birth experience. The purpose of this study is to determine the effectiveness of early intervention EMDR therapy in preventing PTSD and reducing PTSD symptoms in women with a traumatic birth experience.

Methods

The PERCEIVE study is a randomized controlled trial. Women suffering from the consequences of a traumatic birth experience will be randomly allocated at maximum 14 days postpartum to either EMDR therapy or ‘care-as-usual’. Patients in the EMDR group receive two sessions of therapy between 14 (T0) and 35 days postpartum. All participants will be assessed at T0 and at 9 weeks postpartum (T1). At T1, all participants will undergo a CAPS-5 interview about the presence and severity of PTSD symptoms. The primary outcome measure is the severity of PTSD symptoms, whereas the secondary outcomes pertain to fear of childbirth, mother-infant bonding, breastfeeding, depression and quality of life. The study will be conducted at a large city hospital and at multiple midwifery practices in Amsterdam, the Netherlands.

Discussion

It is to be expected that the results of this study will provide more insight about the safety and effectiveness of early intervention EMDR therapy in the prevention and reduction of PTSD (symptoms) in women with a traumatic birth experience.

Trial registration

Netherlands Trial Register NL73231.000.20. Registered on 21 August 2020.
Rapid assessment of West Nile virus circulation in a German zoo based on honey-baited FTA cards in combination with box gravid traps
Authors: Fynmore Noelle , Lühken Renke , Maisch Heike , Risch Tina , Merz Sabine , Kliemke Konstantin , Ziegler Ute , Schmidt-Chanasit Jonas , Becker Norbert
Published: September 2021

Background

For over a decade, monitoring of West Nile virus (WNV) in Germany has consisted of a bird monitoring programme as well as a mosquito-based surveillance programme employing CO2-baited encephalitis vector surveillance (EVS) traps for mass trapping and screening of mosquitoes. In contrast to the EVS traps, the Reiter/Cummings type box gravid trap collects gravid female mosquitoes, which have already taken a blood meal, increasing the likelihood of being infected with pathogens. The traps can be equipped with a honey-baited Flinders Technology Associates® (FTA) card to encourage sugar feeding by the trapped mosquitoes. FTA cards contain nucleic acid preserving substances, which prevent the degradation of viral RNA in the expectorated mosquito saliva and allows for testing the card for flavivirus RNA. This study aimed to assess the suitability of the method for WNV surveillance in Germany as an alternative to previous methods, which are expensive, time-consuming, and predominantly target host-seeking populations less likely to be infected with WNV.

Methods

In the Thüringer Zoopark Erfurt, snowy owls (Nyctea scandiaca) and greater flamingos (Phoenicopterus roseus) died of WNV infections in July and August 2020. In response, five Reiter/Cummings type box gravid traps were positioned during the daytime on the 10th, 13th, and 16th of September in five different locations. The FTA cards and mosquitoes in the chamber were collected, kept in a cool chain, and further processed for virus detection using a modified generic flavivirus reverse transcription PCR.

Results

A total of 15 trappings during September collected a total of 259 female mosquitoes, 97% of which were Culex pipiens sensu lato, as well as 14 honey-baited FTA cards. Eight mosquitoes tested PCR-positive for WNV. Four FTA cards tested PCR-positive for mosquito-borne flaviviruses, two of which were confirmed as WNV, and the remaining two confirmed as Usutu virus.

Conclusion

The suitability of the FTA cards in preserving viral RNA in the field and rapid turnaround time from collection to result is combined with a simple, cost-effective, and highly specific trapping method to create an arbovirus surveillance system, which circumvents many of the difficulties of previous surveillance programmes that required the analysis of mosquitoes in the laboratory.

Graphical Abstract
In vitro and in vivo efficacy of thiacloprid against Echinococcus multilocularis
Authors: Liu Chuanchuan , Fan Haining , Ma Jie , Ma Lan , Ge Ri-li
Published: September 2021

Background

Alveolar echinococcosis (AE) is a chronic zoonosis caused by the larval form ofEchinococcus multilocularis(E. multilocularis). Current chemotherapy against AE has relied on albendazole and mebendazole, which only exhibit parasitostatic and not parasiticidal efficacy. Therefore, novel compounds for the treatment of this disease are needed.

Methods

Phosphoglucose isomerase (PGI) assays were used for compound screening of seven neonicotinoids. The anti-parasitic effects of thiacloprid were then evaluated onE. multilocularismetacestode vesicles, germinal cells and protoscoleces in vitro. Human foreskin fibroblasts (HFF) and Reuber rat hepatoma (RH) cells were used to assess cytotoxicity. Glucose consumption inE. multilocularisprotoscoleces and germinal cells was assessed by measuring uptake of 2-deoxyglucose (2-DG). Molecular docking was used to evaluate the potential binding sites of thiacloprid to acetylcholine receptors. In vivo efficacy of thiacloprid was evaluated in mice by secondary infection withE. multilocularis. In addition, ELISA and flow cytometry were used to evaluate the effects of cytokines and T lymphocyte subsets after thiacloprid treatment. Furthermore, collagen deposition and degradation in the host lesion microenvironment were evaluated.

Results

We found that thiacloprid is the most promising compound, with an IC50of 4.54 ± 1.10 μM and 2.89 ± 0.34 μM, respectively, against in vitro-culturedE. multilocularismetacestodes and germinal cells. Thiacloprid was less toxic for HFF and RH mammalian cell lines than for metacestodes. In addition, thiacloprid inhibited the acetylcholinesterase activity in protoscoleces, metacestodes and germinal cells. Thiacloprid inhibited glucose consumption by protoscoleces and germinal cells. Subsequently, transmission electron microscopy revealed that treatment with thiacloprid damaged the germinal layer. In vivo, metacestode weight was significantly reduced following oral administration of thiacloprid at 15 and 30 mg/kg. The level of CD4+T lymphocytes in metacestodes and spleen increased after thiacloprid treatment. Anti-echinococcosis-related cytokines (IL-2, IL-4, IL-10) were significantly increased. Furthermore, thiacloprid inhibited the expression of matrix metalloproteinases (MMPs 1, 3, 9, 13) and promoted collagen deposition in the host lesion microenvironment.

Conclusions

The results demonstrated that thiacloprid had parasiticidal activity againstE. multilocularisin vitro and in vivo, and could be used as a novel lead compound for the treatment of AE.

Graphical abstract
Population genetics and phylogeography of Tabanus bromius (Diptera: Tabanidae)
Authors: Sanal Demirci Sumeyra Nur , Kilic Volkan , Mutun Serap , Kilic A. Yavuz
Published: September 2021

Background

Tabanus bromius(Diptera: Tabanidae) is one of the most notable Tabanidae species of veterinary and medical importance distributed throughout the Palearctic region. In this study, we investigate the genetic diversity and the phylogeographic structure ofT. bromiussampled from Turkey, Croatia, and Iran.

Methods

For this purpose, a 686-base-pair (bp) fragment of mitochondrial DNA cytochrome oxidase I gene (COI) and 1339 bp of the nuclear DNA internal transcribed spacer (ITS) were sequenced from 247 individuals representing 15 populations.

Results

The sequences generated 169COIhaplotypes and 90 ITS alleles. A higher haplotype/allele diversity (h = 0.9909 for theCOIgene and Ad = 0.8193 for the ITS region) compared to a low nucleotide diversity (π = 0.020605 forCOIgene andπ = 0.013667 for the ITS region), present for a high number of singleton and private haplotypes/alleles imply population expansion in the past. The results of phylogenetic analysis led to the uncovering of geographically significant groupings of lineages with regard to the entrance of the species into Anatolia and the location of major geographic barriers. According to current data, the species appears to have entered Turkey from Caucasia and Iran. A molecular clock applied to theCOIdata suggests thatT. bromiusdiverged from the outgroup species nearly 8.83 million years ago, around the end of the Miocene era.

Conclusions

The results of this study indicate remarkable genetic diversity across the studied range of the species. High haplotype/allele versus low nucleotide diversity and demographic analyses implied that theT. bromiuspopulations have undergone a series of expansions and retreats in the past. Our current findings suggest thatT. bromiussplit from outgroups around the Late Miocene. Subsequent diversification events during the climatic and environmental fluctuation times of the Late Pliocene and Early Pleistocene periods also significantly influenced the species, resulting in the formation of some major genetic lineages. The phylogenetic analyses indicate thatT. bromiusmost likely entered Turkey from the Caucasus region and Iran.

Graphical Abstract
Developmental programming of DNA methylation and gene expression patterns is associated with extreme cardiovascular tolerance to anoxia in the common snapping turtle
Authors: Ruhr Ilan , Bierstedt Jacob , Rhen Turk , Das Debojyoti , Singh Sunil Kumar , Miller Soleille , Crossley Dane A. , Galli Gina L. J.
Published: September 2021

Background

Environmental fluctuation during embryonic and fetal development can permanently alter an organism’s morphology, physiology, and behaviour. This phenomenon, known as developmental plasticity, is particularly relevant to reptiles that develop in subterranean nests with variable oxygen tensions. Previous work has shown hypoxia permanently alters the cardiovascular system of snapping turtles and may improve cardiac anoxia tolerance later in life. The mechanisms driving this process are unknown but may involve epigenetic regulation of gene expression via DNA methylation. To test this hypothesis, we assessed in situ cardiac performance during 2 h of acute anoxia in juvenile turtles previously exposed to normoxia (21% oxygen) or hypoxia (10% oxygen) during embryogenesis. Next, we analysed DNA methylation and gene expression patterns in turtles from the same cohorts using whole genome bisulfite sequencing, which represents the first high-resolution investigation of DNA methylation patterns in any reptilian species.

Results

Genome-wide correlations between CpG and CpG island methylation and gene expression patterns in the snapping turtle were consistent with patterns observed in mammals. As hypothesized, developmental hypoxia increased juvenile turtle cardiac anoxia tolerance and programmed DNA methylation and gene expression patterns. Programmed differences in expression of genes such asSCN5Amay account for differences in heart rate, while genes such asTNNT2andTPM3may underlie differences in calcium sensitivity and contractility of cardiomyocytes and cardiac inotropy. Finally, we identified putative transcription factor-binding sites in promoters and in differentially methylated CpG islands that suggest a model linking programming of DNA methylation during embryogenesis to differential gene expression and cardiovascular physiology later in life. Binding sites for hypoxia inducible factors (HIF1A, ARNT, and EPAS1) and key transcription factors activated by MAPK and BMP signaling (RREB1 and SMAD4) are implicated.

Conclusions

Our data strongly suggests that DNA methylation plays a conserved role in the regulation of gene expression in reptiles. We also show that embryonic hypoxia programs DNA methylation and gene expression patterns and that these changes are associated with enhanced cardiac anoxia tolerance later in life. Programming of cardiac anoxia tolerance has major ecological implications for snapping turtles, because these animals regularly exploit anoxic environments throughout their lifespan.
Comparison of in-person versus tele-ultrasound point-of-care ultrasound training during the COVID-19 pandemic
Authors: Soni Nilam J. , Boyd Jeremy S. , Mints Gregory , Proud Kevin C. , Jensen Trevor P. , Liu Gigi , Mathews Benji K. , Schott Christopher K. , Kurian Linda , LoPresti Charles M. , Andrus Phil , Nathanson Robert , Smith Natalie , Haro Elizabeth K. , Mader Michael J. , Pugh Jacqueline , Restrepo Marcos I. , Lucas Brian P.
Published: September 2021

Background

Lack of training is currently the most common barrier to implementation of point-of-care ultrasound (POCUS) use in clinical practice, and in-person POCUS continuing medical education (CME) courses have been paramount in improving this training gap. Due to travel restrictions and physical distancing requirements during the COVID-19 pandemic, most in-person POCUS training courses were cancelled. Though tele-ultrasound technology has existed for several years, use of tele-ultrasound technology to deliver hands-on training during a POCUS CME course has not been previously described.

Methods

We conducted a retrospective observational study comparing educational outcomes, course evaluations, and learner and faculty feedback from in-person versus tele-ultrasound POCUS courses. The same POCUS educational curriculum was delivered to learners by the two course formats. Data from the most recent pre-pandemic in-person course were compared to tele-ultrasound courses during the COVID-19 pandemic.

Results

Pre- and post-course knowledge test scores of learners from the in-person (n = 88) and tele-ultrasound course (n = 52) were compared. Though mean pre-course knowledge test scores were higher among learners of the tele-ultrasound versus in-person course (78% vs. 71%; p = 0.001), there was no significant difference in the post-course test scores between learners of the two course formats (89% vs. 87%; p = 0.069). Both learners and faculty rated the tele-ultrasound course highly (4.6–5.0 on a 5-point scale) for effectiveness of virtual lectures, tele-ultrasound hands-on scanning sessions, and course administration. Faculty generally expressed less satisfaction with their ability to engage with learners, troubleshoot image acquisition, and provide feedback during the tele-ultrasound course but felt learners completed the tele-ultrasound course with a better basic POCUS skillset.

Conclusions

Compared to a traditional in-person course, tele-ultrasound POCUS CME courses appeared to be as effective for improving POCUS knowledge post-course and fulfilling learning objectives. Our findings can serve as a roadmap for educators seeking guidance on development of a tele-ultrasound POCUS training course whose demand will likely persist beyond the COVID-19 pandemic.
Correlation between short- and mid-term hemoglobin A1c and glycemic control determined by continuous glucose monitoring
Authors: Huang Jen-Hung , Lin Yung-Kuo , Lee Ting-Wei , Liu Han-Wen , Chien Yu-Mei , Hsueh Yu-Chun , Lee Ting-I , Chen Yi-Jen
Published: September 2021

Background

Glucose monitoring is vital for glycemic control in patients with diabetes mellitus (DM). Continuous glucose monitoring (CGM) measures whole-day glucose levels. Hemoglobin A1c (HbA1c) is a vital outcome predictor in patients with DM.

Methods

This study investigated the relationship between HbA1c and CGM, which remained unclear hitherto. Data of patients with DM (n = 91) who received CGM and HbA1c testing (1–3 months before and after CGM) were retrospectively analyzed. Diurnal and nocturnal glucose, highest CGM data (10%, 25%, and 50%), mean amplitude of glycemic excursions (MAGE), percent coefficient of variation (%CV), and continuous overlapping net glycemic action were compared with HbA1c values before and after CGM.

Results

The CGM results were significantly correlated with HbA1c values measured 1 (r = 0.69) and 2 (r = 0.39) months after CGM and 1 month (r = 0.35) before CGM. However, glucose levels recorded in CGM did not correlate with the HbA1c values 3 months after and 2–3 months before CGM. MAGE and %CV were strongly correlated with HbA1c values 1 and 2 months after CGM, respectively. Diurnal blood glucose levels were significantly correlated with HbA1c values 1–2 months before and 1 month after CGM. The nocturnal blood glucose levels were significantly correlated with HbA1c values 1–3 months before and 1–2 months after CGM.

Conclusions

CGM can predict HbA1c values within 1 month after CGM in patients with DM.
Incidence, severity and perceived susceptibility of COVID-19 in the UK CrossFit population
Authors: Redwood-Brown Athalie , Ralston Grant William , Wilson Jennifer
Published: September 2021

Background

Contemporary literature indicates that a higher body mass index (BMI) serves as a risk factor for metabolic disease and is also correlated with greater disease severity. Subsequently, it has been linked to increased COVID-19 severity. The purpose of the study was to investigate whether regular CrossFit™ participation was associated with lower BMI, decreased COVID-19 severity and susceptibility.

Methods

A cross-sectional study was conducted on 1806 CrossFit™ (CF) participants. Participants were asked about their age (yrs), sex (male vs. female), ethnic group, body height (cm) and weight (kg). Body mass index (BMI, kg/m2) was computed and consistent with WHO (2018) criteria. Participants self-reported their training history, health and lifestyle history, nutritional customs, present training status and suspected levels of exposure to COVID-19. Once submitted the collected data were coded, cleaned and analysed.

Results

The final model comprised of 1806 CF individuals from an online survey response rate of 2086. The participants age ranged from 18 to 65+ yrs. Self-reported mean body mass index (BMI: kg/m2) reported that < 1% were underweight, 41% were healthy, 46% overweight, 10% class I obese, 2% class II obese, and < 1% class III obese. A Kruskal–Wallis H test compared gender and self-reported probability of being infected with COVID-19 with significant differences between subgroups (x2 (4, N = 1739) = 10.86, p = 0.03). Analysis of BMI and perceived severity of COVID-19 revealed a difference however not, significant (x2 (4, N = 1739) = 9.46, p = 0.051). Results on BMI and perceived probability of COVID-19 infection revealed no significant difference (x2 (4, N = 1739) = 2.68, p = 0.61). A separate analysis on BMI and perceived COVID-19 susceptibility revealed no significant difference (x2 (4, N = 1740) = 6.02, p = 0.20).

Conclusions

The purpose of the study was to establish whether habitual CrossFit™ participation is associated with reduced BMI, and to further investigate whether habitual participation impacted perceptions of disease. Results of the study indicate that self-reported CrossFit™ participation during the first UK lockdown, measured in minutes of exercise was indicative of a lower BMI. This has been associated with greater host immunity to disease. A history of CrossFit™ participation was not shown to impact perceptions of disease. However, our sample population reported few changes to habitual exercise during lockdown which may be due to the ‘community’ and increased adherence associated with CrossFit™.
Predicting progression and cognitive decline in amyloid-positive patients with Alzheimer’s disease
Authors: Dansson Hákon Valur , Stempfle Lena , Egilsdóttir Hildur , Schliep Alexander , Portelius Erik , Blennow Kaj , Zetterberg Henrik , Johansson Fredrik D. ,   for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: September 2021

Background

In Alzheimer’s disease, amyloid-β(Aβ) peptides aggregate in the lowering CSF amyloid levels - a key pathological hallmark of the disease. However, lowered CSF amyloid levels may also be present in cognitively unimpaired elderly individuals. Therefore, it is of great value to explain the variance in disease progression among patients with Aβpathology.

Methods

A cohort ofn=2293 participants, of whomn=749 were Aβpositive, was selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to study heterogeneity in disease progression for individuals with Aβpathology. The analysis used baseline clinical variables including demographics, genetic markers, and neuropsychological data to predict how the cognitive ability and AD diagnosis of subjects progressed using statistical models and machine learning. Due to the relatively low prevalence of Aβpathology, models fit only to Aβ-positive subjects were compared to models fit to an extended cohort including subjects without established Aβpathology, adjusting for covariate differences between the cohorts.

Results

Aβpathology status was determined based on the Aβ42/Aβ40ratio. The best predictive model of change in cognitive test scores for Aβ-positive subjects at the 2-year follow-up achieved anR2score of 0.388 while the best model predicting adverse changes in diagnosis achieved a weightedF1score of 0.791. Aβ-positive subjects declined faster on average than those without Aβpathology, but the specific level of CSF Aβwas not predictive of progression rate. When predicting cognitive score change 4 years after baseline, the best model achieved anR2score of 0.325 and it was found that fitting models to the extended cohort improved performance. Moreover, using all clinical variables outperformed the best model based only on a suite of cognitive test scores which achieved anR2score of 0.228.

Conclusion

Our analysis shows that CSF levels of Aβare not strong predictors of the rate of cognitive decline in Aβ-positive subjects when adjusting for other variables. Baseline assessments of cognitive function accounts for the majority of variance explained in the prediction of 2-year decline but is insufficient for achieving optimal results in longer-term predictions. Predicting changes both in cognitive test scores and in diagnosis provides multiple perspectives of the progression of potential AD subjects.
Late reinfection with a different severe acute respiratory syndrome coronavirus-2 clade in a patient with refractory arterial hypertension: a case report
Authors: García-Abellán Javier , Galiana Antonio , Fernández-González Marta , Gonzalo-Jiménez Nieves , Ruiz-García Montserrat , Botella Angela , Sanchis Joan , Mascarell Paula , Falcón Selene , Masiá Mar , Gutiérrez Félix
Published: September 2021

Background

Differentiating between persistent infection with intermittent viral shedding and reinfection with severe acute respiratory syndrome coronavirus 2 remains challenging. Although a small number of cases with genomic evidence of second infection have been reported, limited information exists on frequency and determinants of reinfection, time between infections, and duration of immunity after the primary infection.

Case presentation

We report a reinfection with severe acute respiratory syndrome coronavirus 2 in a 52-year-old caucasian male whose primary infection was diagnosed in May 2020, during the first wave of the pandemic in Spain, and the second occurred 8 months later, in January 2021. We present a complete dataset including results from real-time polymerase chain reaction, serology, and genome sequencing confirming reinfection with a different clade. Noteworthy was that the patient was immunocompetent but had multiple cardiometabolic comorbidities, including refractory arterial hypertension, that might increase the individual risk in coronavirus disease 2019.

Conclusions

This case of reinfection with severe acute respiratory syndrome coronavirus 2 occurring several months after the primary infection reports the longest time interval between reinfection and initial infection described to date. It raises concerns on the duration of protective immunity, suggesting that it may begin to wane in patients who acquired the initial infection during the first wave of the pandemic. The potential contributing role of arterial hypertension and cardiometabolic comorbidities as risk factors for reinfection deserves investigation.
Translational models of 3-D organoids and cancer stem cells in gastric cancer research
Authors: Wuputra Kenly , Ku Chia-Chen , Kato Kohsuke , Wu Deng-Chyang , Saito Shigeo , Yokoyama Kazunari K.
Published: September 2021

It is postulated as a general concept of cancer stem cells (CSCs) that they can produce cancer cells overtly and repopulate cancer progenitor cells indefinitely. The CSC niche is part of a specialized cancer microenvironment that is important to keep the phenotypes of CSCs. Stem cell- and induced pluripotent stem cell (iPSC)-derived organoids with genetic manipulation are beneficial to the investigation of the regulation of the microenvironment of CSCs. It would be useful to assess the efficiency of the cancer microenvironment on initiation and progression of cancers. To identify CSCs in cancer tissues, normal cell organoids and gastric cancer organoids from the cancerous areas, as well as iPSCs, were established several years ago. However, many questions remain about the extent to which these cultures recapitulate the development of the gastrointestinal tract and the mechanism of Helicobacter pylori-induced cancer progression. To clarify the fidelity of human organoid models, we have noted several key issues for the cultivation of, and differences between, normal and cancerous organoids. We developed precise culture conditions for gastric organoids in vitro to improve the accuracy of the generation of organoid models for therapeutic and medical applications. In addition, the current knowledge on gastrointestinal CSC research, including the topic of CSC markers, cancer cell reprogramming, and application to target cancer cell plasticity through niches, should be reinforced. We discuss the progression of cancers derived from human gastric organoids and the identification of CSCs.
Computational Applications in Secondary Metabolite Discovery (CAiSMD): an online workshop
Authors: Ntie-Kang Fidele , Telukunta Kiran K. , Fobofou Serge A. T. , Chukwudi Osamor Victor , Egieyeh Samuel A. , Valli Marilia , Djoumbou-Feunang Yannick , Sorokina Maria , Stork Conrad , Mathai Neann , Zierep Paul , Chávez-Hernández Ana L. , Duran-Frigola Miquel , Babiaka Smith B. , Tematio Fouedjou Romuald , Eni Donatus B. , Akame Simeon , Arreyetta-Bawak Augustine B. , Ebob Oyere T. , Metuge Jonathan A. , Bekono Boris D. , Isa Mustafa A. , Onuku Raphael , Shadrack Daniel M. , Musyoka Thommas M. , Patil Vaishali M. , van der Hooft Justin J. J. , da Silva Bolzani Vanderlan , Medina-Franco José L. , Kirchmair Johannes , Weber Tilmann , Tastan Bishop Özlem , Medema Marnix H. , Wessjohann Ludger A. , Ludwig-Müller Jutta
Published: September 2021

We report the major conclusions of the online open-access workshop “Computational Applications in Secondary Metabolite Discovery (CAiSMD)” that took place from 08 to 10 March 2021. Invited speakers from academia and industry and about 200 registered participants from five continents (Africa, Asia, Europe, South America, and North America) took part in the workshop. The workshop highlighted the potential applications of computational methodologies in the search for secondary metabolites (SMs) or natural products (NPs) as potential drugs and drug leads. During 3 days, the participants of this online workshop received an overview of modern computer-based approaches for exploring NP discovery in the “omics” age. The invited experts gave keynote lectures, trained participants in hands-on sessions, and held round table discussions. This was followed by oral presentations with much interaction between the speakers and the audience. Selected applicants (early-career scientists) were offered the opportunity to give oral presentations (15 min) and present posters in the form of flash presentations (5 min) upon submission of an abstract. The final program available on the workshop website (https://caismd.indiayouth.info/) comprised of 4 keynote lectures (KLs), 12 oral presentations (OPs), 2 round table discussions (RTDs), and 5 hands-on sessions (HSs). This meeting report also references internet resources for computational biology in the area of secondary metabolites that are of use outside of the workshop areas and will constitute a long-term valuable source for the community. The workshop concluded with an online survey form to be completed by speakers and participants for the goal of improving any subsequent editions.
Periodic solutions for second-order difference equations with quadratic–supquadratic condition
Authors: Ding Liang , Tian Rongrong , Wei Jinlong
Published: September 2021

In this paper, we consider the existence of multiple periodic solutions for a class of second-order difference equations with quadratic–supquadratic growth condition at infinity. Moreover, we give three examples to illustrate our main result.
Effects of supplemental xylanase and xylooligosaccharides on production performance and gut health variables of broiler chickens
Authors: Singh Amit K. , Mishra Birendra , Bedford Michael R. , Jha Rajesh
Published: September 2021

Background

This study evaluated the effects of supplemental xylanase and xylooligosaccharides (XOS) in a corn-soybean meal (SBM)-based diet on growth performance and intestinal health of broilers. A total of 288 day-old chicks (Cobb 500) were allocated to 36 floor pens (8 birds/pen) equally in 9 dietary treatments in a 3 × 3 factorial arrangement. The treatments were combinations of 3 levels of xylanase (0, 0.005% and 0.01% Econase XT) and 3 levels of prebiotics (0, 0.005% and 0.01% XOS) added to basal mash diets formulated in three phases (starter, d 0–14; grower, d 15–28; finisher, d 29–42). The feed intake and body weights were recorded weekly. On d 42, ileal sections were collected for histomorphometric and gene expression analysis, and cecal content was collected for determining short-chain fatty acids (SCFA) and microbiota.

Results

Xylanase linearly (P < 0.01) increased the average daily gain (ADG) in both the finisher and total period and the final body weight gain (FBWG, 2940 & 2932 vs. 2760 g) of broilers. XOS did not significantly increase either ADG or FBWG (P > 0.05). Supplemental xylanase and XOS did not affect average daily feed intake and feed conversion ratio (P > 0.05). Xylanase and XOS did not change villus height (VH) or crypt depth (CD) ratio (P > 0.05). However, xylanase exhibited a trend (P = 0.097) on VH:CD ratio. The inclusion of 0.01% XOS without xylanase increased the level of IL-10 (a marker of anti-inflammatory cytokine) and IL-4 (a T-cell differentiation cytokine) genes compared with control (P < 0.05). The acetate production was increased by xylanase (P < 0.01) and XOS (P < 0.05) without an additive effect. Xylanase increased total SCFA (P < 0.01) while XOS had a tendency to increase (P = 0.052). Alpha and beta diversity of microbiota among treatments were not different (P > 0.05). However, the mean proportion of familyRuminococcaceaewas increased by the supplemental 0.01% xylanase (P < 0.01).

Conclusion

It can be concluded that XOS can enhance cecal fermentation, while xylanase can increase the body weight gain along with the fermentation metabolites in the ceca of broilers fed the corn-SBM-based diet but the effects may not always translate into an improved mucosal absorptive capacity and a better feed efficiency.
Unsupervised feature learning-based encoder and adversarial networks
Authors: Suryawati Endang , Pardede Hilman F. , Zilvan Vicky , Ramdan Ade , Krisnandi Dikdik , Heryana Ana , Yuwana R. Sandra , Kusumo R. Budiarianto Suryo , Arisal Andria , Supianto Ahmad Afif
Published: September 2021

In this paper, we propose a novel deep learning-based feature learning architecture for object classification. Conventionally, deep learning methods are trained with supervised learning for object classification. But, this would require large amount of training data. Currently there are increasing trends to employ unsupervised learning for deep learning. By doing so, dependency on the availability of large training data could be reduced. One implementation of unsupervised deep learning is for feature learning where the network is designed to “learn” features automatically from data to obtain good representation that then could be used for classification. Autoencoder and generative adversarial networks (GAN) are examples of unsupervised deep learning methods. For GAN however, the trajectories of feature learning may go to unpredicted directions due to random initialization, making it unsuitable for feature learning. To overcome this, a hybrid of encoder and deep convolutional generative adversarial network (DCGAN) architectures, a variant of GAN, are proposed. Encoder is put on top of the Generator networks of GAN to avoid random initialisation. We called our method as EGAN. The output of EGAN is used as features for two deep convolutional neural networks (DCNNs): AlexNet and DenseNet. We evaluate the proposed methods on three types of dataset and the results indicate that better performances are achieved by our proposed method compared to using autoencoder and GAN.
Leopard syndrome: the potential cardiac defect underlying skin phenotypes
Authors: Yue Xiaojie , Zhao Xiong , Dai Yefeng , Yu. Lan
Published: September 2021

LEOPARD syndrome (OMIM #151,100) caused by a germline PTPN11 mutation are characterized as multisystemic anomalies and variable marked phenotypes such as multiple lentigines and cafe´-au-lait spots, electrocardiographic conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Phenotype overlap complicates clinical discrimination within RASopathies, making the diagnosis of LEOPARD more confusing and challenging. Besides, LEOPARD patients do not usually present with all these typical clinical features, increasing the possibility of underdiagnosis or misdiagnosis.

Herein, we report a case of LEOPARD syndrome in a patient who only presented with pigmented skin spots and was initially diagnosed with multiple acquired melanocytic nevi. Subsequent pathological examination confirmed the diagnosis of multiple lentigines rather than melanocytic nevi. A genetic study showed a germline PTPN11 (Tyr279Cys) mutation and raised the suspicion of LEOPARD syndrome. A subsequent ECG examination detected potential cardiac defects and confirmed the diagnosis of LEOPARD. We considered that the potential damage of other systems underlying the skin multiple lentigines should not be ignored. The diagnosis of LEOPARD syndrome in an early stage before cardiac damage has reached a serious and irreversible stage can be meaningful for patients to fully understand the potential risks, complications and prognosis of the disease and to take appropriate precautions to prevent the potential risk of cardiac damage.
Translation and validation of the Urdu version of the European organization for research and treatment of cancer core quality of life questionnaire (EORTC QLQ-C30) and brain module (QLQ-BN20) in primary brain tumor patients
Authors: Zahid Nida , Martins Russell Seth , Zahid Wajeeha , Khalid Wardah , Azam Iqbal , Bhamani Shireen Shehzad , Asad Nargis , Ahmad Khabir , Jabbar Adnan Abdul , Shamim Muhammad Shahzad , Khan Rashid Jooma , Javed Gohar , Bari Ehsan , Enam Syed Ather
Published: September 2021

Introduction

This study translated and validated the Urdu version of the European Organization for Research and Treatment of Cancer Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) and Brain Module (QLQ-BN20) amongst patients with primary brain tumors (PBT) in Pakistan, and assessed the correlation of QoL with resilience, depression, and anxiety.

Methods

Translation of the EORTC QLQ-C30 and QLQ-BN20 was performed as per EORTC guidelines. A survey comprising of Urdu translations of EORTC QLQ-C30, QLQ-BN20, Wagnild and Young Resilience Scale (RS-14) and Hospital Anxiety and Depression Scale was administered to patients with PBT at a tertiary care hospital in Pakistan. Reliability (via Cronbach alpha), content validity index (CVI) scores, construct validity, and inter-scale correlations were assessed.

Results

Our sample consisted of 250 patients with PBT, most commonly glioma (46.8%) and meningioma (21.2%). All patients were able to understand the Urdu translations. The Cronbach alphas for the QLQ-C30 and the QLQ-BN20 were 0.860 and 0.880, respectively. The CVI scores for clarity and relevance were high for both the EORTC QLQ-C30 (0.98 and 0.96, respectively) and the QLQ-BN20 tool (0.81 and 0.95, respectively). The global QoL domain (EORTC QLQ-C30) showed significant positive correlations with resilience (r = 0.422), and significant negative correlations with depression (r =  − 0.541) and anxiety (r =  − 0.502). Strong inter-scale correlations were observed between physical functioning and insomnia (r =  − 0.690) and role functioning and insomnia (r =  − 0.641).

Conclusion

Our study confirms the Urdu versions of the EORTC QLQ-C30 and QLQ-BN20 as valid clinical tools for the measurement of QoL in primary brain tumors patients within the cultural and socioeconomic context of Pakistan.
Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2
Authors: de Oliveira Victor Moreira , da Rocha Matheus Nunes , Magalhães Emanuel Paula , da Silva Mendes Francisco Rogênio , Marinho Márcia Machado , de Menezes Ramon Róseo Paula Pessoa Bezerra , Sampaio Tiago Lima , dos Santos Hélcio Silva , Martins Alice Maria Costa , Marinho Emmanuel Silva
Published: September 2021

Background

The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19.

Results

Molecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target.

Conclusions

Hybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.
Risk, demand, capacity and outcomes in adult specialist eating disorder services in South-East of England before and since COVID-19
Authors: Ayton Agnes , Viljoen David , Ryan Sharon , Ibrahim Ali , Ford Duncan
Published: September 2021

Aims and method

This is a longitudinal cohort study describing the demand, capacity and outcomes of adult specialist eating disorder in-patient services covering a population of 3.5 million in a South-East England provider collaborative before and since the COVID-19 pandemic, between July 2018 and March 2021.

Results

There were 351 referrals for admission; 97% were female, 95% had a diagnosis of anorexia nervosa and 19% had a body mass index (BMI) <13. Referrals have increased by 21% since the start of pandemic, coinciding with reduced capacity. Waiting times have increased from 33 to 46 days. There were significant differences in outcomes between providers. A novel, integrated enhanced cognitive behaviour theapy treatment model showed a 25% reduction in length of stay and improved BMI on discharge (50% v. 16% BMI >19), compared with traditional eclectic in-patient treatment.

Clinical implications

Integrated enhanced cognitive behaviour theapy reduced length of stay and improved outcomes, and can offer more effective use of healthcare resources.
Somatostatin Receptor Antagonism Reverses Glucagon Counterregulatory Failure in Recurrently Hypoglycemic Male Rats
Authors: Hoffman Emily G , Jahangiriesmaili Mahsa , Mandel Erin R , Greenberg Caylee , Aiken Julian , D’Souza Ninoschka C , Pasieka Aoibhe , Teich Trevor , Chan Owen , Liggins Richard , Riddell Michael C
Published: September 2021

Recent antecedent hypoglycemia is a known source of defective glucose counter-regulation in diabetes; the mechanisms perpetuating the cycle of progressive α-cell failure and recurrent hypoglycemia remain unknown. Somatostatin has been shown to suppress the glucagon response to acute hypoglycemia in rodent models of type 1 diabetes. We hypothesized that somatostatin receptor 2 antagonism (SSTR2a) would restore glucagon counterregulation and delay the onset of insulin-induced hypoglycemia in recurrently hypoglycemic, nondiabetic male rats. Healthy, male, Sprague–Dawley rats (n = 39) received bolus injections of insulin (10 U/kg, 8 U/kg, 5 U/kg) on 3 consecutive days to induce hypoglycemia. On day 4, animals were then treated with SSTR2a (10 mg/kg; n = 17) or vehicle (n = 12) 1 hour prior to the induction of hypoglycemia using insulin (5 U/kg). Plasma glucagon level during hypoglycemia was ~30% lower on day 3 (150 ± 75 pg/mL; P < .01), and 68% lower on day 4 in the vehicle group (70 ± 52 pg/mL; P < .001) compared with day 1 (219 ± 99 pg/mL). On day 4, SSTR2a prolonged euglycemia by 25 ± 5 minutes (P < .05) and restored the plasma glucagon response to hypoglycemia. Hepatic glycogen content of SSTR2a-treated rats was 35% lower than vehicle controls after hypoglycemia induction on day 4 (vehicle: 20 ± 7.0 vs SSTR2a: 13 ± 4.4 µmol/g; P < .01). SSTR2a treatment reverses the cumulative glucagon deficit resulting from 3 days of antecedent hypoglycemia in healthy rats. This reversal is associated with decreased hepatic glycogen content and delayed time to hypoglycemic onset. We conclude that recurrent hypoglycemia produces glucagon counterregulatory deficiency in healthy male rats, which can be improved by SSTR2a.