bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study
Authors: Vanassche T. , Engelen M. M. , Van Thillo Q. , Wauters J. , Gunst J. , Wouters C. , Vandenbriele C. , Rex S. , Liesenborghs L. , Wilmer A. , Meersseman P. , Van den Berghe G. , Dauwe D. , Verbeke G. , Thomeer M. , Fivez T. , Mesotten D. , Ruttens D. , Heytens L. , Dapper I. , Tuyls S. , De Tavernier B. , Verhamme P. ,   DAWn consortium members, Gyselinck Iwein , Teuwen Laure-Anne , Geldhof Vincent , Landeloos Ewout , Geukens Tatjana , Ceunen Helga , Debaveye Barbara , Devooght Caroline , Ockerman Anna , Servaes Veerle , Belmans Ann
Published: December 2020

Background

The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19.

Methods

In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement.

Discussion

In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome.

Trial registration

The EU Clinical Trials Register 2020-001739-28. Registered on April 10, 2020.
Clinical trial protocol to evaluate the efficacy of cefixime in the treatment of early syphilis
Authors: Mehta Shivani N. , Stafylis Chrysovalantis , Tellalian David M. , Burian Pamela L. , Okada Cliff M. , Millner Carl E. , Mejia Christopher M. , Klausner Jeffrey D.
Published: December 2020

Background

Syphilis rates have been increasing both in the USA and internationally with incidence higher among men-who-have-sex-with-men and people living with human immunodeficiency virus (HIV) infection. Currently, benzathine penicillin is the recommended treatment for syphilis in all patients. Global shortages and cost increases in benzathine penicillin call for alternative treatment options. This study evaluates the efficacy of oral cefixime for the treatment of early syphilis.

Methods

We are conducting a randomized, multisite, open-label, non-comparative clinical trial in Los Angeles and Oakland, CA. Eligible participants are ≥ 18 years old, with primary, secondary, or early latent syphilis (rapid plasma reagin [RPR] titer ≥ 1:8). Patients with HIV infection must have a viral load≤ 200 copies/mL and CD4+ T cell count ≥ 350 cells/μL during the past 6 months. Participants are randomized to receive either 2.4 M IU benzathine penicillin G intramuscularly once or cefixime 400 mg orally twice a day for 10 days. Participants return at 3, 6, and 12 months post-treatment for follow-up RPR serological testing. The primary outcome is the proportion of participants who achieve ≥ 4-fold RPR titer decrease at 3 or 6 months post-treatment.

Discussion

Clinical trials evaluating the efficacy of alternative antibiotics to penicillin are urgently needed.

Trial registration

Clinicaltrials.govNCT03660488. Registered on 4 September 2018.
Improving mental health care for unaccompanied young refugees through a stepped-care approach versus usual care+: study protocol of a cluster randomized controlled hybrid effectiveness implementation trial
Authors: Rosner Rita , Sachser Cedric , Hornfeck Fabienne , Kilian Reinhold , Kindler Heinz , Muche Rainer , Müller Lauritz Rudolf Floribert , Thielemann Jonathan , Waldmann Tamara , Ziegenhain Ute , Unterhitzenberger Johanna , Pfeiffer Elisa
Published: December 2020

Background

More than half of the unaccompanied young refugees (UYRs) resettled in Europe report elevated levels of posttraumatic stress symptoms (PTSS) and comorbid symptoms. Earlier studies have highlighted the effectiveness of the trauma-focused preventive group intervention “Mein Weg” (English “My Way”), and the feasibility of trauma-focused cognitive behavioral therapy (TF-CBT) for UYRs. Both interventions are deemed to be empirically supported treatments (ESTs). However, UYRs seldom receive ESTs or, in fact, any treatment at all. In view of the high need and the limited treatment resources available, a stepped-care approach is indicated but has not been evaluated so far. The purpose of this trial is to compare the stepped-care approach BETTER CARE with usual care enhanced with screening and indication (usual care+).

Methods

In a cluster randomized controlled trial involving N = 540 UYRs living in up to N = 54 child and youth welfare service (CYWS) facilities, BETTER CARE will be compared with usual care+. We will randomize clusters comprising a CYWS facility with at least one eligible psychotherapist. BETTER CARE consists of step (1) screening and indication and either step (2) preventive trauma-focused group intervention “Mein Weg” delivered by trained CYWS staff or step (3) TF-CBT delivered by trained community therapists and supported by trained translators if necessary. Participants will be assessed 6 and 12 months after randomization. The primary outcome is the severity of PTSS after 12 months. Secondary outcomes are depressive and anxiety symptoms, quality of life, and proxy reported PTSS. Furthermore, drug use, health costs, benefits, and long-term effects on integration/acculturation will be assessed.

Discussion

The trial will directly integrate a stepped-care approach into existing structures of the German child welfare and (mental) health system. It could, therefore, serve as a blueprint for how to implement ESTs for UYRs. If successful, screening, prevention, and intervention will be sustainably implemented in CYWS in southern Germany.

Trial registration

German Clinical Trials Register DRKS00017453. Registered on 11 December 2019.
Disruption of Plasmodium falciparum histidine-rich protein 2 may affect haem metabolism in the blood stage
Authors: Yang Yingchao , Tang Tongke , Feng Bo , Li Shanshan , Hou Nan , Ma Xiao , Jiang Lubin , Xin Xiaofang , Chen Qijun
Published: December 2020

Background

Haem is a key metabolic factor in the life cycle of the malaria parasite. In the blood stage, the parasite acquires host haemoglobin to generate amino acids for protein synthesis and the by-product haem for metabolic use. The malaria parasite can also synthesize haem de novo on its own. Plasmodium falciparum-specific histidine-rich protein 2 (PfHRP2) has a haem-binding site to mediate the formation of haemozoin, a biocrystallized form of haem aggregates. Notably, the gene regulates the mechanism of haemoglobin-derived haem metabolism and the de novo haem biosynthetic pathway in the Pfhrp2-disrupted parasite line during the intraerythrocytic stages.

Methods

The CRISPR/Cas9 system was used to disrupt the gene locus of Pfhrp2. DNA was extracted from the transgenic parasite, and PCR, Southern blotting and Western blotting were used to confirm the establishment of transgenic parasites. RNA-sequencing and comparative transcriptome analysis were performed to identify differences in gene expression between 3D7 and Pfhrp2--3D7 parasites.

Results

Pfhrp2- transgenic parasites were successfully established by the CRISPR/Cas9 system. A total of 964, 1261, 3138, 1064, 2512 and 1778 differentially expressed genes (DEGs) were identified in the six comparison groups, respectively, with 373, 520, 1499, 353, 1253 and 742 of these DEGs upregulated and 591, 741, 1639, 711, 1259 and 1036 of them downregulated, respectively. Five DEGs related to haem metabolism and synthesis were identified in the comparison groups at six time points (0, 8, 16, 24, 32, and 40 h after merozoite invasion). The genes encoding delta-aminolevulinic acid synthetase and ferrochelatase, both related to haem biosynthesis, were found to be significantly upregulated in the comparison groups, and those encoding haem oxygenase, stromal-processing peptidase and porphobilinogen deaminase were found to be significantly downregulated. No GO terms were significantly enriched in haem-related processes (Q value = 1).

Conclusion

Our data revealed changes in the transcriptome expression profile of the Pfhrp2--3D7 parasite during the intraerythrocytic stages. The findings provide insight at the gene transcript level that will facilitate further research on and development of anti-malaria drugs.

Graphical Abstract
Wolbachia infection in wild mosquitoes (Diptera: Culicidae): implications for transmission modes and host-endosymbiont associations in Singapore
Authors: Ding Huicong , Yeo Huiqing , Puniamoorthy Nalini
Published: December 2020

Background

Wolbachia are intracellular bacterial endosymbionts found in most insect lineages. In mosquitoes, the influence of these endosymbionts on host reproduction and arboviral transmission has spurred numerous studies aimed at using Wolbachia infection as a vector control technique. However, there are several knowledge gaps in the literature and little is known about natural Wolbachia infection across species, their transmission modes, or associations between various Wolbachia lineages and their hosts. This study aims to address these gaps by exploring mosquito-Wolbachia associations and their evolutionary implications.

Methods

We conducted tissue-specific polymerase chain reaction screening for Wolbachia infection in the leg, gut and reproductive tissues of wild mosquitoes from Singapore using the Wolbachia surface protein gene (wsp) molecular marker. Mosquito-Wolbachia associations were explored using three methods—tanglegram, distance-based, and event-based methods—and by inferred instances of vertical transmission and host shifts.

Results

Adult mosquitoes (271 specimens) representing 14 genera and 40 species were screened for Wolbachia. Overall, 21 species (51.2%) were found positive for Wolbachia, including five in the genus Aedes and five in the genus Culex. To our knowledge, Wolbachia infections have not been previously reported in seven of these 21 species: Aedes nr. fumidus, Aedes annandalei, Uranotaenia obscura, Uranotaenia trilineata, Verrallina butleri, Verrallina sp. and Zeugnomyia gracilis. Wolbachia were predominantly detected in the reproductive tissues, which is an indication of vertical transmission. However, Wolbachia infection rates varied widely within a mosquito host species. There was no clear signal of cophylogeny between the mosquito hosts and the 12 putative Wolbachia strains observed in this study. Host shift events were also observed.

Conclusions

Our results suggest that the mosquito-Wolbachia relationship is complex and that combinations of transmission modes and multiple evolutionary events likely explain the observed distribution of Wolbachia diversity across mosquito hosts. These findings have implications for a better understanding of the diversity and ecology of Wolbachia and for their utility as biocontrol agents.

Graphical Abstract
Downregulated RPS-30 in Angiostrongylus cantonensis L5 plays a defensive role against damage due to oxidative stress
Authors: Sun Wei-Wei , Yan Xiu-Mei , Shi Qing , Zhang Yuan-Jiao , Huang Jun-Ting , Huang Hui-Cong , Shi Hong-Fei , Yan Bao-Long
Published: December 2020

Background

Eosinophilic meningitis, caused by fifth-stage larvae of the nematode (roundworm) Angiostrongylus cantonensis, is mainly attributed to the contribution of eosinophils to tissue inflammatory responses in helminthic infections. Eosinophils are associated with the killing of helminths via peroxidative oxidation and hydrogen peroxide generated by the dismutation of superoxide produced during respiratory bursts. In contrast, when residing in the host with high level of eosinophils, helminthic worms have evolved to attenuate eosinophil-mediated tissue inflammatory responses for their survival in the hosts. In a previous study we demonstrated that the expression of the A. cantonensis RPS 30 gene (Acan-rps-30) was significantly downregulated in A. cantonensis L5 roundworms residing in cerebrospinal fluid with a high level of eosinophils. Acan-RPS-30 is a protein homologous to the human Fau protein that plays a pro-apoptotic regulatory role and may function in protecting worms from oxidative stress.

Methods

The isolation and structural characterization of Acan-RPS-30 were performed using rapid amplification of cDNA ends (RACE), genome walking and bioinformatics. Quantitative real-time-PCR and microinjection were used to detect the expression patterns of Acan-rps-30. Feeding RNA interference (RNAi) was used to knockdown the apoptosis gene ced-3. Microinjection was performed to construct transgenic worms. An oxidative stress assay was used to determine the functions of Acan-RPS-30.

Results

Our results showed that Acan-RPS-30 consisted of 130 amino acids. It was grouped into clade V with C. elegans in the phylogenetic analysis. It was expressed ubiquitously in worms and was downregulated in both L5 larvae and adult A. cantonensis. Worms expressing pCe-rps30::Acan-rps-30::rfp, with the refractile “button-like” apoptotic corpses, were susceptible to oxidative stress. Apoptosis genes ced-3 and ced-4 were both upregulated in the transgenic worms. The phenotype susceptible to oxidative stress could be converted with a ced-3 defective mutation and RNAi. rps-30−/− mutant worms were resistant to oxidative stress, with ced-3 and ced-4 both downregulated. The oxidative stress-resistant phenotype could be rescued and inhibited by through the expression of pCe-rps30::Acan-rps-30::rfp in rps-3−/− mutant worms.

Conclusion

In C. elegans worms, downregulated RPS-30 plays a defensive role against damage due to oxidative stress, facilitating worm survival by regulating downregulated ced-3. This observation may indicate the mechanism by which A. cantonensis L5 worms, with downregulated Acan-RPS-30, survive in the central nervous system of humans from the immune response of eosinophils.

Graphical Abstract
Differential vector competence of Ornithodoros soft ticks for African swine fever virus: What if it involves more than just crossing organic barriers in ticks?
Authors: Pereira De Oliveira Rémi , Hutet Evelyne , Lancelot Renaud , Paboeuf Frédéric , Duhayon Maxime , Boinas Fernando , Pérez de León Adalberto A. , Filatov Serhii , Le Potier Marie-Frédérique , Vial Laurence
Published: December 2020

Background

Several species of soft ticks in genus Ornithodoros are known vectors and reservoirs of African swine fever virus (ASFV). However, the underlying mechanisms of vector competence for ASFV across Ornithodoros species remain to be fully understood. To that end, this study compared ASFV replication and dissemination as well as virus vertical transmission to descendants between Ornithodorosmoubata, O. erraticus, and O. verrucosus in relation to what is known about the ability of these soft tick species to transmit ASFV to pigs. To mimic the natural situation, a more realistic model was used where soft ticks were exposed to ASFV by allowing them to engorge on viremic pigs.

Methods

Ornithodoros moubata ticks were infected with the ASFV strains Liv13/33 (genotype I) or Georgia2007/1 (genotype II), O. erraticus with OurT88/1 (genotype I) or Georgia2007/1 (genotype II), and O. verrucosus with Ukr12/Zapo (genotype II), resulting in five different tick–virus pairs. Quantitative PCR (qPCR) assays targeting the VP72 ASFV gene was carried out over several months on crushed ticks to study viral replication kinetics. Viral titration assays were also carried out on crushed ticks 2 months post infection to confirm virus survival in soft ticks. Ticks were dissected. and DNA was individually extracted from the following organs to study ASFV dissemination: intestine, salivary glands, and reproductive organs. DNA extracts from each organ were tested by qPCR. Lastly, larval or first nymph-stage progeny emerging from hatching eggs were tested by qPCR to assess ASFV vertical transmission.

Results

Comparative analyses revealed higher rates of ASFV replication and dissemination in O. moubata infected with Liv13/33, while the opposite was observed for O. erraticus infected with Georgia2007/1 and for O. verrucosus with Ukr12/Zapo. Intermediate profiles were found for O. moubata infected with Georgia2007/1 and for O. erraticus with OurT88/1. Vertical transmission occurred efficiently in O. moubata infected with Liv13/33, and at very low rates in O. erraticus infected with OurT88/1.

Conclusions

This study provides molecular data indicating that viral replication and dissemination in Ornithodoros ticks are major mechanisms underlying ASFV horizontal and vertical transmission. However, our results indicate that other determinants beyond viral replication also influence ASFV vector competence. Further research is required to fully understand this process in soft ticks.

Graphical Abstract
Clinical predictors of multiple failure to biological therapy in patients with rheumatoid arthritis
Authors: Novella-Navarro Marta , Plasencia Chamaida , Tornero Carolina , Navarro-Compán Victoria , Cabrera-Alarcón José L. , Peiteado-López Diana , Nuño Laura , Monjo-Henry Irene , Franco-Gómez Karen , Villalba Alejandro , Balsa Alejandro
Published: December 2020

Background

Biological therapies have improved the clinical course and quality of life of rheumatoid arthritis (RA) patients. Despite the availability and effectiveness of these treatments, some patients experience multiple failures to biologic disease-modifying antirheumatic drugs (bDMARDs), constituting a particular challenge to clinicians.

Objectives

This study aims to determine the percentage of rheumatoid arthritis (RA) patients who fail to respond to subsequent bDMARDs, describe their characteristics, and identify specific baseline and early features during the first bDMARD as possible predictors of consecutive multiple bDMARD failure.

Methods

This is a longitudinal study involving RA patients from the prospective biological cohort drawn from the La Paz University Hospital RA Registry (RA-Paz), starting a bDMARD during the years 2000 to 2019. Patients who presented insufficient response (due to primary or secondary inefficacy) to at least three bDMARDs or two bDMARDs with different mechanism of action were considered multi-refractory (MR-patients). Patients who achieved low disease activity or remission (by DAS-28) with the first bDMARD and maintained this over a follow-up period of at least 5 years were considered non-refractory (NR-patients).

Results

A total of 41 out of 402 (10%) patients were MR-patients and 71 (18%) NR-patients. In the multivariate analysis, the presence of erosions, younger age, higher baseline DAS-28 and mostly achieving delta-DAS < 1.2 after 6 months of the first bDMARD (OR 11.12; 95% CI 3.34–26.82) were independently associated with being MR-patients to bDMARDs.

Conclusions

In our cohort, 10% of patients with RA were observed to have multi-refractoriness to bDMARDs. This study supports the contention that younger patients with erosive disease and especially the early absence of clinical response to the first bDMARDs are predictors of multi-refractoriness to consecutive biologics. Hence, patients with these characteristics should be monitored more closely and may benefit from personalized treatments.
Warm-up durations in a hot-dry climate affect thermoregulation, mean power-output and fatigue, but not peak power in specific soccer repeated-sprint ability
Authors: Frikha Mohamed , Chaâri Nesrine , Said Noureddine Ben , Alibrahim Mohammed Shaab
Published: December 2020

Background

This study addressed the lack of data on the effect of warm-up (WU) duration in hot-dry climate (~ 30 °C; ~ 18% RH), on thermoregulation, muscular power-output, and fatigue after specific soccer repeated-sprint test (RSA).

Methods

Eleven amateur soccer players participated in a cross-over randomized study and they underwent the Bangsbo repeated-sprint test, after three WU durations (i.e. WU10, WU15 and WU20 min) at 70% of MAV, and on different days. Peak power (PP), mean power (MP) and the fatigue index (FI) were recorded and analyzed. Likewise, heart rate (HR), tympanic temperature (Ttym), mean body temperature (MBT) and rating of perceived exertion (RPE) were recorded during each session.

Results

The repeated measure ANOVA showed that MP improved after WU15 in comparison to WU10 and WU20 (p = 0.04 and p = 0.001; respectively). Nonetheless, no significant effect on PP was recorded after all WU durations. FI during RSA increased after WU20 in comparison to WU15 and WU10 (p < 0.001 and p = 0.003; respectively). Higher RPE values (p < 0.001) were recorded after WU15 and WU20 in comparison to WU10 duration. The two-way ANOVA showed higher ΔTtym and ΔMBT values after WU15 and WU20 compared to WU10 (p = 0.039 and p < 0.001for Ttym; p = 0.005 and p < 0.001 for MBT, respectively).

Conclusions

The WU15 at 70% of MAV better assists mean power-output during soccer RSA in hot-dry (~ 30 °C; 18% RH) climate, but not peak power. Reducing WU duration up to 10 min seems to be insufficient to induce beneficial physiological changes necessary for optimizing repeated-sprint performance, while its extension up to 20 min remains detrimental for muscular power and induces higher fatigue.
Performance indicators for radiation protection management: suggestions from the European Society of Radiology
Authors:   European Society of Radiology (ESR)
Published: December 2020

In 2013, the new European Basic Safety Standards Directive 2013/59/Euratom (BSS Directive), which defines the new legal framework for the use of ionising radiation in medical imaging and radiotherapy, was published. In 2014, the ESR EuroSafe Imaging Initiative was founded with a goal in mind “to support and strengthen medical radiation protection across Europe following a holistic, inclusive approach”. To support radiology departments in developing a programme of clinical audit, the ESR developed a Guide to Clinical Audit and an accompanying audit tool in 2017, with an expanded second edition released in 2019 and published under the name of Esperanto – ESR Guide to Clinical Audit in Radiology and the ESR Clinical Audit Tool, 2019. Audits represent specific aspects at a certain point in time, usually with retrospective evaluation of data. Key performance indicators (KPIs), on the other hand, are intended to enable continuous monitoring of relevant parameters, for example to provide warnings or a dashboard. KPIs, which can, for example, be recorded automatically and visualised in dashboards, are suitable for this purpose. This paper will discuss a selection of indicators covering different areas and include suggestions for their implementation.
Allogeneic human umbilical cord Wharton’s jelly stem cells increase several-fold the expansion of human cord blood CD34+ cells both in vitro and in vivo
Authors: Lin Hao Daniel , Fong Chui-Yee , Biswas Arijit , Bongso Ariff
Published: December 2020

Background

The transplantation of human umbilical cord blood (UCB) CD34+ cells has been successfully used to treat hematological disorders but one major limitation has been the low cell numbers available. Mesenchymal stem cells (MSCs) lying within the bone marrow in vivo behave like a scaffold on which CD34+ cells interact and proliferate. We therefore evaluated the use of allogeneic MSCs from the human UC Wharton’s jelly (hWJSCs) as stromal support for the ex vivo expansion of CD34+ cells.

Methods

We performed an in-depth evaluation of the primitiveness, migration, adhesion, maturation, mitochondrial behavior, and pathway mechanisms of this platform using conventional assays followed by the evaluation of engraftment potential of the expanded CD34+ cells in an in vivo murine model.

Results

We demonstrate that hWJSCs and its conditioned medium (hWJSC-CM) support the production of significantly high fold changes of CD34+, CD34+CD133+, CD34+CD90+, CD34+ALDH+, CD34+CD45+, and CD34+CD49f+ cells after 7 days of interaction when compared to controls. In the presence of hWJSCs or hWJSC-CM, the CD34+ cells produced significantly more primitive CFU-GEMM colonies, HoxB4, and HoxA9 gene expression and lower percentages of CD34+CXCR4+ cells. There were also significantly higher N-cadherin+ cell numbers and increased cell migration in transwell migration assays. The CD34+ cells expanded with hWJSCs had significantly lower mitochondrial mass, mitochondrial membrane potential, and oxidative stress. Green Mitotracker-tagged mitochondria from CD34+ cells were observed lying within red CellTracker-tagged hWJSCs under confocal microscopy indicating mitochondrial transfer via tunneling nanotubes. CD34+ cells expanded with hWJSCs and hWJSC-CM showed significantly reduced oxidative phosphorylation (ATP6VIH and NDUFA10) and increased glycolytic (HIF-1a and HK-1) pathway-related gene expression. CD34+ cells expanded with hWJSCs for 7 days showed significant greater CD45+ cell chimerism in the bone marrow of primary and secondary irradiated mice when transplanted intravenously.

Conclusions

In this report, we confirmed that allogeneic hWJSCs provide an attractive platform for the ex vivo expansion of high fold numbers of UCB CD34+ cells while keeping them primitive. Allogeneic hWJSCs are readily available in abundance from discarded UCs, can be easily frozen in cord blood banks, thawed, and then used as a platform for UCB-HSC expansion if numbers are inadequate.
Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre-Chotzen syndrome
Authors: Pribadi Clara , Camp Esther , Cakouros Dimitrios , Anderson Peter , Glackin Carlotta , Gronthos Stan
Published: December 2020

Background

During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading to craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form of craniosynostosis, caused byTWIST-1gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications.

Methods

The present study utilizedTwist-1haploinsufficient (Twist-1del/+) mice as SCS mouse model to investigate the inhibition of Kdm6a and Kdm6b activity using the pharmacological inhibitor, GSK-J4, on calvarial cell osteogenic potential.

Results

This study showed that the histone methyltransferaseEZH2, an osteogenesis inhibitor, is downregulated in calvarial cells derived fromTwist-1del/+mice, whereas the counter histone demethylases,Kdm6aandKdm6b, known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition ofKdm6aandKdm6bexpression suppressed osteogenic differentiation ofTwist-1del/+calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation byTwist-1del/+calvarial cells in vitro and reduced mineralized bone formation inTwist-1del/+calvarial explant cultures. Chromatin immunoprecipitation and Western blot analyses found that GSK-J4 treatment elevated the levels of the Kdm6a and Kdm6b epigenetic target, the repressive mark of tri-methylated lysine 27 on histone 3, on osteogenic genes leading to repression ofRunx2andAlkaline Phosphataseexpression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria ofTwist-1del/+mice prevented premature suture fusion and kept the sutures open up to postnatal day 20.

Conclusion

The inhibition of Kdm6a and Kdm6b activity by GSK-J4 could be used as a potential non-invasive therapeutic strategy for preventing craniosynostosis in children with SCS.

Graphical abstract

Pharmacological targeting of Kdm6a/b activity can alleviate craniosynostosis in Saethre-Chotzen syndrome. Aberrant osteogenesis by Twist-1 mutant cranial suture mesenchymal progenitor cells occurs via deregulation of epigenetic modifiers Ezh2 and Kdm6a/Kdm6b. Suppression of Kdm6a- and Kdm6b-mediated osteogenesis with GSK-J4 inhibitor can prevent prefusion of cranial sutures.
Neural field models with transmission delays and diffusion
Authors: Spek Len , Kuznetsov Yuri A. , van Gils Stephan A.
Published: December 2020

A neural field models the large scale behaviour of large groups of neurons. We extend previous results for these models by including a diffusion term into the neural field, which models direct, electrical connections. We extend known and prove new sun-star calculus results for delay equations to be able to include diffusion and explicitly characterise the essential spectrum. For a certain class of connectivity functions in the neural field model, we are able to compute its spectral properties and the first Lyapunov coefficient of a Hopf bifurcation. By examining a numerical example, we find that the addition of diffusion suppresses non-synchronised steady-states while favouring synchronised oscillatory modes.
18F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography
Authors: Bulat Flaviu , Hesse Friederike , Hu De-En , Ros Susana , Willminton-Holmes Connor , Xie Bangwen , Attili Bala , Soloviev Dmitry , Aigbirhio Franklin , Leeper Finian. J. , Brindle Kevin M. , Neves André A.
Published: December 2020

Introduction

Trialing novel cancer therapies in the clinic would benefit from imaging agents that can detect early evidence of treatment response. The timing, extent and distribution of cell death in tumors following treatment can give an indication of outcome. We describe here an 18F-labeled derivative of a phosphatidylserine-binding protein, the C2A domain of Synaptotagmin-I (C2Am), for imaging tumor cell death in vivo using PET.

Methods

A one-pot, two-step automated synthesis of N-(5-[18F]fluoropentyl)maleimide (60 min synthesis time, > 98% radiochemical purity) has been developed, which was used to label the single cysteine residue in C2Am within 30 min at room temperature. Binding of 18F-C2Am to apoptotic and necrotic tumor cells was assessed in vitro, and also in vivo, by dynamic PET and biodistribution measurements in mice bearing human tumor xenografts treated with a TRAILR2 agonist or with conventional chemotherapy. C2Am detection of tumor cell death was validated by correlation of probe binding with histological markers of cell death in tumor sections obtained immediately after imaging.

Results

18F-C2Am showed a favorable biodistribution profile, with predominantly renal clearance and minimal retention in spleen, liver, small intestine, bone and kidney, at 2 h following probe administration. 18F-C2Am generated tumor-to-muscle (T/m) ratios of 6.1 ± 2.1 and 10.7 ± 2.4 within 2 h of probe administration in colorectal and breast tumor models, respectively, following treatment with the TRAILR2 agonist. The levels of cell death (CC3 positivity) following treatment were 12.9–58.8% and 11.3–79.7% in the breast and colorectal xenografts, respectively. Overall, a 20% increase in CC3 positivity generated a one unit increase in the post/pre-treatment tumor contrast. Significant correlations were found between tracer uptake post-treatment, at 2 h post-probe administration, and histological markers of cell death (CC3: Pearson R = 0.733, P = 0.0005; TUNEL: Pearson R = 0.532, P = 0.023).

Conclusion

The rapid clearance of 18F-C2Am from the blood pool and low kidney retention allowed the spatial distribution of cell death in a tumor to be imaged during the course of therapy, providing a rapid assessment of tumor treatment response. 18F-C2Am has the potential to be used in the clinic to assess early treatment response in tumors.
Systematic review and validity assessment of methods used in discrete choice experiments of primary healthcare professionals
Authors: Merlo Gregory , van Driel Mieke , Hall Lisa
Published: December 2020

Introduction

Discrete choice experiments (DCEs) have been used to measure patient and healthcare professionals preferences in a range of settings internationally. Using DCEs in primary care is valuable for determining how to improve rational shared decision making. The purpose of this systematic review is to assess the validity of the methods used for DCEs assessing the decision making of healthcare professionals in primary care.

Main body

A systematic search was conducted to identify articles with original data from a discrete choice experiment where the population was primary healthcare professionals. All publication dates from database inception to 29th February 2020 were included. A data extraction and validity assessment template based on guidelines was used. After screening, 34 studies met the eligibility criteria and were included in the systematic review. The sample sizes of the DCEs ranged from 10 to 3727. The published DCEs often provided insufficient detail about the process of determining the attributes and levels. The majority of the studies did not involve primary care healthcare professionals outside of the research team in attribute identification and selection. Less than 80% of the DCEs were piloted and few papers investigated internal or external validity.

Conclusions

For findings to translate into improvements in rational shared decision making in primary care DCEs need to be internally and externally valid and the findings need to be able to be communicated to stakeholders in a way that is understandable and relevant.
Botulinum toxin type A alleviates neuropathic pain and suppresses inflammatory cytokines release from microglia by targeting TLR2/MyD88 and SNAP23
Authors: Wang Xuan , Tian Sheng , Wang Hansen , Liu Pan , Zheng Heqing , Wu Lanxiang , Liu Qian , Wu Wei
Published: December 2020

Background

Botulinum toxin type A (BTX-A) was considered to be a new potential drug for neuropathic pain (NP) treatment.

Results

In vivo, BTX-A attenuated chronic compression injury (CCI)-induced pain in rats, and reduced production of pro-inflammatory factors. The inhibition of BTX-A to expression and phosphorylation of SNAP23 were partly reversed by TLR2/MyD88 upregulation. In LPS-stimulated microglia, we also found that BTX-A suppressed TLR2, MyD88, p-SNAP23 and SNAP23 expression, and reduced pro-inflammatory factors secretion. Upregulation of TLR2 and MyD88 recued the inhibition of BTX-A to LPS-induced activation of SNAP23. Then, we demonstrated that BTX-A reduced expression of SNAP23 through inhibition of IKKα/β phosphorylation. Besides, the inhibition of BTX-A to LPS-induced upregulation of SNAP23 can be reversed by proteasome inhibitor. NEDD4, an E3 ubiquitin ligase, was proved to be bind with SNAP23. BTX-A reduced expression of SNAP23 via facilitating ubiquitin-mediated degradation of SNAP23.

Conclusion

Overall, our data demonstrated that BTX-A attenuated NP via reducing the secretion of pro-inflammatory factors from microglia by inhibition of TLR2/MyD88 signaling. BTX-A downregulated expression of SNAP23 via reducing phosphorylation of IKKα/β, and enhancing ubiquitination of SNAP23 by suppressing TLR2/MyD88 signaling.
Treatment of allergic rhinitis during and outside the pollen season using mobile technology. A MASK study
Authors:   the MASK study group, Bédard A. , Basagaña X. , Anto J. M. , Garcia-Aymerich J. , Devillier P. , Arnavielhe S. , Bedbrook A. , Onorato G. L. , Czarlewski W. , Murray R. , Almeida R. , Fonseca J. A. , Correia da Sousa J. , Costa E. , Morais-Almeida M. , Todo-Bom A. , Cecchi L. , De Feo G. , Illario M. , Menditto E. , Monti R. , Stellato C. , Ventura M. T. , Annesi-Maesano I. , Bosse I. , Fontaine J. F. , Pham-Thi N. , Thibaudon M. , Schmid-Grendelmeier P. , Spertini F. , Chavannes N. H. , Fokkens W. J. , Reitsma S. , Dubakiene R. , Emuzyte R. , Kvedariene V. , Valiulis A. , Kuna P. , Samolinski B. , Klimek L. , Mösges R. , Pfaar O. , Shamai S. , Roller-Wirnsberger R. E. , Tomazic P. V. , Ryan D. , Sheikh A. , Haahtela T. , Toppila-Salmi S. , Valovirta E. , Cardona V. , Mullol J. , Valero A. , Makris M. , Papadopoulos N. G. , Prokopakis E. P. , Psarros F. , Bachert C. , Hellings P. W. , Pugin B. , Bindslev-Jensen C. , Eller E. , Kull I. , Melén E. , Wickman M. , De Vries G. , van Eerd M. , Agache I. , Ansotegui I. J. , Bosnic-Anticevich S. , Cruz A. A. , Casale T. , Ivancevich J. C. , Larenas-Linnemann D. E. , Sofiev M. , Wallace D. , Waserman S. , Yorgancioglu A. , Laune D. , Bousquet J.
Published: December 2020

Background

The analysis of mobile health (mHealth) data has generated innovative insights into improving allergic rhinitis control, but additive information is needed. A cross-sectional real-world observational study was undertaken in 17 European countries during and outside the estimated pollen season. The aim was to collect novel information including the phenotypic characteristics of the users.

Methods

The Allergy Diary–MASK-air–mobile phone app, freely available via Google Play and App, was used to collect the data of daily visual analogue scales (VASs) for overall allergic symptoms and medication use. Fluticasone Furoate (FF), Mometasone Furoate (MF), Azelastine Fluticasone Proprionate combination (MPAzeFlu) and eight oral H1-antihistamines were studied. Phenotypic characteristics were recorded at entry. The ARIA severity score was derived from entry data. This was an a priori planned analysis.

Results

9037 users filled in 70,286 days of VAS in 2016, 2017 and 2018. The ARIA severity score was lower outside than during the pollen season. Severity was similar for all treatment groups during the pollen season, and lower in the MPAzeFlu group outside the pollen season. Days with MPAzeFlu had lower VAS levels and a higher frequency of monotherapy than the other treatments during the season. Outside the season, days with MPAzeFlu also had a higher frequency of monotherapy. The number of reported days was significantly higher with MPAzeFlu during and outside the season than with MF, FF or oral H1-antihistamines.

Conclusions

This study shows that the overall efficacy of treatments is similar during and outside the pollen season and indicates that medications are similarly effective during the year.
A novel method in determining a layered periodic structure
Authors: Cui Yanli , Li Xiliang , Qu Fenglong
Published: December 2020

This paper is concerned with the inverse scattering of time-harmonic waves by a penetrable structure. By applying the integral equation method, we establish the uniform $L^{p}_{\alpha }\ (1< p\leq 2)$

L
α
p

(
1
<
p
≤
2
)
estimates for the scattered and transmitted wave fields corresponding to a series of incident point sources. Based on these a priori estimates and a mixed reciprocity relation, we prove that the penetrable structure can be uniquely identified by means of the scattered field measured only above the structure induced by a countably infinite number of quasi-periodic incident plane waves.
The Pohozaev-type inequalities and their applications for a kind of elliptic equation (system)
Authors: Kou Bingyu , An Tianqing , Wang Zeyan
Published: December 2020

In this paper, we first derive a new kind of Pohozaev-type inequalities for p-Laplacian equations in a more general class of non-star-shaped domains, and then we take two examples and their graphs to explain the shape of the new kind of the non-star-shaped domain. At last, we extend the results of Pohozaev-type inequalities to elliptic systems, which are used to derive the nonexistence of positive solutions of this type of systems in the non-star-shaped domains. On this basis, we also discuss the existence of positive solutions of a kind of elliptic systems with double critical growth.
Some Ramanujan-type circular summation formulas
Authors: Ge Ji-Ke , Luo Qiu-Ming
Published: December 2020

In this paper, we give two Ramanujan-type circular summation formulas by applying the way of elliptic functions and the properties of theta functions. As applications, we obtain the corresponding imaginary transformation formulas for Ramanujan-type circular summations and some theta function identities.
High-order compact finite volume scheme for the 2D multi-term time fractional sub-diffusion equation
Authors: Su Baojin , Jiang Ziwen
Published: December 2020

Based on anL1 interpolation operator, a new high-order compact finite volume scheme is derived for the 2D multi-term time fractional sub-diffusion equation. It is shown that the difference scheme is unconditionally convergent and stable in$L_{\infty }$L∞-norm. The convergence order is$O(\tau ^{2-\alpha }+h_{1}^{4}+h_{2}^{4})$O(τ2−α+h14+h24), whereτis the temporal step size and$h_{1}$h1is the spatial step size in one direction,$h_{2}$h2is the spatial step size in another direction. Two numerical examples are implemented, testifying to their efficiency and confirming their convergence order.
Existence and uniqueness of solutions for a mixed p-Laplace boundary value problem involving fractional derivatives
Authors: Wang Shuqi , Bai Zhanbing
Published: December 2020

In this article, the existence and uniqueness of solutions for a multi-point fractional boundary value problem involving two different left and right fractional derivatives with p-Laplace operator is studied. A novel approach is used to acquire the desired results, and the core of the method is Banach contraction mapping principle. Finally, an example is given to verify the results.
A new generalization of Mittag-Leffler function via q-calculus
Authors: Nadeem Raghib , Usman Talha , Nisar Kottakkaran Sooppy , Abdeljawad Thabet
Published: December 2020

The present paper deals with a new different generalization of the Mittag-Leffler function through q-calculus. We then investigate its remarkable properties like convergence, recurrence relation, integral representation, q-derivative formula, q-Laplace transformation, and image formula under q-derivative operator. In addition to this, we consider some specific cases to give the utilization of our main results.
Distributed data hiding in multi-cloud storage environment
Authors: Moyou Metcheka Leonel , Ndoundam René
Published: December 2020

Classical or traditional steganography aims at hiding a secret in cover media such as text, image, audio, video or even in network protocols. Recent research has improved this approach called distributed steganography by fragmenting the secret message and embedding each secret piece into a distinct cover media. The major interest of this approach is to make the secret message detection extremely difficult. However, these file modifications leave fingerprints which can reveal a secret channel to an attacker. Our contribution is a new steganography paradigm transparent to any attacker and resistant to the detection and the secret extraction. Two properties contribute to achieve these goals: the files do not undergo any modification while the distribution of the secret in the multi-cloud storage environment allows us to hide the existence of the covert channel between the communicating parties. Information’s are usually hidden inside the cover media. In this work, the covert media is a pointer to information. Therefore the file carries the information without being modified and the only way to access it is to have the key. Experiments show interesting comparison results with remarkable security contributions. The work can be seen as a new open direction for further research in the field.
Comparative evaluation of the effect of different growth media on in vitro sensitivity to azithromycin in multi-drug resistant Pseudomonas aeruginosa isolated from cystic fibrosis patients
Authors: Sörensen Michael , Khakimov Bakhodur , Nurjadi Dennis , Boutin Sébastien , Yi Buqing , Dalpke Alexander H. , Eigenbrod Tatjana
Published: December 2020

Long-term treatment with azithromycin is a therapeutic option in Cystic Fibrosis (CF) patients chronically infected with P. aeruginosa. It was recently shown that azithromycin has direct antimicrobial activity when P. aeruginosa isolates are tested in Roswell Park Memorial Institute medium supplemented with fetal calf serum (RPMI 1640/FCS) by broth microdilution. We now investigated whether (i) azithromycin might also be active against multidrug resistant (MDR) P. aeruginosa isolated from CF patients and (ii) how in vitro sensitivity assays perform in synthetic cystic fibrosis sputum medium (SCFM), a medium that mimics the particular CF airway environment.
In 17 (59%) out of 29 MDR P. aeruginosa CF isolates MICs for azithromycin ranged between 0.25 and 8 μg/ml and 12 isolates (41%) showed a MIC ≥512 μg/ml when measured in RPMI/FCS. In contrast, MICs were ≥ 256 μg/ml for all P. aeruginosa MDR isolates when tested in either SCFM or in conventional cation-adjusted Mueller Hinton Broth. High MIC values observed in CF adapted medium SCFM for both PAO1 and MDR P. aeruginosa CF isolates, as opposed to findings in RPMI, argue against routine azithromycin MIC testing of CF isolates.