bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

AbstractIn 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

Abstract
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.