bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of a computerized decision support tool deployed in two intensive care units on acute kidney injury progression and guideline compliance: a prospective observational study
Authors: Bourdeaux Christopher , Ghosh Erina , Atallah Louis , Palanisamy Krishnamoorthy , Patel Payaal , Thomas Matthew , Gould Timothy , Warburton John , Rivers Jon , Hadfield John
Published: November 2020

Background

Acute kidney injury (AKI) affects a large proportion of the critically ill and is associated with worse patient outcomes. Early identification of AKI can lead to earlier initiation of supportive therapy and better management. In this study, we evaluate the impact of computerized AKI decision support tool integrated with the critical care clinical information system (CCIS) on patient outcomes. Specifically, we hypothesize that integration of AKI guidelines into CCIS will decrease the proportion of patients with Stage 1 AKI deteriorating into higher stages of AKI.

Methods

The study was conducted in two intensive care units (ICUs) at University Hospitals Bristol, UK, in a before (control) and after (intervention) format. The intervention consisted of the AKIN guidelines and AKI care bundle which included guidance for medication usage, AKI advisory and dashboard with AKI score. Clinical data and patient outcomes were collected from all patients admitted to the units. AKI stage was calculated using the Acute Kidney Injury Network (AKIN) guidelines. Maximum AKI stage per admission, change in AKI stage and other metrics were calculated for the cohort. Adherence to eGFR-based enoxaparin dosing guidelines was evaluated as a proxy for clinician awareness of AKI.

Results

Each phase of the study lasted a year, and a total of 5044 admissions were included for analysis with equal numbers of patients for the control and intervention stages. The proportion of patients worsening from Stage 1 AKI decreased from 42% (control) to 33.5% (intervention), p = 0.002. The proportion of incorrect enoxaparin doses decreased from 1.72% (control) to 0.6% (intervention), p < 0.001. The prevalence of any AKI decreased from 43.1% (control) to 37.5% (intervention), p < 0.05.

Conclusions

This observational study demonstrated a significant reduction in AKI progression from Stage 1 and a reduction in overall development of AKI. In addition, a reduction in incorrect enoxaparin dosing was also observed, indicating increased clinical awareness. This study demonstrates that AKI guidelines coupled with a newly designed AKI care bundle integrated into CCIS can impact patient outcomes positively.
Low temperature tolerance of three Aedes albopictus strains (Diptera: Culicidae) under constant and fluctuating temperature scenarios
Authors: Tippelt Lisa , Werner Doreen , Kampen Helge
Published: November 2020

Background

Aedes albopictus, a vector of numerous viruses and filarial worms, has already established in 20 countries in Europe, mainly colonising subtropical regions. Continuing adaptation to climatic conditions in temperate areas would probably result in a spread to more northern European countries, producing an increasing risk of mosquito-borne pathogen transmission over a much greater area. Based on previous studies showing thatAe. albopictusis able to overwinter in Germany, this study aims to determine more exactly its ecological limits of enduring low temperatures.

Methods

Non-diapausing and experimentally induced diapausing eggs of three differentAe. albopictusstrains (tropical, subtropical and temperate origins) were exposed to four different regimes with constant temperatures and three different regimes with fluctuating temperatures in a course of a day for a minimum of 2 and a maximum of 30 days. The hatching rate of larvae after cold exposure of the eggs was taken as a measure of cold tolerance.

Results

The experiments showed that the tropicalAe. albopictusstrain had a lower cold tolerance than the subtropical and the temperate strains. The eggs of all used strains were able to survive constant temperatures as low as −5 °C for an exposure period of 30 days, while constant temperatures as low as −10 °C were endured for 2 days by the tropical strain and for 10 and 20 days by the subtropical and temperate strains, respectively. At fluctuating temperatures, both the subtropical and the temperate strains exhibited hatching under all temperature regimes, even with a minimum temperature of −10 °C, whereas the tropical strain ceased hatching after an exposure period of 30 days under the temperature regime with a minimum temperature of −10 °C. The analyses showed that the temperature played the major role in interpreting the hatching rates of the eggs. The condition, whether the eggs were diapausing or not, had no significant influence, although results indicated a slightly higher cold tolerance of diapausing eggs at −10 °C.

Conclusions

It must be expected that subtropical and temperate strains ofAe. albopictusare able to withstand common central European winters and are able to establish in considerable parts of the continent.
Histone modifications associated with gene expression and genome accessibility are dynamically enriched at Plasmodium falciparum regulatory sequences
Authors: Tang Jingyi , Chisholm Scott A. , Yeoh Lee M. , Gilson Paul R. , Papenfuss Anthony T. , Day Karen P. , Petter Michaela , Duffy Michael F.
Published: November 2020

Background

The malaria parasite Plasmodium falciparum has an unusually euchromatic genome with poorly conserved positioning of nucleosomes in intergenic sequences and poorly understood mechanisms of gene regulation. Variant histones and histone modifications determine nucleosome stability and recruit trans factors, but their combinatorial contribution to gene regulation is unclear.

Results

Here, we show that the histone H3 acetylations H3K18ac and H3K27ac and the variant histone Pf H2A.Z are enriched together at regulatory sites upstream of genes. H3K18ac and H3K27ac together dynamically mark regulatory regions of genes expressed during the asexual life cycle. In contrast, H3K4me1 is depleted in intergenic sequence and dynamically depleted upstream of expressed genes. The temporal pattern of H3K27ac and H3K18ac enrichment indicates that they accumulate during S phase and mitosis and are retained at regulatory sequences until at least G1 phase and after cessation of expression of the cognate genes. We integrated our ChIPseq data with existing datasets to show that in schizont stages H3K18ac, H3K27ac and Pf H2A.Z colocalise with the transcription factor PfAP2-I and the bromodomain protein PfBDP1 and are enriched at stably positioned nucleosomes within regions of exposed DNA at active transcriptional start sites. Using transient transfections we showed that sequences enriched with colocalised H3K18ac, H3K27ac and Pf H2A.Z possess promoter activity in schizont stages, but no enhancer-like activity.

Conclusions

The dynamic H3 acetylations define P. falciparum regulatory sequences and contribute to gene activation. These findings expand the knowledge of the chromatin landscape that regulates gene expression in P. falciparum.
Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors
Authors: Zhang Zhao , Jing Ji , Ye Youqiong , Chen Zhiao , Jing Ying , Li Shengli , Hong Wei , Ruan Hang , Liu Yaoming , Hu Qingsong , Wang Jun , Li Wenbo , Lin Chunru , Diao Lixia , Zhou Yubin , Han Leng
Published: November 2020

Background

Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer.

Methods

We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis.

Results

We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions. We experimentally characterized the dual function of two genes, DNAJC9 and HSPA14, in lung cancer cells. We further demonstrated the generalization of this dual direction of associations between HSPs and cancer hallmarks, suggesting the necessity to more carefully evaluate HSPs as therapeutic targets and develop highly specific HSP inhibitors for cancer intervention.

Conclusions

Our study furnishes a holistic view of functional associations of HSPs with cancer hallmarks to aid the development of HSP inhibitors as well as other drugs in cancer therapy.
Genotype imputation and variability in polygenic risk score estimation
Authors: Chen Shang-Fu , Dias Raquel , Evans Doug , Salfati Elias L. , Liu Shuchen , Wineinger Nathan E. , Torkamani Ali
Published: November 2020

Background

Polygenic risk scores (PRSs) are a summarization of an individual’s genetic risk for a disease or trait. These scores are being generated in research and commercial settings to study how they may be used to guide healthcare decisions. PRSs should be updated as genetic knowledgebases improve; however, no guidelines exist for their generation or updating.

Methods

Here, we characterize the variability introduced in PRS calculation by a common computational process used in their generation—genotype imputation. We evaluated PRS variability when performing genotype imputation using 3 different pre-phasing tools (Beagle, Eagle, SHAPEIT) and 2 different imputation tools (Beagle, Minimac4), relative to a WGS-based gold standard. Fourteen different PRSs spanning different disease architectures and PRS generation approaches were evaluated.

Results

We find that genotype imputation can introduce variability in calculated PRSs at the individual level without any change to the underlying genetic model. The degree of variability introduced by genotype imputation differs across algorithms, where pre-phasing algorithms with stochastic elements introduce the greatest degree of score variability. In most cases, PRS variability due to imputation is minor (< 5 percentile rank change) and does not influence the interpretation of the score. PRS percentile fluctuations are also reduced in the more informative tails of the PRS distribution. However, in rare instances, PRS instability at the individual level can result in singular PRS calculations that differ substantially from a whole genome sequence-based gold standard score.

Conclusions

Our study highlights some challenges in applying population genetics tools to individual-level genetic analysis including return of results. Rare individual-level variability events are masked by a high degree of overall score reproducibility at the population level. In order to avoid PRS result fluctuations during updates, we suggest that deterministic imputation processes or the average of multiple iterations of stochastic imputation processes be used to generate and deliver PRS results.
Effects of balance training on balance performance in youth: role of training difficulty
Authors: Schedler Simon , Tenelsen Florian , Wich Laura , Muehlbauer Thomas
Published: November 2020

Background

Cross-sectional studies have shown that balance performance can be challenged by the level of task difficulty (e.g., varying stance conditions, sensory manipulations). However, it remains unclear whether the application of different levels of task difficulty during balance training (BT) leads to altered adaptations in balance performance. Thus, we examined the effects of BT conducted under a high versus a low level of task difficulty on balance performance.

Methods

Forty male adolescents were randomly assigned to a BT program using a low (BT-low: n = 20; age: 12.4 ± 2.0 yrs) or a high (BT-high: n = 20; age: 12.5 ± 2.5 yrs) level of balance task difficulty. Both groups trained for 7 weeks (2 sessions/week, 30–35 min each). Pre- and post-training assessments included measures of static (one-legged stance [OLS] time), dynamic (10-m gait velocity), and proactive (Y-Balance Test [YBT] reach distance, Functional Reach Test [FRT]; Timed-Up-and-Go Test [TUG]) balance.

Results

Significant main effects of Test (i.e., pre- to post-test improvements) were observed for all but one balance measure (i.e., 10-m gait velocity). Additionally, a Test x Group interaction was detected for the FRT in favor of the BT-high group (Δ + 8%, p < 0.001, d = 0.35). Further, tendencies toward significant Test x Group interactions were found for the YBT anterior reach (in favor of BT-high: Δ + 9%, p < 0.001, d = 0.60) and for the OLS with eyes opened and on firm surface (in favor of BT-low: Δ + 31%, p = 0.003, d = 0.67).

Conclusions

Following 7 weeks of BT, enhancements in measures of static, dynamic, and proactive balance were observed in the BT-high and BT-low groups. However, BT-high appears to be more effective for increasing measures of proactive balance, whereas BT-low seems to be more effective for improving proxies of static balance.

Trial registration

Current Controlled Trials ISRCTN83638708 (Retrospectively registered 19th June, 2020).
DNA methylation signatures to predict the cervicovaginal microbiome status
Authors: Nené Nuno R. , Barrett James , Jones Allison , Evans Iona , Reisel Daniel , Timms John F. , Paprotka Tobias , Leimbach Andreas , Franchi Dorella , Colombo Nicoletta , Bjørge Line , Zikan Michal , Cibula David , Widschwendter Martin
Published: November 2020

Background

The composition of the microbiome plays an important role in human health and disease. Whether there is a direct association between the cervicovaginal microbiome and the host’s epigenome is largely unexplored.

Results

Here we analyzed a total of 448 cervicovaginal smear samples and studied both the DNA methylome of the host and the microbiome using the Illumina EPIC array and next-generation sequencing, respectively. We found that those CpGs that are hypo-methylated in samples with non-lactobacilli (O-type) dominating communities are strongly associated with gastrointestinal differentiation and that a signature consisting of 819 CpGs was able to discriminate lactobacilli-dominating (L-type) from O-type samples with an area under the receiver operator characteristic curve (AUC) of 0.84 (95% CI = 0.77–0.90) in an independent validation set. The performance found in samples with more than 50% epithelial cells was further improved (AUC 0.87) and in women younger than 50 years of age was even higher (AUC 0.91). In a subset of 96 women, the buccal but not the blood cell DNA showed the same trend as the cervicovaginal samples in discriminating women with L- from O-type cervicovaginal communities.

Conclusions

These findings strongly support the view that the epithelial epigenome plays an essential role in hosting specific microbial communities.
The eIF4E homolog 4EHP (eIF4E2) regulates hippocampal long-term depression and impacts social behavior
Authors: Wiebe Shane , Meng Xiang Qi , Kim Sung-Hoon , Zhang Xu , Lacaille Jean-Claude , Aguilar-Valles Argel , Sonenberg Nahum
Published: November 2020

Background

The regulation of protein synthesis is a critical step in gene expression, and its dysfunction is implicated in autism spectrum disorder (ASD). The eIF4E homologous protein (4EHP, also termed eIF4E2) binds to the mRNA 5′ cap to repress translation. The stability of 4EHP is maintained through physical interaction with GRB10 interacting GYF protein 2 (GIGYF2). Gene-disruptive mutations in GIGYF2 are linked to ASD, but causality is lacking. We hypothesized that GIGYF2 mutations cause ASD by disrupting 4EHP function.

Methods

Since homozygous deletion of either gene is lethal, we generated a cell-type-specific knockout model where Eif4e2 (the gene encoding 4EHP) is deleted in excitatory neurons of the forebrain (4EHP-eKO). In this model, we investigated ASD-associated synaptic plasticity dysfunction, ASD-like behaviors, and global translational control. We also utilized mice lacking one copy of Gigyf2, Eif4e2 or co-deletion of one copy of each gene to further investigate ASD-like behaviors.

Results

4EHP is expressed in excitatory neurons and synaptosomes, and its amount increases during development. 4EHP-eKO mice display exaggerated mGluR-LTD, a phenotype frequently observed in mouse models of ASD. Consistent with synaptic plasticity dysfunction, the mice displayed social behavior impairments without being confounded by deficits in olfaction, anxiety, locomotion, or motor ability. Repetitive behaviors and vocal communication were not affected by loss of 4EHP in excitatory neurons. Heterozygous deletion of either Gigyf2, Eif4e2, or both genes in mice did not result in ASD-like behaviors (i.e. decreases in social behavior or increases in marble burying). Interestingly, exaggerated mGluR-LTD and impaired social behaviors were not attributed to changes in hippocampal global protein synthesis, which suggests that 4EHP and GIGYF2 regulate the translation of specific mRNAs to mediate these effects.

Limitations

This study did not identify which genes are translationally regulated by 4EHP and GIGYF2. Identification of mistranslated genes in 4EHP-eKO mice might provide a mechanistic explanation for the observed impairment in social behavior and exaggerated LTD. Future experiments employing affinity purification of translating ribosomes and mRNA sequencing in 4EHP-eKO mice will address this relevant issue.

Conclusions

Together these results demonstrate an important role of 4EHP in regulating hippocampal plasticity and ASD-associated social behaviors, consistent with the link between mutations in GIGYF2 and ASD.
COVID-19 pneumonia: the great radiological mimicker
Authors: Duzgun Selin Ardali , Durhan Gamze , Demirkazik Figen Basaran , Akpinar Meltem Gulsun , Ariyurek Orhan Macit
Published: November 2020

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread worldwide since December 2019. Although the reference diagnostic test is a real-time reverse transcription-polymerase chain reaction (RT-PCR), chest-computed tomography (CT) has been frequently used in diagnosis because of the low sensitivity rates of RT-PCR. CT findings of COVID-19 are well described in the literature and include predominantly peripheral, bilateral ground-glass opacities (GGOs), combination of GGOs with consolidations, and/or septal thickening creating a “crazy-paving” pattern. Longitudinal changes of typical CT findings and less reported findings (air bronchograms, CT halo sign, and reverse halo sign) may mimic a wide range of lung pathologies radiologically. Moreover, accompanying and underlying lung abnormalities may interfere with the CT findings of COVID-19 pneumonia. The diseases that COVID-19 pneumonia may mimic can be broadly classified as infectious or non-infectious diseases (pulmonary edema, hemorrhage, neoplasms, organizing pneumonia, pulmonary alveolar proteinosis, sarcoidosis, pulmonary infarction, interstitial lung diseases, and aspiration pneumonia). We summarize the imaging findings of COVID-19 and the aforementioned lung pathologies that COVID-19 pneumonia may mimic. We also discuss the features that may aid in the differential diagnosis, as the disease continues to spread and will be one of our main differential diagnoses some time more.
The 100 top-cited meta-analyses of diagnostic accuracy in radiology journals: a bibliometric analysis
Authors: Yaxley Kaspar L. , To Minh-Son
Published: November 2020

Purpose

To identify the 100 top-cited meta-analyses of diagnostic accuracy studies published in radiology, medical imaging and nuclear medicine journals.

Methods

A PubMed search with pre-defined criteria was performed. The 100 top-cited articles meta-analyses were retrieved, using a custom Python script and the Scopus Application Programming Interface (Elsevier). Publication, citation and affiliation details were extracted from each meta-analysis. No formal statistical analysis was performed.

Results

The top meta-analysis was cited 394 times, the 100th meta-analysis 38 times. The USA was the top country represented in the papers (33 meta-analyses) followed by The Netherlands, China and Germany. The journal Radiology published 24 studies. The most common modality reported was positron emission tomography (PET) or PET computed tomography (36 instances), followed by magnetic resonance imaging (30 instances) and computed tomography (27 instances). Cardiac (19 meta-analyses), abdominal (18 meta-analyses), followed by neurological (12 meta-analyses) investigations were the most frequently encountered in the top 100 cited meta-analyses.

Conclusions

The 100 top-cited meta-analyses encompass a broad range of imaging modalities and body regions. This may comprise a useful resource for identifying influential evidence-based diagnostic accuracy information in radiology.
Application of adipose-derived stem cells in photoaging: basic science and literature review
Authors: Chen Shidie , He Zhigang , Xu Jinghong
Published: November 2020

Photoaging is mainly induced by continuous exposure to sun light, causing multiple unwanted skin characters and accelerating skin aging. Adipose-derived stem cells(ADSCs) are promising in supporting skin repair because of their significant antioxidant capacity and strong proliferation, differentiation, and migration ability, as well as their enriched secretome containing various growth factors and cytokines. The identification of the mechanisms by which ADSCs perform these functions for photoaging has great potential to explore therapeutic applications and combat skin aging. We also review the basic mechanisms of UV-induced skin aging and recent improvement in pre-clinical applications of ADSCs associated with photoaging. Results showed that ADSCs are potential to address photoaging problem and might treat skin cancer. Compared with ADSCs alone, the secretome-based approaches and different preconditionings of ADSCs are more promising to overcome the current limitations and enhance the anti-photoaging capacity.
Ventilator-associated pneumonia in patients with SARS-CoV-2-associated acute respiratory distress syndrome requiring ECMO: a retrospective cohort study
Authors: Luyt Charles-Edouard , Sahnoun Tarek , Gautier Melchior , Vidal Pauline , Burrel Sonia , Pineton de Chambrun Marc , Chommeloux Juliette , Desnos Cyrielle , Arzoine Jeremy , Nieszkowska Ania , Bréchot Nicolas , Schmidt Matthieu , Hekimian Guillaume , Boutolleau David , Robert Jérôme , Combes Alain , Chastre Jean
Published: November 2020

Background

The data on incidence, clinical presentation, and outcomes of ventilator-associated pneumonia (VAP) in patients with severe coronavirus disease 2019 (COVID-19) pneumonia requiring mechanical ventilation (MV) are limited. We performed this retrospective cohort study to assess frequency, clinical characteristics, responsible pathogens, and outcomes of VAP in patients COVID-19 pneumonia requiring MV between March 12th and April 24th, 2020 (all had RT-PCR-confirmed SARS-CoV-2 infection). Patients with COVID-19-associated acute respiratory distress syndrome (ARDS) requiring ECMO were compared with an historical cohort of 45 patients with severe influenza-associated ARDS requiring ECMO admitted to the same ICU during the preceding three winter seasons.

Results

Among 50 consecutive patients with Covid-19-associated ARDS requiring ECMO included [median (IQR) age 48 (42–56) years; 72% male], 43 (86%) developed VAP [median (IQR) MV duration before the first episode, 10 (8–16) days]. VAP-causative pathogens were predominantly Enterobacteriaceae (70%), particularly inducible AmpC-cephalosporinase producers (40%), followed by Pseudomonas aeruginosa (37%). VAP recurred in 34 (79%) patients and 17 (34%) died. Most recurrences were relapses (i.e., infection with the same pathogen), with a high percentage occurring on adequate antimicrobial treatment. Estimated cumulative incidence of VAP, taking into account death and extubation as competing events, was significantly higher in Covid-19 patients than in influenza patients (p = 0.002). Despite a high P. aeruginosa-VAP rate in patients with influenza-associated ARDS (54%), the pulmonary infection recurrence rate was significantly lower than in Covid-19 patients. Overall mortality was similar for the two groups.

Conclusions

Patients with severe Covid-19-associated ARDS requiring ECMO had a very high late-onset VAP rate. Inducible AmpC-cephalosporinase-producing Enterobacteriaceae and Pseudomonas aeruginosa frequently caused VAP, with multiple recurrences and difficulties eradicating the pathogen from the lung.
Valorization of organic waste fractions: a theoretical study on biomethane production potential and the recovery of N and P in Austria
Authors: Rosenfeld Daniel C. , Lindorfer Johannes , Ellersdorfer Markus
Published: November 2020

Background

Due to climate change and the rising world population, sustainable energy and fertilizer production faces many challenges. The utilization of organic waste fractions is one possible solution for promoting sustainability. Organic waste fractions have a high potential for biomethane production, which could positively contribute to the current energy mix. Furthermore, organic waste fractions could be used for nutrient recovery (i.e., the recovery of N and P) concurrently to their use in biomethane production. This study examined the theoretical potential of organic waste fractions for valorization in Austria. Further, it provides a theoretical overview of biomethane production and nutrient-recovery potential.

Results

This analysis revealed a total substrate potential of 13 Mt per year in Austria, with the highest contribution from manure. Over 900 million Nm3 of biomethane could potentially be produced from organic waste fractions. Furthermore, developing organic waste fractions as an energy source could improve the impact of the natural gas consuming sectors on climate, reducing 2.4 Mt of CO2 emissions annually. Regarding nutrient recovery, more than 60 kt of N and 20 kt of P could potentially be recovered per year.

Conclusion

The study shows a high potential for producing biomethane from organic waste fractions in Austria. The overall production potential could substitute up to 11% of the Austrian natural gas demand, which could highly decrease the CO2 emissions from fossil energy carriers. Furthermore, a high nutrient recovery potential was identified for an inclusive implementation of an efficient recovery.
Sulfadiazine plasma concentrations in women with pregnancy-acquired compared to ocular toxoplasmosis under pyrimethamine and sulfadiazine therapy: a case–control study
Authors: Reiter-Owona Ingrid , Hlobil Harald , Enders Martin , Klarmann-Schulz Ute , Gruetzmacher Barbara , Rilling Veronika , Hoerauf Achim , Garweg Justus G.
Published: November 2020

Background

Dosing recommendations for the treatment of pregnancy-acquired toxoplasmosis are empirical and widely based on experimental data. There are no pharmacological data on pregnant women with acute Toxoplasma gondii infection under treatment with pyrimethamine (PY) and sulfadiazine (SA) and our study intends to tighten this gap.

Methods

In this retrospective case–control study, we included 89 pregnant women with primary Toxoplasma infection (PT) treated with PY (50 mg first dose, then 25 mg/day), SA (50 mg/kg of body weight/day), and folinic acid (10–15 mg per week). These were compared to a group of 17 women with acute ocular toxoplasmosis (OT) treated with an initial PY dose of 75 mg, thereafter 25 mg twice a day but on the same SA and folinic acid regimen. The exact interval between drug intake and blood sampling and co-medication had not been recorded. Plasma levels of PY and SA were determined 14 ± 4 days after treatment initiation using liquid chromatography–mass spectrometry and compared using the Mann–Whitney U test at a p < 0.05 level.

Results

In 23 PT patients (26%), SA levels were below 20 mg/l. Fifteen of these 23 patients (17% of all patients) in parallel presented with PY levels below 700 µg/l. Both drug concentrations differed remarkably between individuals and groups (PY: PT median 810 µg/l, 95% CI for the median [745; 917] vs. OT 1230 µg/l [780; 1890], p = 0.006; SA: PT 46.2 mg/l [39.9; 54.4] vs. OT 70.4 mg/l [52.4; 89], p = 0.015) despite an identical SA dosing scheme.

Conclusions

SA plasma concentrations were found in the median 34% lower in pregnant women with PT compared to OT patients and fell below a lower reference value of 50 mg/l in a substantial portion of PT patients. The interindividual variability of plasma concentrations in combination with systematically lower drug levels and possibly a lower compliance in pregnant women may thus account for a still not yet supportable transmission risk. Systematic drug-level testing in PT under PY/SA treatment deserves to be considered.
Cerebrospinal fluid α-synuclein predicts neurodegeneration and clinical progression in non-demented elders
Authors:   Alzheimer’s Disease Neuroimaging Initiative, Li Jie-Qiong , Bi Yan-Lin , Shen Xue-Ning , Wang Hui-Fu , Xu Wei , Tan Chen-Chen , Dong Qiang , Wang Yan-Jiang , Tan Lan , Yu Jin-Tai
Published: November 2020

Background

Accumulating reports have suggested that α-synuclein is involved in the pathogenesis of Alzheimer’s disease (AD). As the cerebrospinal fluid (CSF) α-synuclein has been suggested as a potential biomarker of AD, this study was set out to test whether CSF α-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in non-demented elders.

Methods

The associations between CSF α-synuclein and other AD biomarkers were investigated at baseline in non-demented Chinese elders. The predictive values of CSF α-synuclein for longitudinal neuroimaging change and the conversion risk of non-demented elders were assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively, in the Alzheimer’s disease Neuroimaging Initiative (ADNI) database.

Results

The CSF α-synuclein levels correlated with AD-specific biomarkers, CSF total tau and phosphorylated tau levels, in 651 Chinese Han participants (training set). These positive correlations were replicated in the ADNI database (validation set). Using a longitudinal cohort from ADNI, the CSF α-synuclein concentrations were found to increase with disease severity. The CSF α-synuclein had high diagnostic accuracy for AD based on the “ATN” (amyloid, tau, neurodegeneration) system (A + T+ versus A − T − control) (area under the receiver operating characteristic curve, 0.84). Moreover, CSF α-synuclein predicted longitudinal hippocampus atrophy and conversion from MCI to AD dementia.

Conclusions

CSF α-synuclein is associated with CSF tau levels and could predict neurodegeneration and clinical progression in non-demented elders. This finding indicates that CSF α-synuclein is a potentially useful early biomarker for AD.
Perinatal environment shapes microbiota colonization and infant growth: impact on host response and intestinal function
Authors: Selma-Royo M. , Calatayud Arroyo M. , García-Mantrana I. , Parra-Llorca A. , Escuriet R. , Martínez-Costa C. , Collado M. C.
Published: November 2020

Background

Early microbial colonization triggers processes that result in intestinal maturation and immune priming. Perinatal factors, especially those associated with birth, including both mode and place of delivery are critical to shaping the infant gut microbiota with potential health consequences.

Methods

Gut microbiota profile of 180 healthy infants (n= 23 born at home andn= 157 born in hospital, 41.7% via cesarean section [CS]) was analyzed by 16S rRNA gene sequencing at birth, 7 days, and 1 month of life. Breastfeeding habits and infant clinical data, including length, weight, and antibiotic exposure, were collected up to 18 months of life. Long-term personalized in vitro models of the intestinal epithelium and innate immune system were used to assess the link between gut microbiota composition, intestinal function, and immune response.

Results

Microbiota profiles were shaped by the place and mode of delivery, and they had a distinct biological impact on the immune response and intestinal function in epithelial/immune cell models. Bacteroidetes andBifidobacteriumgenus were decreased in C-section infants, who showed higherz-scores BMI and W/L during the first 18 months of life. Intestinal simulated epithelium had a stronger epithelial barrier function and intestinal maturation, alongside a higher immunological response (TLR4 route activation and pro-inflammatory cytokine release), when exposed to home-birth fecal supernatants, compared with CS. Distinct host response could be associated with different microbiota profiles.

Conclusions

Mode and place of birth influence the neonatal gut microbiota, likely shaping its interplay with the host through the maturation of the intestinal epithelium, regulation of the intestinal epithelial barrier, and control of the innate immune system during early life, which can affect the phenotypic responses linked to metabolic processes in infants.

Trial registration

NCT03552939.
The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression: a window-of-opportunity breast cancer trial
Authors: Feldt Maria , Menard Julien , Rosendahl Ann H. , Lettiero Barbara , Bendahl Pär-Ola , Belting Mattias , Borgquist Signe
Published: November 2020

Background

Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism.

Methods

This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post-atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level.

Results

In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. Following atorvastatin treatment, the expression of LDLR was significantly increased (P= 0.004), while the intratumoral levels of total cholesterol remained stable. A positive association between intratumoral cholesterol levels and tumor proliferation measured by Ki-67 expression was found. In agreement with the clinical findings, results from in vitro experiments showed no significant changes of the intracellular cholesterol levels after atorvastatin treatment while increased expression of the LDLR was found, although not reaching statistical significance.

Conclusions

This study shows an upregulation of LDLR and preserved intratumoral cholesterol levels in breast cancer patients treated with statins. Together with previous findings on the anti-proliferative effect of statins in breast cancer, the present data suggest a potential role for LDLR in the statin-induced regulation of breast cancer cell proliferation.

Trial registration

The study has been registered at ClinicalTrials.gov (i.e., ID number:NCT00816244, NIH), December 30, 2008.
Anti-Aβ antibodies bound to neuritic plaques enhance microglia activity and mitigate tau pathology
Authors: Laversenne Vanessa , Nazeeruddin Sameer , Källstig Emma C. , Colin Philippe , Voize Christel , Schneider Bernard L.
Published: November 2020

The brain pathology of Alzheimer’s disease (AD) is characterized by the misfolding and aggregation of both the amyloid beta (Aβ) peptide and hyperphosphorylated forms of the tau protein. Initial Aβ deposition is considered to trigger a sequence of deleterious events contributing to tau pathology, neuroinflammation and ultimately causing the loss of synapses and neurons. To assess the effect of anti-Aβ immunization in this context, we generated a mouse model by overexpressing the human tau protein in the hippocampus of 5xFAD mice. Aβ plaque deposition combined with human tau overexpression leads to an array of pathological manifestations including the formation of tau-positive dystrophic neurites and accumulation of hyperphosphorylated tau at the level of neuritic plaques. Remarkably, the presence of human tau reduces microglial clustering in proximity to the Aβ plaques, which may affect the barrier role of microglia. In this mouse model, continuous administration of anti-Aβ antibodies enhances the clustering of microglial cells even in the presence of tau. Anti-Aβ immunization increases plaque compaction, reduces the spread of tau in the hippocampal formation and prevents the formation of tau-positive dystrophic neurites. However, the treatment does not significantly reduce tau-induced neurodegeneration in the dentate gyrus. These results highlight that anti-Aβ immunization is able to enhance microglial activity around neuritic plaques, mitigating part of the tau-induced pathological manifestations.
TERT promoter mutation confers favorable prognosis regardless of 1p/19q status in adult diffuse gliomas with IDH1/2 mutations
Authors: Arita Hideyuki , Matsushita Yuko , Machida Ryunosuke , Yamasaki Kai , Hata Nobuhiro , Ohno Makoto , Yamaguchi Shigeru , Sasayama Takashi , Tanaka Shota , Higuchi Fumi , Iuchi Toshihiko , Saito Kuniaki , Kanamori Masayuki , Matsuda Ken-ichiro , Miyake Yohei , Tamura Kaoru , Tamai Sho , Nakamura Taishi , Uda Takehiro , Okita Yoshiko , Fukai Junya , Sakamoto Daisuke , Hattori Yasuhiko , Pareira Eriel Sandika , Hatae Ryusuke , Ishi Yukitomo , Miyakita Yasuji , Tanaka Kazuhiro , Takayanagi Shunsaku , Otani Ryohei , Sakaida Tsukasa , Kobayashi Keiichi , Saito Ryuta , Kurozumi Kazuhiko , Shofuda Tomoko , Nonaka Masahiro , Suzuki Hiroyoshi , Shibuya Makoto , Komori Takashi , Sasaki Hikaru , Mizoguchi Masahiro , Kishima Haruhiko , Nakada Mitsutoshi , Sonoda Yukihiko , Tominaga Teiji , Nagane Motoo , Nishikawa Ryo , Kanemura Yonehiro , Kuchiba Aya , Narita Yoshitaka , Ichimura Koichi
Published: November 2020

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90–100%) were associated with favorable prognosis (p < 0.05). A multivariable Cox regression model revealed that TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio = 0.421, p = 0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio = 0.648, p = 0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n = 17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n = 185) (5-year overall survival, 94% and 77%, respectively; p = 0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.
Does substrate colour affect the visual appearance of gilded medieval sculptures? Part I: colorimetry and interferometric microscopy of gilded models
Authors: Wu Qing , Hauldenschild Meret , Rösner Benedikt , Lombardo Tiziana , Schmidt-Ott Katharina , Watts Benjamin , Nolting Frithjof , Ganz David
Published: November 2020

In the history of medieval gilding, a common view has been circulated for centuries that the substrate colour can influence the visual appearance of a gilded surface. In order to fully understand the correlation between the gilding substrate and the colour appearance of the gold leaf laid above, in this paper (Part I) analytical techniques such as colorimetry and interferometric microscopy are implemented on models made from modern gold leaves. This study demonstrates that the substrate colour is not perceptible for gold leaf of at least 100 nm thickness, however the surface burnishing can greatly alter the visual appearance of a gold surface, and the quality of the burnishing is dependent on the substrate materials. Additionally, surface roughness and texture of the substrate can play supplementary roles, which can be visually observed through digital microscopy and quantified through interferometric microscopy. The findings in this paper will form the basis for the study of gold leaf samples taken from medieval European gilded sculptures in Part II.
A survey and analysis of intrusion detection models based on CSE-CIC-IDS2018 Big Data
Authors: Leevy Joffrey L. , Khoshgoftaar Taghi M.
Published: November 2020

The exponential growth in computer networks and network applications worldwide has been matched by a surge in cyberattacks. For this reason, datasets such as CSE-CIC-IDS2018 were created to train predictive models on network-based intrusion detection. These datasets are not meant to serve as repositories for signature-based detection systems, but rather to promote research on anomaly-based detection through various machine learning approaches. CSE-CIC-IDS2018 contains about 16,000,000 instances collected over the course of ten days. It is the most recent intrusion detection dataset that is big data, publicly available, and covers a wide range of attack types. This multi-class dataset has a class imbalance, with roughly 17% of the instances comprising attack (anomalous) traffic. Our survey work contributes several key findings. We determined that the best performance scores for each study, where available, were unexpectedly high overall, which may be due to overfitting. We also found that most of the works did not address class imbalance, the effects of which can bias results in a big data study. Lastly, we discovered that information on the data cleaning of CSE-CIC-IDS2018 was inadequate across the board, a finding that may indicate problems with reproducibility of experiments. In our survey, major research gaps have also been identified.
SARS-CoV-2 analysis on environmental surfaces collected in an intensive care unit: keeping Ernest Shackleton’s spirit
Authors: Escudero Dolores , Boga José Antonio , Fernández Javier , Forcelledo Lorena , Balboa Salvador , Albillos Rodrigo , Astola Iván , García-Prieto Emilio , Álvarez-Argüelles Marta Elena , Martín Gabriel , Jiménez Josu , Vázquez Fernando
Published: November 2020

Background

Intensive care unit workers are at high risk of acquiring COVID-19 infection, especially when performing invasive techniques and certain procedures that generate aerosols (< 5 μm). Therefore, one of the objectives of the health systems should implement safety practices to minimize the risk of contagion among these health professionals. Monitoring environmental contamination of SARS-CoV-2 may help to determine the potential of the environment as a transmission medium in an area highly exposed to SARS-CoV-2, such as an intensive care unit. The objective of the study was to analyze the environmental contamination by SARS-CoV-2 on surfaces collected in an intensive care unit, which is dedicated exclusively to the care of patients with COVID-19 and equipped with negative pressure of – 10 Pa and an air change rate of 20 cycles per hour. Furthermore, all ICU workers were tested for COVID-19 by quantitative RT-PCR and ELISA methods.

Results

A total of 102 samples (72 collected with pre-moistened swabs used for collection of nasopharyngeal exudates and 30 with moistened wipes used in the environmental microbiological control of the food industry) were obtained from ventilators, monitors, perfusion pumps, bed rails, lab benches, containers of personal protective equipment, computer keyboards and mice, telephones, workers’ shoes, floor, and other areas of close contact with COVID-19 patients and healthcare professionals who cared for them. The analysis by quantitative RT-PCR showed no detection of SARS-CoV-2 genome in environmental samples collected by any of the two methods described. Furthermore, none of the 237 ICU workers was infected by the virus.

Conclusions

Presence of SARS-CoV-2 on the ICU surfaces could not be determined supporting that a strict cleaning protocol with sodium hypochlorite, a high air change rate, and a negative pressure in the ICU are effective in preventing environmental contamination. These facts together with the protection measures used could also explain the absence of contagion among staff inside ICUs.