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Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the pregnancy and childhood epigenetics consortium
Get PDFAltered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels
Classification and specific primer design for accurate detection of SARS-CoV-2 using deep learning
Get PDFIn this paper, deep learning is coupled with explainable artificial intelligence techniques for the discovery of representative genomic sequences in SARS-CoV-2. A convolutional neural network classifier is first trained on 553 sequences from the National Genomics Data Center repository, separating the genome of different virus strains from the Coronavirus family with 98.73% accuracy. The network’s behavior is then analyzed, to discover sequences used by the model to identify SARS-CoV-2, ultimately uncovering sequences exclusive to it. The discovered sequences are validated on samples from the National Center for Biotechnology Information and Global Initiative on Sharing All Influenza Data repositories, and are proven to be able to separate SARS-CoV-2 from different virus strains with near-perfect accuracy. Next, one of the sequences is selected to generate a primer set, and tested against other state-of-the-art primer sets, obtaining competitive results. Finally, the primer is synthesized and tested on patient samples (n = 6 previously tested positive), delivering a sensitivity similar to routine diagnostic methods, and 100% specificity. The proposed methodology has a substantial added value over existing methods, as it is able to both automatically identify promising primer sets for a virus from a limited amount of data, and deliver effective results in a minimal amount of time. Considering the possibility of future pandemics, these characteristics are invaluable to promptly create specific detection methods for diagnostics
Exploring determinants of hand hygiene compliance in LTCFs: a qualitative study using Flottorps’ integrated checklist of determinants of practice
Get PDFBackground: Elderly residents in long-term care facilities (LTCFs) are vulnerable to healthcare-associated infections. Although hand hygiene is a leading measure for preventing infection, the compliance of healthcare workers is low. The aim of this study is to identify determinants that influence hand hygiene compliance of nursing staff in LTCFs. This information on determinants can eventually be used to develop a tailored implementation strategy for LTCFs. Methods: This is an explorative, descriptive study using qualitative methods. We performed semi-structured focus group discussions with 31 nurses and nurse assistants from five Dutch LTCFs. Our focus group discussions continued until no new information could be identified from the data. We used Flottorps’ comprehensive checklist for identifying determinants of practice (the TICD checklist) to guide data collection and analysis. The audiotapes were transcribed verbatim and two authors independently analysed the transcripts with Atlas.ti software. Results: LTCFs for the elderly have setting specific determinants that are decisive in explaining hand hygiene compliance. Most of these determinants are related to the residents with whom nurses build close relationships and for whom they want to create a homelike atmosphere. Residents can complicate the provision of care with unpredictable behaviour, being unwilling to receive care or use shared facilities. Our study also discovered setting-transcending determinants related to knowledge, professional interactions, guidelines, and incentives/resources. Conclusions: Nurses in LTCFs are constantly pursuing a balance between working hygienically, responding adequately to acute care needs, and maintaining a homelike environment for their residents. As a result, setting-specific determinants affect hand hygiene compliance, as do the known determinants that are important in other care settings. To improve compliance in LTCFs, interventions should be selected on a theoretical base while linking these determinants to change interventions. Trial registration: Registration number 50-53000-98-113, Compliance With Hand Hygiene in Nursing Homes: Go for a Sustainable Effect (CHANGE) on ClinicalTrials.gov. Date of registration 28-6-2016
Article development of a new hyaluronic acid based redox-responsive nanohydrogel for the encapsulation of oncolytic viruses for cancer immunotherapy
Get PDFOncolytic viruses (OVs) are emerging as promising and potential anti-cancer therapeutic agents, not only able to kill cancer cells directly by selective intracellular viral replication, but also to promote an immune response against tumor. Unfortunately, the bioavailability under systemic administration of OVs is limited because of undesired inactivation caused by host immune system and neutralizing antibodies in the bloodstream. To address this issue, a novel hyaluronic acid based redox responsive nanohydrogel was developed in this study as delivery system for OVs, with the aim to protect the OVs following systemic administration. The nanohydrogel was formulated by water in oil (W/O) nanoemulsion method and crosslinked by disulfide bonds derived from the thiol groups of synthesized thiolated hyaluronic acid. One DNA OV Ad[I/PPT-E1A] and one RNA OV Rigvir® ECHO-7 were encapsulated into the developed nanohydrogel, respectively, in view of their potential of immunovirotherapy to treat cancers. The nanohydrogels showed particle size of approximately 300–400 nm and negative zeta potential of around −13 mV by dynamic light scattering (DLS). A uniform spherical shape of the nanohydrogel was observed under the scanning electron microscope (SEM) and transmission electron microscope (TEM), especially, the successfully loading of OV into nanohydrogel was revealed by TEM. The crosslinking between the hyaluronic acid chains was confirmed by the appearance of new peak assigned to disulfide bond in Raman spectrum. Furthermore, the redox responsive ability of the nanohydrogel was determined by incubating the nanohydrogel into phosphate buffered saline (PBS) pH 7.4 with 10 µM or 10 mM glutathione at 37◦ C which stimulate the normal physiological environment (extracellular) or reductive environment (intracellular or tumoral). The relative turbidity of the sample was real time monitored by DLS which indicated that the nanohydrogel could rapidly degrade within 10 h in the reductive environment due to the cleavage of disulfide bonds, while maintaining the stability in the normal physiological environment after 5 days. Additionally, in vitro cytotoxicity assays demonstrated a good oncolytic activity of OVs-loaded nanohydrogel against the specific cancer cell lines. Overall, the results indicated that the developed nanohydrogel is a delivery system appropriate for viral drugs, due to its hydrophilic and porous nature, and also thanks to its capacity to maintain the stability and activity of encapsulated viruses. Thus, nanohydrogel can be considered as a promising candidate carrier for systemic administration of oncolytic immunovirotherapy
Passive autonomy: Hygromorphic rotational actuators
Get PDFInspired by phenomena in the plant world, a meteoro-sensitive rotational actuator is developed. The design uses a hygro-active shell, whose water-based swelling is restricted at selective locations to form a helicoid structure. The influence of geometrical parameters on the performance is investigated using a numerical analysis of various geometries, by looking at resulting rotation and torque during this rotation. Prototypes are built of five key geometries in the design space, to validate the simulations and to investigate the behaviour of the design experimentally. These prototypes are submerged in water to investigate their deformation, after which they are placed in a torsion machine to investigate the torque during rotation. The experiments result in similar rotations and torques as the simulations. The designed Hygromorphic Rotational Actuator is capable of passively rotating its own structure, thereby expanding the possibilities of engineers and designers when designing passive autonomous systems
Tissue-Specific DNA Repair Activity of ERCC-1/XPF-1
Get PDFSabatella et al. image the DNA repair endonuclease ERCC-1/XPF-1 in C. elegans to show that nucleotide excision repair exhibits tissue-specific activity. DNA lesions are very rapidly removed from the entire genome in oocytes but only from transcribed genes in somatic cells. Neurons are more sensitive to DNA damage than muscle cells.Hereditary DNA repair defects affect tissues differently, suggesting that in vivo cells respond differently to DNA damage. Knowledge of the DNA damage response, however, is largely based on in vitro and cell culture studies, and it is currently unclear whether DNA repair changes depending on the cell type. Here, we use in vivo imaging of the nucleotide excision repair (NER) endonuclease ERCC-1/XPF-1 in C. elegans to demonstrate tissue-specific NER activity. In oocytes, XPF-1 functions as part of global genome NER (GG-NER) to ensure extremely rapid removal of DNA-helix-distorting lesions throughout the genome. In contrast, in post-mitotic neurons and muscles, XPF-1 participates in NER of transcribed genes only. Strikingly, muscle cells appear more resistant to the effects of DNA damage than neurons. These results suggest a tissue-specific organization of the DNA damage response and may help to better understand pleiotropic and tissue-specific consequences of accumulating DNA damage
Who May Represent the Country? Football, Citizenship, Migration, and National Identity at the FIFA World Cup
Get PDFABSTRACT
The terms ‘citizenship’, ‘nation’, and ‘nationality’ contain different, albeit overlapping, meanings of belonging and identity. The history of the FIFA (Fed
eration Internationale de Football Association) World Cup provides excellent examples and cases to unveil these meanings in different historical contexts. Three overlapping categories of historical realities are proposed to understand the historical complexities of migration, citizenship and national identity from a historical sports perspective. The first category considers diaspora teams, using the examples of Italy in 1934 and Morocco in 2018. The second category examines teams
from expanding and dissolving states, exemplified by Germany in 1938 and Yugoslavia in 1990. The third category explores colonial and post-colonial realities, illustrated by Portugal in 1966 and France in 2018. The relationship among national belonging, citizenship, and migration challenges the self-evident notions of
membership and belonging. The historical concepts of ius sanguinis (blood ties) and ius soli (territorial birthright) are well-known markers and symbols of national belonging and citizenship. In nation states, the feeling of belonging is created by membership in an ‘imagined community’, which is often self-evidently bound
by these markers. The proposed historical categories partly legitimize and pave the way for diaspora and post-colonial football players who will become more visible in national teams at the World Cup in the future
Intestinal-derived ILCs migrating in lymph increase IFNγ production in response to Salmonella Typhimurium infection
Get PDFInnate lymphoid cells (ILCs) are enriched in mucosae and have been described as tissue-resident. Interestingly, ILCs are also present within lymph nodes (LNs), in the interfollicular regions, the destination for lymph-migratory cells. We have previously shown that LN ILCs are supplemented by peripheral tissue-derived ILCs. Using thoracic duct cannulations, we here enumerate the intestinal lymph ILCs that traffic from the intestine to the mesenteric LNs (MLNs). We provide, for the first time, a detailed characterisation of these lymph-migratory ILCs. We show that all ILC subsets migrate in lymph, and while global transcriptional analysis reveals a shared signature with tissue-resident ILCs, lymph ILCs express migration-associated genes including S1PRs, SELL (CD62L) and CCR7. Interestingly, we discovered that while Salmonella Typhimurium infections do not increase the numbers of migrating ILCs, infection changes their composition and cytokine profile. Infection increases the proportions of RORyt+ T-bet+ ILCs, levels of IFNγ, and IFNγ/GM-CSF co-expression. Infection-induced changes in migratory ILCs are reflected in colon-draining MLN ILCs, where RORyt+ T-bet+ ILCs accumulate and display corresponding increased cytokine expression. Thus, we reveal that ILCs respond rapidly to intestinal infection and can migrate to the MLN where they produce cytokines
Recurrent glioblastoma: From molecular landscape to new treatment perspectives
Get PDFGlioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients
Clinically relevant potential drug-drug interactions in intensive care patients: A large retrospective observational multicenter study
Get PDFPurpose: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. Materials & methods: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. Results: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when considering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. Conclusions: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients