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Purpose of the ReviewNeuro-ophthalmologists rapidly adopted telehealth during the COVID-19 pandemic to minimize disruption to patient care. This article reviews recent research on tele-neuro-ophthalmology adoption, current limitations, and potential use beyond the pandemic. The review considers how digital transformation, including machine learning and augmented reality, may be applied to future iterations of tele-neuro-ophthalmology.Recent FindingsTelehealth utilization has been sustained among neuro-ophthalmologists throughout the pandemic. Adoption of tele-neuro-ophthalmology may provide solutions to subspecialty workforce shortage, patient access, physician wellness, and trainee educational needs within the field of neuro-ophthalmology. Digital transformation technologies have the potential to augment tele-neuro-ophthalmology care delivery by providing automated workflow solutions, home-based visual testing and therapies, and trainee education via simulators.SummaryTele-neuro-ophthalmology use has and will continue beyond the COVID-19 pandemic. Digital transformation technologies, when applied to telehealth, will drive and revolutionize the next phase of tele-neuro-ophthalmology adoption and use in the years to come.

Background Sample index cross-talk can result in false positive calls when massively parallel sequencing (MPS) is used for sensitive applications such as low-frequency somatic variant discovery, ancient DNA investigations, microbial detection in human samples, or circulating cell-free tumor DNA (ctDNA) variant detection. Therefore, the limit-of-detection of an MPS assay is directly related to the degree of index cross-talk. Results Cross-talk rates up to 0.29% were observed when using standard, combinatorial adapters, resulting in 110,180 (0.1% cross-talk rate) or 1,121,074 (0.29% cross-talk rate) misassigned reads per lane in non-patterned and patterned Illumina flow cells, respectively. Here, we demonstrate that using unique, dual-matched indexed adapters dramatically reduces index cross-talk to ≤1 misassigned reads per flow cell lane. While the current study was performed using dual-matched indices, using unique, dual-unrelated indices would also be an effective alternative. Conclusions For sensitive downstream analyses, the use of combinatorial indices for multiplexed hybrid capture and sequencing is inappropriate, as it results in an unacceptable number of misassigned reads. Cross-talk can be virtually eliminated using dual-matched indexed adapters. These results suggest that use of such adapters is critical to reduce false positive rates in assays that aim to identify low allele frequency events, and strongly indicate that dual-matched adapters be implemented for all sensitive MPS applications.

Severe influenza infection has no effective treatment available. One of the key barriers to developing host-directed therapy is a lack of reliable prognostic factors needed to guide such therapy. Here, we use a network analysis approach to identify host factors associated with severe influenza and fatal outcome. In influenza patients with moderate-to-severe diseases, we uncover a complex landscape of immunological pathways, with the main changes occurring in pathways related to circulating neutrophils. Patients with severe disease display excessive neutrophil extracellular traps formation, neutrophil-inflammation and delayed apoptosis, all of which have been associated with fatal outcome in animal models. Excessive neutrophil activation correlates with worsening oxygenation impairment and predicted fatal outcome (AUROC 0.817–0.898). These findings provide new evidence that neutrophil-dominated host response is associated with poor outcomes. Measuring neutrophil-related changes may improve risk stratification and patient selection, a critical first step in developing host-directed immune therapy. Identification of host factors associated with severe influenza infection could provide insights into treatment options. Here, the authors provide transcriptomic analyses of blood from >100 influenza infected patients and show that changes in circulating neutrophils are associated with severe influenza infection.

Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 μM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2–PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs.

Background Psoriasis is an immune-mediated, inflammatory disorder of the skin characterized by chronic inflammation and hyperproliferation of the epidermis. Differential expression analysis of microarray or RNA-seq data have shown that thousands of coding and non-coding genes are differentially expressed between psoriatic and healthy control skin. However, differential expression analysis may fail to detect perturbations in gene coexpression networks. Sensitive detection of such networks may provide additional insight into important disease-associated pathways. In this study, we applied weighted gene coexpression network analysis (WGCNA) on RNA-seq data from psoriasis patients and healthy controls. Results RNA-seq was performed on skin samples from 18 psoriasis patients (pre-treatment and post-treatment with the TNF-α inhibitor adalimumab) and 16 healthy controls, generating an average of 52.3 million 100-bp paired-end reads per sample. Using WGCNA, we identified 3 network modules that were significantly correlated with psoriasis and 6 network modules significantly correlated with biologic treatment, with only 16 % of the psoriasis-associated and 5 % of the treatment-associated coexpressed genes being identified by differential expression analysis. In a majority of these correlated modules, more than 50 % of coexpressed genes were long non-coding RNAs (lncRNA). Enrichment analysis of these correlated modules revealed that short-chain fatty acid metabolism and olfactory signaling are amongst the top pathways enriched for in modules associated with psoriasis, while regulation of leukocyte mediated cytotoxicity and regulation of cell killing are amongst the top pathways enriched for in modules associated with biologic treatment. A putative autoantigen, LL37, was coexpressed in the module most correlated with psoriasis. Conclusions This study has identified several networks of coding and non-coding genes associated with psoriasis and biologic drug treatment, including networks enriched for short-chain fatty acid metabolism and olfactory receptor activity, pathways that were not previously identified through differential expression analysis and may be dysregulated in psoriatic skin. As these networks are comprised mostly of non-coding genes, it is likely that non-coding genes play critical roles in the regulation of pathways involved in the pathogenesis of psoriasis.

Toll-like receptor (TLR) is essential for the immune response to Mycobacterium tuberculosis (MTB) infection. However, the mechanism whereby TLR mediates the MTB-induced pleural mesothelial hyperpermeability in tuberculous pleural effusion (TBPE) remains unclear. Pleural effusion size and pleural fluid levels of vascular endothelial growth factor (VEGF) and soluble TLR2 (sTLR2) in patients with TBPE (n = 36) or transudative pleural effusion (TPE, n = 16) were measured. The effects of MTB H37Ra (MTBRa) on pleural mesothelial permeability and the expression of VEGF and zonula occludens (ZO)-1 in human pleural mesothelial cells (PMCs) were assessed. Levels of VEGF and sTLR2 were significantly elevated in TBPE compared to TPE. Moreover, effusion VEGF levels correlated positively, while sTLR2 values correlated negatively, with pleural effusion size in TBPE. In human PMCs, MTBRa substantially activated JNK/AP-1 signaling and upregulated VEGF expression, whereas knockdown of TLR2 remarkably inhibited MTBRa-induced JNK phosphorylation and VEGF overexpression. Additionally, both MTBRa and VEGF markedly reduced ZO-1 expression and induced pleural mesothelial permeability, while TLR2 silencing or pretreatment with anti-VEGF antibody significantly attenuated the MTBRa-triggered effects. Collectively, TLR2 mediates VEGF overproduction and downregulates ZO-1 expression in human PMCs, leading to mesothelial hyperpermeability in TBPE. Targeting TLR2/VEGF pathway may confer a potential treatment strategy for TBPE.

Objectives Hospitalized patients who presented within the last 24 h with a bacterial infection were recruited. Participants were assigned into sepsis and uncomplicated infection groups. In addition, healthy volunteers were recruited as controls. RNA was prepared from whole blood, depleted from beta-globin mRNA and sequenced. This dataset represents a highly valuable resource to better understand the biology of sepsis and to identify biomarkers for severe sepsis in humans. Data description The data presented here consists of raw and processed transcriptome data obtained by next generation RNA sequencing from 105 peripheral blood samples from patients with uncomplicated infections, patients who developed sepsis, septic shock patients, and healthy controls. It is provided as raw sequenced reads and as normalized log 2 transformed relative expression levels. This data will allow performing detailed analyses of gene expression changes between uncomplicated infections and sepsis patients, such as identification of differentially expressed genes, co-regulated modules as well as pathway activation studies.

A potentiometric enzyme biosensor is a convenient detector for quantification of urea concentrations in industrial processes, or for monitoring patients with diabetes, kidney damage or liver malfunction. In this work, poly(3-hexylthiophene-co-3-thiopheneacetic acid) (P(3HT-co-3TAA)) was chemically synthesized, characterized and spin-coated onto conductive indium tin oxide (ITO) glass electrodes. Urease (Urs) was covalently attached to the smooth surface of this copolymer via carbodiimide coupling. The electrochemical behavior and stability of the modified Urs/P(3HT-co-3TAA)/ITO glass electrode were investigated by cyclic voltammetry, and the bound enzyme activity was confirmed by spectrophotometry. Potentiometric response studies indicated that this electrode could determine the concentration of urea in aqueous solutions, with a quasi-Nernstian response up to about 5 mM. No attempt was made to optimize the response speed; full equilibration occurred after 10 min, but the half-time for response was typically <1 min.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS . Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS . T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

The novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS). On Days 0 and 4, an intravenous infusion of 2 × 10 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed. None of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO /FiO ratio, Murray's lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1β, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4 T cells (namely, CD4 naïve T cells and CD4 memory T cell subtypes), Treg cells, CD19 B cells (namely, CD19 naïve B cells, CD27 switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14 monocytes (namely, CD16 classical and CD16 non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy. pc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4 T cells and CD19 B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.