Comparison of Entropy vs. Bispectral Index Anesthetic Depth Monitoring during Isoflurane Anesthesia in Living Donor Liver Transplantation: Observational Study

Liver transplantation (LT) recipients are known to require less anesthetic agents. Providing minimally required anesthetics while avoiding awareness is especially important in LT recipients because it would help manage perioperative hemodynamic instability with less vasopressor and fast track recovery. This study aims to compare state entropy (SE) against bispectral index (BIS) during isoflurane anesthesia in LT. We adjusted anesthesia to BIS values 40 - 60, and compared it with concomitant SE values. BIS, SE values, and anesthetic requirements according to liver failure severity, etiology and LT stages were analyzed. For BIS-SE differences, SE value that is different from the concomitant BIS by more than 15 was defined as a significant disagreement. Mann Whitney, Kruskal Wallis test and a Poisson exact test were used for analysis. The BIS-SE pair sets of 2895 from 38 patients were analyzed. BIS, SE values and anesthetic requirements were significantly lower in MELD ≥ 20 (p < 0.001 in all) and in alcoholic etiology (p < 0.001 in all). For BIS-SE differences, 320 disagreement data pairs were seen at a rate of 1.33 times/hr (95% CI = [1.19, 1.48], p < 0.001). A significant disagreement was delineated in MELD score ≥ 20 (3.04 times/hr, CI = [2.64, 3.49], p < 0.001), alcoholic etiology (3.19 times/hr, [2.67, 3.78], p < 0.001) and postreperfusion stage (1.63 times/hr, [1.43, 1.85], p < 0.001). In these significant BIS-SE differences, 95.9% (307/320 disagreement data pairs) showed higher BIS than SE. In conclusion, in high MELD and alcoholic etiology, anesthetic requirements were significantly less, and BIS and SE showed great discrepancy with lower SE values. Therefore, when SE monitoring is used during LT, anesthesiologists may need to consider that in high MELD and alcoholic etiology, SE tends to show lower values than the concomitant BIS values that are within optimal anesthetic depth ranges.

Development of living floor spaces on the basis of ecological economic and social programs

Human activities moves to an ecological disaster. The technocratic approach to the organization of activity breaking environment ecology forces to defend the Nature accidents. The mankind crossed line of technological development when the Planet became vulnerable. Will help to rescue mankind from an ecological disaster, ecological thinking and behavior of people, and their ecological responsibility, the moral relation to the nature;harmonization of vital system by waste-free industrial cycles of the combined productions;eco-world formation. The problem of global ecological stabilization can be solved by implementation of social and economic interdisciplinary programs, such as, first, the ecological program “Clean Air, Clear Water, Pure Food, Net Energy, Pure Cities and Villages, Pure Nature”, secondly, the program of development ecological and health the preserving with the filled economy resources, thirdly, the “Development Health of the Preserving Medicine and Health System” program, fourthly, the program of the ecological focused interdisciplinary education, fifthly, the program of peaceful, humane environmental policy, sixthly, the program of civil education of harmonious life for a sustainable development, seventhly, the program of formation of fair democracy as way of life of society. Social and economic programs for stabilization of ecology need to be realized under the competent direction and control of the institutionalized infrastructure of scientific and educational society and on the basis of ecological thinking and behavior of all segments of the population. World community will have to undertake decisive measures to stabilize the environmental ecological processes in order to keep modern and future generations supplied with a harmony between the meeting of their reasonable needs, social and economic problems decision, with the life on the Earth being preserved.

Communication of Internal Speech with Communicative Associative Robot via Spectral Neurointerface

Thought communications with an associative-communicative robot are carried out through the spectral neurointerface of internal speech.Internal speech is an energy physiological process.Internal speech is vibration from the mental vibration of thought.Mental vibration of thought is a process in the mental ethereal field.The vibrations of thoughts are reflected and observed by the mind in the form of semantic sensual images.Vibrations of semantic sensual images generate vibrations of internal speech action(internal speech)in the form of language communicative and associative stereotypes which are perceived by a touch zone of a brain of Wernicke.In­ternal speech is a linguistic mental vibration.It is felt and becomes internal­ly audible and drawn to attention.The perception of vibrations of internal speech is carried out through energy channels,such as the internal posterior median canal of the spine.The spectral neurointerface perceives these vi­brations.Neocortex makes us a reasonable person-allows us to think and talk.The spectral neurointerface is based on the principles of biosensors,bioenergy detectors,spectral analyzers and electrocorticography for neuro­imaging parts of the brain that record vibrations of internal speech,such as the lower frontal gyrus,the upper and middle temporal gyrus,the medial prefrontal cortex,the hind parts of the wedge and precline and the dark temporal region,including the posterior Internal speech activity is associat­ed with the semantic memory of the neocortex.

Ovalicin attenuates atopic dermatitis symptoms by inhibiting IL-31 signaling and intracellular calcium influx

Atopic dermatitis(AD)is a common skin disorder difficult to be treated with medication.This study investigated the potential of ovalicin extracted from Cordyceps militaris for the treatment of AD using in vitro and in vivo models.We found that,in canine macrophage cell line DH82,lipopolysaccharide(LPS)upregulated the expression of genes associated with inflammation and pruritic responses through activating calcium and interleukin-31(IL-31)signaling,and the upregulation could be suppressed by ovalicin,with an effect significantly stronger than dexamethasone.Ovalicin also reduced the expression of IL-31 downstream genes,including JAK2(Janus kinase 2),TRPV1(transient receptor potential vanilloid receptor-1),and HRH2(histamine receptor H2).Ovalicin significantly alleviated the allergic symptoms in the AD mouse model.Histologically,the number of macrophages and mast cells infiltrated in the dermis was significantly reduced by ovalicin treatment.In the skin tissue of AD mice,reduction of IL-31 receptor was observed in the ovalicin treated group compared to the group without ovalicin treatment.To our knowledge,this is the first study to elucidate the anti-atopic mechanism of ovalicin,which could be an alternative to steroidal drugs commonly used for AD treatment.

Control of Surface Wrinkles on Shape Memory PLA/PPDO Micro‑nanofibers and Their Applications in Drug Release and Anti‑scarring

Micro-and nano-fibers of shape memory polymers(SMP)offer multiple advantages like high specific surface area,poros-ity,and intelligence,and are suitable for biomedical applications.In this study,biodegradable poly(p-dioxanone)(PPDO)materials were incorporated to improve the brittleness of shape memory polylactic acid(PLA),and plasticizers were used to reduce the transition temperature of SMP composites such that their transitions could be induced close to body temperature.Furthermore,an electrostatic spinning technology was applied to prepare SMP fibers with wrinkled structures and regulate their microstructures and morphologies such that the intelligent transition of wrinkled and smooth morphologies can be achieved on the fiber surface.The application of this controllable-morphology fiber membrane in intelligent controlled drug release and scar inhibition after Ahmed Glaucoma Valve(AGV)implantation was also studied.The drug release from the stretched and deformed drug-loaded fiber membranes was faster than those from membranes with the original shape.This membrane with micro-and nano-fibers had good anti-scarring effects that improved after drug loading.The achievement of intelligent controlled drug release and the evident anti-scarring effects of the membrane broaden the application of SMP fibers in the biomedical field.

Direct detection of C9orf72 hexanucleotide repeat expansions by nanopore biosensor

Diagnostic C9orf72 hexanucleotide repeat expansions(C9-HRE)is essential for the early and accurate diagnosis of amyotrophic lateral sclerosis(ALS)and will provide support for the prognosis and gene therapy of ALS.In the present study,by combining catalytic hairpin assembly(CHA)with Mycobacterium smegmatis porin A(MspA)nanopore,a new nanopore-based strategy for the detection of C9-HRE was reported.Less than 30 repeats of C9-HRE could be detected via this method,and the results have the potential to help distinguish between patients and healthy individuals.Moreover,the method demonstrated its great specificity for C9-HRE by identifying other repeat expansions.Given the high selectivity,this approach had been successfully used to detect C9-HRE in cell and blood samples with high accuracy.This detection strategy is user-friendly and has a strong anti-interference ability,thus providing a powerful tool for clinical diagnosis.

Epigenetic mechanisms involved in the neuroprotective effect of scorpion extract in a Parkinson's disease murine model based on multi-omics approach

OBJECTIVE: To investigate whether scorpion extract elicits a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated mice models, and the genes associated with the therapeutic effects using RNA sequencing(seq)analysis.METHODS: This study investigated the changes in interaction between messenger ribonucleic acid(m RNA) expression and deoxyribonucleic acid(DNA) methylation related to the protective effects of scorpion extracts, in the substantia nigra(SN)region of a MPTP-induced Parkinson's disease(PD)model.RESULTS: In this model, scorpion extracts attenuated the motor impairment as demonstrated by the rotarod and open field tests. Scorpion extracts consistently attenuated the decrease of tyrosine hydroxylase(TH) positive neural cells in the SN and striatum of mice. We profiled genomewide DNA methylation using Methyl-Seq and measured the transcriptome using RNA-Seq in murine SN in the following groups: vehicle-treated MPTP-induced PD mice and scorpion extracttreated MPTP-induced PD mice. In total, 13 479 differentially expressed genes were identified in association with the anti-PD effect of the scorpion extract, mainly in the promoter and coding regions.Among them, 47 were negatively correlated downregulated genes. Nineteen genes out of 47 downregulated genes were negatively correlated with the expression of the other 28 genes. Among these genes, SGSM1 was related to dopaminergic neurons including dopamine transporters, TH, dihydroxyphenylalanine decarboxylase, and dopamine D2 receptor.CONCLUSION: This study provides insights into the anti-parkinsonian effects of scorpion extract and reveals the epigenetic targets in its therapeutic mechanism.

Dramatic Response to Cabozantinib in a Patient with Refractory Hepatocellular Carcinoma with c-MET Amplification

We report a case of a patient with c-MET amplified hepato-cellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to four previous lines of systemic therapy. The patient had previously received re-gorafenib plus nivolumab as first-line treatment, lenvatinib as second-line, sorafenib as third-line, and ipilimumab plus nivolumab as fourth-line treatment in sequence. However, all regimens showed early progression within 2 months. The pa-tient’s HCC was well-controlled, with a partial response (PR) of over 9 months after beginning cabozantinib treatment. Although there were mild adverse events such as diarrhea and elevated liver enzymes, they were tolerable. Next-gen-eration sequencing (NGS) of the patient’s previous surgical specimen indicated amplification of c-MET genes. Although it is well known that cabozantinib has excellent effectiveness for inhibiting c-MET at the preclinical level, to the best of our knowledge this is the first case of dramatic response to cabozantinib in a patient with advanced HCC with c-MET am-plification.

A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

Interleukin-1 receptor-associated kinase 4(IRAK4)is a pivotal enzyme in the Toll-like receptor(TLR)/MYD88 dependent signaling pathway,which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL).Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma.Moreover,proviral integration site for Moloney murine leukemia virus 1(PIM1)functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance.We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo.In rheumatoid arthritis mouse models,treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation.KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs.In addition,KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 kinase.Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.

PD-1 blockade-unresponsive human tumor-infiltrating CD8^(+)T cells are marked by loss of CD28 expression and rescued by IL-15

Blockade of programmed death-1(PD-1)reinvigorates exhausted CD8^(+)T cells,resulting in tumor regression in cancer patients.Recently,reinvigoration of exhausted CD8^(+)T cells following PD-1 blockade was shown to be CD28-dependent in mouse models.Herein,we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8^(+)T cells(CD8^(+)TILs)obtained from non-small-cell lung cancer patients.Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8^(+)TILs.Furthermore,we found that human CD28^(+)CD8^(+)but not CD28^(–)CD8^(+)TILs responded to PD-1 blockade irrespective of B7/CD28 blockade,indicating that CD28 costimulation in human CD8^(+)TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8^(+)TILs.Transcriptionally and phenotypically,PD-1 blockade-unresponsive human CD28^(–)PD-1^(+)CD8^(+)TILs exhibited characteristics of terminally exhausted CD8^(+)T cells with low TCF1 expression.Notably,CD28^(–)PD-1^(+)CD8^(+)TILs had preserved machinery to respond to IL-15,and IL-15 treatment enhanced the proliferation of CD28^(–)PD-1^(+)CD8^(+)TILs as well as CD28^(+)PD-1^(+)CD8^(+)TILs.Taken together,these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8^(+)TILs with a TCF1–signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.