Purpose: To assess the prevalence and related factors of a newly developed insomnia disorder following craniotomy for brain tumor resection. Furthermore, we examined the association of pre- and postoperative insomnia with the 2-year mortality rate.

Methods: The South Korean national registration cohort database was used as the data source. This study includes all adult patients who underwent craniotomy for brain tumor resection from January 1, 2011, to December 31, 2017. G47.0 and F51.0 (International Statistical Classification of Diseases and Related Health Problems 10th Revision codes) were used to identify insomnia disorders.

Results: In total, 4,851 patients were included. Among them, 913 (18.8%) and 447 (9.2%) patients were assigned to the preoperative and postoperative insomnia groups, respectively. After modeling using multivariable logistic regression, older age (odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.03; P < 0.001), reoperation within 1 year (OR 2.12, 95% CI 1.47-3.06; P < 0.001), and newly acquired brain disability (OR 1.32, 95% CI 1.01-1.71; P = 0.043) were associated with an increased prevalence of newly developed postoperative insomnia disorder. After modeling using multivariable Cox regression, the preoperative and postoperative insomnia disorder groups showed a 1.17-fold (hazard ratio (HR) 1.17, 95% CI 1.02-1.34; P = 0.021) and a 1.85-fold (HR 1.85, 95% CI 1.59-2.15, P < 0.001) increased 2-year all-cause mortality risk compared to the control group, respectively.

Conclusion: In South Korea, 9.2% of the patients with brain tumors were newly diagnosed with an insomnia disorder following craniotomy for brain tumor resection, which was associated with an increased risk of 2-year mortality.

Keywords: Brain neoplasms; Craniotomy; Neurosurgery; Sleep initiation and maintenance disorders; Sleep–wake disorders.

Intestinal macrophages play a vital role in the maintenance of gut homeostasis through signals derived from the microbiota. We previously demonstrated that microbial-derived metabolites can shape the metabolic functions of macrophages. Here, we show that antibiotic-induced disruption of the intestinal microbiota dramatically alters both the local metabolite environment, and the metabolic functions of macrophages in the colon. Broad-spectrum antibiotic administration in mice increased expression of the large neutral amino acid transporter LAT1 and accordingly, amino acid uptake. Subsequently, antibiotic administration enhanced the metabolic functions of colonic macrophages, increasing phosphorylation of components of mammalian/mechanistic target of rapamycin (mTOR) signalling pathways, with increased expression of genes involved in glycolysis and oxidative phosphorylation (OXPHOS), increased mitochondrial function, increased rate of extracellular acidification (ECAR; measure of glycolysis) and increased rate of oxygen consumption (OCR; measure of OXPHOS). Small bowel macrophages were less metabolically active than their colonic counterparts, with macrophage metabolism in the small intestine being independent of the microbiota. Finally, we reveal tissue resident Tim4⁺ CD4⁺ macrophages exhibit enhanced fatty acid uptake alongside reduced fatty acid synthesis compared to recruited macrophages. Thus, the microbiota shapes gut macrophage metabolism in a compartment-specific manner, with important implications for monocyte recruitment and macrophage differentiation.

Background: In selected patients with refractory out-of-hospital cardiac arrest, extracorporeal cardiopulmonary resuscitation represents a promising approach when conventional cardiopulmonary resuscitation fails to achieve return of spontaneous circulation. This systematic review and meta-analysis aimed to compare extracorporeal cardiopulmonary resuscitation to conventional cardiopulmonary resuscitation.

Methods: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials up to November 28, 2021, for randomized trials and observational studies reporting propensity score-matched data and comparing adults with out-of-hospital cardiac arrest treated with extracorporeal cardiopulmonary resuscitation with those treated with conventional cardiopulmonary resuscitation. The primary outcome was survival with favorable neurological outcome at the longest follow-up available. Secondary outcomes were survival at the longest follow-up available and survival at hospital discharge/30 days.

Results: We included six studies, two randomized and four propensity score-matched studies. Patients treated with extracorporeal cardiopulmonary resuscitation had higher rates of survival with favorable neurological outcome (81/584 [14%] vs. 46/593 [7.8%]; OR = 2.11; 95% CI, 1.41-3.15; p < 0.001, number needed to treat 16) and of survival (131/584 [22%] vs. 102/593 [17%]; OR = 1.40; 95% CI, 1.05-1.87; p = 0.02) at the longest follow-up available compared with conventional cardiopulmonary resuscitation. Survival at hospital discharge/30 days was similar between the two groups (142/584 [24%] vs. 122/593 [21%]; OR = 1.26; 95% CI, 0.95-1.66; p = 0.10).

Conclusions: Evidence from randomized trials and propensity score-matched studies suggests increased survival and favorable neurological outcome in patients with refractory out-of-hospital cardiac arrest treated with extracorporeal cardiopulmonary resuscitation. Large, multicentre randomized studies are still ongoing to confirm these findings.

Keywords: extracorporeal cardiopulmonary resuscitation; extracorporeal membrane oxygenation; neurological outcome; out-of-hospital cardiac arrest.

Objectives: This study aimed to identify formation of tubular dentin induced by Transforming growth factor-β (TGF-β) and bone morphogenic protein (BMP) signaling pathway in dental epithelial cells.

Methods: We collected conditioned medium (CM) of rTGF-β1/rBMP-2 treated HAT-7 and treated to MDPC-23 cells. The expression levels of odontoblast differentiation markers, KLF4, DMP1, and DSP were evaluated by real-time PCR and western blot analysis. To evaluate whether CM of rTGF-β1/rBMP-2 induces tubular dentin formation, we made a beagle dog tooth defect model.

Results: Here, we show that Cpne7 is regulated by Smad4-dependent TGF-β1/BMP2 signaling pathway in dental epithelial cells. CM of rTGF-β1/rBMP-2 treated HAT-7, or rCPNE7 raises the expression levels of KLF4, DMP1, and DSP in MDPC-23 cells. When rTGF-β1 or rBMP-2 is directly treated to MDPC-23 cells, however, expression levels of Cpne7-regulated genes remain unchanged. In a beagle dog defect model, application of rTGF-β1/BMP2 treated CM resulted in tubular tertiary dentin mixed with osteodentin at cavity-prepared sites, while rTGF-β1 group exhibited homogenous osteodentin.

Conclusions: Taken together, Smad4-dependent TGF-β1/BMP2 signaling regulates Cpne7 in dental epithelial cells, and CPNE7 protein secreted from pre-ameloblasts mediates odontoblast differentiation via epithelial-mesenchymal interaction.

Keywords: Cell differentiation; Cell signaling; Dentinogenesis; Epithelial-mesenchymal interactions; Odontoblast(s); Tooth development.

Word senses are the fundamental unit of description in lexicography, yet it is rarely the case that different dictionaries reach any agreement on the number and definition of senses in a language. With the recent rise in natural language processing and other computational approaches there is an increasing demand for quantitatively validated sense catalogues of words, yet no consensus methodology exists. In this paper, we look at four main approaches to making sense distinctions: formal, cognitive, distributional, and intercultural and examine the strengths and weaknesses of each approach. We then consider how these may be combined into a single sound methodology. We illustrate this by examining two English words, "wing" and "fish," using existing resources for each of these four approaches and illustrate the weaknesses of each. We then look at the impact of such an integrated method and provide some future perspectives on the research that is necessary to reach a principled method for making sense distinctions.

Keywords: cognitive semantics; distributional semantics; generative lexicon; lexicography; multilinguality; semantics; word senses; wordnets.

Coronary artery perforation is a rare but serious complication during percutaneous coronary intervention. Distal or small vessel perforation is usually treated by coil, fat, or microsphere embolization. We describe 5 cases of distal coronary perforation that were managed successfully by a novel technique that uses absorbable sutures. (Level of Difficulty: Advanced.).

Keywords: CAP, coronary artery perforation; CTO, chronic total occlusion; LCx, left circumflex artery; PCI, percutaneous coronary intervention; PLB, posterolateral branch; RCA, right coronary artery; absorbable suture; coronary artery perforation.

Acute kidney injury (AKI) refers to a clinical syndrome in which renal function declines rapidly in a short period of time caused by various pathological factors. During the development of AKI, renal tubules with the functions of reabsorption and excretion are prone to cell death due to external pathological stimuli, which is an important cause of impaired renal function. In recent years, a variety of new cell death pathways have been gradually recognized. Researchers have now found that regulated cell death (RCD), such as necroptosis, pyroptosis and ferroptosis, are important regulatory mechanisms of AKI. This article will summarize the research advances of various types of RCD involved in the process of AKI, aiming to deepen the understanding of AKI and provide innovative thoughts for the clinical treatment of AKI.

Granuloma annulare (GA) and cutaneous sarcoidosis show clinicopathological overlap and they are also aetiopathogenically related. Given the similarities of sarcoidal GA and sarcoidosis, and the reports of association of sarcoidal GA with systemic sarcoidosis, this diagnosis should prompt further investigation to exclude systemic involvement. Being aware of the subtle histopathological clues is of the utmost importance for an accurate diagnosis of this rare variant, but correlation with the clinical setting and use of ancillary investigations are also warranted to confidently exclude sarcoidosis.

Rotenone is a commercial pesticide commonly used to model Parkinson's disease (PD) due to its ability to induce dopaminergic degeneration. Studies have confirmed that rotenone causes microglial activation, which seems to contribute to the toxic effects seen in rodent models. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related neuropeptides that have robust neuroprotective and anti-inflammatory properties. However, their ability to regulate microglial activity in response to rotenone is not fully understood. Using rotenone as an inflammatory stimulus, we tested whether PACAP or VIP could mitigate microglial activation in BV2 microglial cells. Rotenone dose-dependently reduced cell viability and the percentage of apoptotic cells. It also increased the release of nitric oxide (NO) in culture media and the expression of microglial activation markers and pro-inflammatory markers, including CD11b, MMP-9 and IL-6, and heightened the endogenous levels of PACAP and its preferring receptor PAC1. Co-treatment with PACAP or VIP prevented rotenone-induced increase of NO, CD11b, MMP-9 and IL-6. These results indicate that both PACAP and VIP are able to prevent the pro-inflammatory effects of rotenone in BV2 cells, supporting the idea that these molecules can have therapeutic value in slowing down PD progression.

Keywords: Microglia; Neuroinflammation; Pituitary adenylate cyclase-activating peptide (PACAP); Rotenone; Vasoactive intestinal peptide (VIP).

The discovery of new drugs is a time consuming and expensive process. Methods such as virtual screening, which can filter out ineffective compounds from drug libraries prior to expensive experimental study, have become popular research topics. As the computational drug discovery community has grown, in order to benchmark the various advances in methodology, organizations such as the Drug Design Data Resource have begun hosting blinded grand challenges seeking to identify the best methods for ligand pose-prediction, ligand affinity ranking, and free energy calculations. Such open challenges offer a unique opportunity for researchers to partner with junior students (e.g., high school and undergraduate) to validate basic yet fundamental hypotheses considered to be uninteresting to domain experts. Here, we, a group of high school-aged students and their mentors, present the results of our participation in Grand Challenge 4 where we predicted ligand affinity rankings for the Cathepsin S protease, an important protein target for autoimmune diseases. To investigate the effect of incorporating receptor dynamics on ligand affinity rankings, we employed the Relaxed Complex Scheme, a molecular docking method paired with molecular dynamics-generated receptor conformations. We found that Cathepsin S is a difficult target for molecular docking and we explore some advanced methods such as distance-restrained docking to try to improve the correlation with experiments. This project has exemplified the capabilities of high school students when supported with a rigorous curriculum, and demonstrates the value of community-driven competitions for beginners in computational drug discovery.

Keywords: Computational biophysics; Drug discovery; Ensemble docking; Molecular dynamics; Restrained docking.

The mean estimation task, which explicitly asks observers to estimate the mean feature value of multiple stimuli, is a fundamental paradigm in research areas such as ensemble coding and cue integration. The current study uses computational models to formalize how observers summarize information in mean estimation tasks. We compare model predictions from our Fidelity-based Integration Model (FIM) and other models on their ability to simulate observed patterns in within-trial weight distribution, across-trial information integration, and set-size effects on mean estimation accuracy. Experiments show non-equal weighting within trials in both sequential and simultaneous mean estimation tasks. Observers implicitly overestimated trial means below the global mean and underestimated trial means above the global mean. Mean estimation performance declined and stabilized with increasing set sizes. FIM successfully simulated all observed patterns, while other models failed. FIM's information sampling structure provides a new way to interpret the capacity limit in visual working memory and sub-sampling strategies. As a model framework, FIM offers task-dependent modeling for various ensemble coding paradigms, facilitating research synthesis across different studies in the literature.

Keywords: Implicit/explicit memory; Memory: Visual working and short-term memory; Visual perception.

Introduction: The evidence base for parenteral nutrition (PN) in advanced cancer patients is limited. We studied healthcare providers' (HCPs') experiences with PN in cancer patients, focusing on perceived treatment benefits and challenges.

Methods: An 18-item online survey was emailed to HCPs attending one of three regional palliative care seminars held within a 6-month period. The survey included single-response items, multiple-response items, and free text boxes concerning PN. Descriptive statistics and qualitative thematic content analysis were applied.

Results: One hundred and two seminar participants completed the survey. Ninety-three percent were female, 86% were nurses/oncological nurses, and 80% worked in primary care. Respondents reported a well-functioning collaboration across levels of care. They perceived that PN may increase the patients' level of energy, improve the general condition, and reduce eating-related distress. On the downside, HCPs observed burdensome side effects, that the treatment was resource-demanding, and that decisions on PN withdrawal were difficult.

Conclusion: The study results are based on the perspectives of more than 100 HCPs with comprehensive clinical experience with PN. Their knowledge represents an important experience base for improvement of healthcare services and advanced care planning.

Keywords: End-of-life care; Healthcare provider; Palliative cancer care; Parenteral nutrition.

Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual level when phenotypes are not necessarily already known. We investigated the stability of PGS in European American (EUR) and African American (AFR)-ancestry individuals from the Philadelphia Neurodevelopmental Cohort and the Adolescent Brain Cognitive Development study using different discovery genome-wide association study (GWAS) results for post-traumatic stress disorder (PTSD), type 2 diabetes (T2D), and height. We found that pairs of EUR-ancestry GWAS for the same trait had genetic correlations >0.92. However, PGS calculated from pairs of same-ancestry and different-ancestry GWAS had correlations that ranged from <0.01 to 0.74. PGS stability was greater for height than for PTSD or T2D. A series of height GWAS in the UK Biobank suggested that correlation between PGS is strongly dependent on the extent of sample overlap between the discovery GWAS. Focusing on the upper end of the PGS distribution, different discovery GWAS do not consistently identify the same individuals in the upper quantiles, with the best case being 60% of individuals above the 80th percentile of PGS overlapping from one height GWAS to another. The degree of overlap decreases sharply as higher quantiles, less heritable traits, and different-ancestry GWAS are considered. PGS computed from different discovery GWAS have only modest correlation at the individual level, underscoring the need to proceed cautiously with integrating PGS into precision medicine applications.

Keywords: Adolescent Brain Cognitive Development study; African American; PRS-CS; PTSD; Philadelphia Neurodevelopmental Cohort; UK Biobank; ancestry; height; methods development; type 2 diabetes.

Respiratory syncytial virus (RSV) is the most common viral pathogen causing respiratory disease in the pediatric population. An unexpected sudden upsurge of RSV infections among children was observed in September 2021 in Greece. Forty-one rhinopharyngeal samples from children under the age of 2 years with confirmed RSV bronchiolitis were tested to identify the genotype(s) of the RSV strain(s). The children were hospitalized during September-November 2021 in three tertiary hospitals in northern Greece. A one-step RT-PCR which amplifies a fragment of the second hypervariable region of the G protein gene was applied. PCR products were sequenced, and phylogenetic analysis was performed. Most (80.5%) RSV cases were typed as RSV-A, with RSV-B accounting for 19.5% of cases. RSV-A and RSV-B sequences clustered within the ON1 and BA genotypes, respectively. Since the same genotypes were detected in cases observed during 2016-2018 in northern Greece, it was suggested that the early upsurge of infections was not related to the emergence of novel strain(s), but it was the result of the absence of immunity among children and their mothers due to the restriction measures taken during the COVID-19 pandemic in the previous RSV season. Awareness is needed to diagnose even the out-of-season RSV infections, while molecular epidemiology plays a key role in monitoring the efficacy of currently available therapeutics and for those under development. This article is protected by copyright. All rights reserved.

Keywords: Greece; Respiratory syncytial virus; bronchiolitis; children; genotype.

The DNA damage response (DDR) pathway is critical for maintaining genomic integrity and sustaining organismal development. Viruses can either utilize or circumvent the DDR to facilitate their replication. Pseudorabies virus (PRV) infection was shown to induce apoptosis via stimulating DDR. However, the underlying mechanisms have not been fully explored to date. This study showed that PRV infection robustly activates the ATM and DNA-PK signaling pathways shortly after infection. However, inhibition of ATM, but not DNA-PK, could dampen PRV replication in cells. Importantly, we found that PRV-encoded serine/threonine kinase UL13 interacts with and subsequently phosphorylates H2AX. Furthermore, we found that UL13 deletion largely attenuates PRV neuroinvasiveness and virulence in vivo. In addtion, we showed that UL13 contributes to H2AX phosphorylation upon PRV infection both in vitro and in vivo, but does not affect ATM phosphorylation. Finally, we showed that knockdown of H2AX reduces PRV replication, while this reduction can be further enhanced by deletion of UL13. Taken together, we conclude that PRV-encoded kinase UL13 regulates DNA damage marker γH2AX and UL13-mediated H2AX phosphorylation plays a pivotal role in efficient PRV replication and progeny production.

Keywords: ATM; DNA damage response; UL13; pseudorabies virus; γH2AX.

Zirconium diboride (ZrB₂ ) is considered as one of the most promising ultra-high temperature materials for the applications in extreme environments. However, the difficulty in fabrication of ZrB₂ limits its industrial applications. In this study, fully dense and grain-refined ZrB₂ is prepared under ultra-high pressure of 15 GPa at low temperature of 1450 °C. The as-prepared ZrB₂ exhibits excellent mechanical and oxidation-resistant properties. Compared with raw powder, the grain size decreases 56%. Compared with high-temperature sintered control specimen beyond 2000 °C, the hardness and fracture toughness increase about 46% and 69%, respectively, the dislocation density increase 3 orders of magnitude, while the grain size considerably decrease 96%. According to work hardening, Hall-Petch and Taylor dislocation hardening effects, the refined grains, substructures, and high dislocation density caused by plastic deformation during sintering can enhance the mechanical properties. The unique structure contributes to a threshold oxidation temperature increase of ≈250 °C relative to the high-temperature sintered ZrB₂ , achieving one of the highest values (1100 °C) among the reported monolithic ultra-high temperature ceramics. A developed densification mechanism of dislocation multiplication with grain refining is proposed and proved to dominate the sintering, which is responsible for simultaneous improvements in mechanical and oxidation-resistant properties.

Keywords: dislocation multiplication; grain-refining; oxidation resistance; plastic deformation; ultra-high pressure sintering.

Chimeric antigen receptor (CAR) redirected T-cells has shown efficacy in the treatment of B-cell leukemia/lymphoma, however, high numbers of relapses occur due to loss of targeted antigen or intrinsic failure of the CAR T-cells. In this situation modifications of the basic strategy are envisaged to reduce the risk of relapse, some of them are in early clinical exploration. These include simultaneous targeting of multiple antigens or combination of CAR T-cell therapy with other treatment modalities such as checkpoint inhibitors. The review evaluates and discusses these modified advanced therapies and pre-clinical approaches with respect to their potential to control leukemia and lymphoma in the long-term.

Keywords: Chimeric antigen receptor; Clinical trial; Hematological cancer.

Objectives: Immunogenicity to the SARS-CoV-2 mRNA vaccines in adolescents and young adults (AYA) with childhood-onset rheumatic diseases (cRD) is unknown. We aimed to evaluate the humoral immunogenicity and safety of the vaccines in our AYA with cRD.

Methods: A monocentric observational study with 159 AYA (50.3% female and 70.4% Chinese). Humoral immunogenicity was assessed at 2-3 and 4-6 weeks following first and second vaccination by cPass™ SARS-CoV-2 Neutralisation Antibody Assay. Inhibition signal of ≥ 30% defined the cut-off for positive detection of the SARS-CoV-2 neutralising antibodies. Vaccine safety and disease activity were assessed within 6 weeks after second vaccination.

Results: 64.9% and 99.1% of 159 patients (median age 16.9-year-old, IQR : 14.7-19.5) mounted positive SARS-CoV-2 neutralising responses after first and second vaccination, respectively. Most patients (89.8%) had ≥90% inhibition signal after second vaccination. Methotrexate and mycophenolate mofetil increased the risk associated with negative cPass neutralisation responses following the first vaccination. Holding both medications after each vaccination did not affect immunogenicity. There was no symptomatic COVID-19 infection. Local reaction remained the most common (23.3-25.2%) adverse event, without serious complication. Two and seven patients flared following the first and second vaccination, respectively. Subgroup analyses of the 12-18-year-old cohort did not show any differences in vaccine efficacy, predictors of poor response and general safety, but higher proportion of disease flares.

Conclusions: SARS-CoV-2 mRNA vaccines were efficacious after the two-dose regimen in almost all AYA with cRD without serious adverse event. The rate of disease flare observed is 4.4% after the second mRNA vaccine dose.

Keywords: COVID-19; SARS-CoV-2 vaccine; childhood-onset rheumatic disease; paediatric age; paediatric rheumatology; vaccine efficacy; vaccine safety.

Disruption of circadian rhythms occurs in rotating shift-work, jetlag, and in individuals with irregular sleep schedules. Circadian disruption is known to alter inflammatory responses and impair immune function. However, there is limited understanding of how circadian disruption modulates cancer-induced inflammation. Inflammation is a hallmark of cancer and is linked to worse prognosis and impaired brain function in cancer patients. Here, we investigated the effect of circadian disruption on cancer-induced inflammation in an orthotopic breast cancer model. Using a validated chronic jetlag protocol that advances the light-cycle by 8 ​h every 2 days to disrupt circadian rhythms, we found that circadian disruption alters cancer-induced inflammation in a tissue-specific manner, increasing inflammation in the body and brain while decreasing inflammation within the tumor tissue. Circadian disruption did not affect inflammation in mice without tumors, suggesting that the impact of circadian disruption may be particularly detrimental in the context of underlying inflammatory conditions, such as cancer. Importantly, circadian disruption did not affect tumor burden, suggesting that increased inflammation was not a result of increased cancer progression. Overall, these findings identify the importance of healthy circadian rhythms for limiting cancer-induced inflammation.

Keywords: 4T1 breast Cancer; Chronic jetlag; Circadian rhythms; Clock genes; Cytokines; Metastasis; Neuroinflammation.

GroES/GroEL is the only bacterial chaperone essential under all conditions, making it a potential antibiotic target. Rationally targeting ESKAPE GroES/GroEL as an antibiotic strategy necessitates studying their structure and function. Herein, we outline the structural similarities between Escherichia coli and ESKAPE GroES/GroEL and identify significant differences in intra- and inter-ring cooperativity, required in the refolding cycle of client polypeptides. Previously, we observed that one-half of ESKAPE GroES/GroEL family members could not support cell viability when each was individually expressed in GroES/GroEL-deficient E. coli cells. Cell viability was found to be dependent on the allosteric compatibility between ESKAPE and E. coli subunits within mixed (E. coli and ESKAPE) tetradecameric GroEL complexes. Interestingly, differences in allostery did not necessarily result in differences in refolding rate for a given homotetradecameric chaperonin. Characterization of ESKAPE GroEL allostery, ATPase, and refolding rates in this study will serve to inform future studies focused on inhibitor design and mechanism of action studies.

Keywords: ESKAPE; GroEL; GroES; allostery; chaperone; chaperonin.