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Purpose: To compare the image quality of CT obtained using a deep learning-based image reconstruction (DLIR) engine with images with adaptive statistical iterative reconstruction-V (AV)., Materials and Methods: Using a phantom, the noise power spectrum (NPS) and task-based transfer function (TTF) were measured in images with different reconstructions (filtered back projection [FBP], AV30, 50, 100, DLIR-L, M, H) at multiple doses. One hundred and twenty abdominal CTs with 30% dose reduction were processed using AV30, AV50, DLIR-L, M, H. Objective and subjective analyses were performed., Results: The NPS peak of DLIR was lower than that of AV30 or AV50. Compared with AV30, the NPS average spatial frequencies were higher with DLIR-L or DLIR-M. For lower contrast objects, TTF in images with DLIR were higher than those with AV. The standard deviation in DLIR-H and DLIR-M was significantly lower than AV30 and AV50. The overall image quality was the best for DLIR-M ( p < 0.001 )., Conclusions: DLIR showed improved image quality and decreased noise under a decreased radiation dose., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Degenerative changes of the spine can cause spinal misalignment, with part of the spine arching beyond normal limits or moving in an incorrect direction, potentially resulting in back pain and significantly limiting a person's mobility. The most important parameters related to spinal misalignment include pelvic incidence, pelvic tilt, lumbar lordosis, thoracic kyphosis, and cervical lordosis. As a general rule, alignment of the spine for diagnosis and surgical treatment is estimated based on geometrical parameters measured manually by experienced doctors. However, these measurements consume the time and effort of experts to perform repetitive tasks that could be automated, especially with the powerful support of current artificial intelligence techniques. This paper focuses on creation of a decentralized convolutional neural network to precisely measure 12 spinal alignment parameters. Specifically, this method is based on detecting regions of interest with its dimensions that decrease by three orders of magnitude to focus on the necessary region to provide the output as key points. Using these key points, parameters representing spinal alignment are calculated. The quality of the method's performance, which is the consistency of the measurement results with manual measurement, is validated by 30 test cases and shows 10 of 12 parameters with a correlation coefficient > 0.8, with pelvic tilt having the smallest absolute deviation of 1.156°., (© 2022. The Author(s).)

CXCR4, a CXCL12 receptor, is expressed on epithelial cells, fibroblasts, and inflammatory cells. The CXCR4-CXCL12 interaction is related to the migration of neutrophils and monocytes/macrophages. Periodontitis, an inflammatory disease mainly caused by gram-negative bacteria, is characterized by infiltration of circulating inflammatory cells and alveolar bone (AB) loss. To investigate whether CXCR4 is involved in the distribution of neutrophils and monocytes/macrophages early after periodontitis induction, we examined the effects of AMD3100 (AMD), a CXCR4 antagonist, in ligature-induced periodontitis mice and LPS-injected air pouch mice. The periodontitis study was accomplished in control (C), periodontitis (P), and P + AMD groups. Periodontitis was induced by ligation of the mandibular first molar. AMD was intraperitoneally administered daily beginning the day before ligation until sacrifice on the third day after ligation. The air pouch study was accomplished in C, lipopolysaccharide (LPS), and LPS + AMD groups. Air pouches on mice backs were formed by subcutaneous injection of sterilized air. AMD was administered and then LPS was injected into the air pouch. For the detection of neutrophils and monocytes/macrophages in blood and air pouch exudates, flow cytometry was performed with anti-Ly6G/anti-CD11b antibodies (Abs) and anti-CD115 Ab, respectively. In periodontal tissue, Ly6G + cells and CD115 + cells were counted by immunohistological analysis. AB loss was estimated by the periodontal ligament area in the furcation. In the periodontitis study, the P group showed higher numbers of Ly6G + cells and CD115 + cells in blood and periodontal tissue than the C group. The P + AMD group showed a greater number of Ly6G + cells and CD115 + cells in blood, but not in periodontal tissue compared to the P group. There was no difference in AB loss between the P and P + AMD groups. In the air pouch study, the LPS group had higher levels of Ly6G + CD11b + cells and CD115 + cells in both blood and exudates than the C group. The number of these cells in the LPS + AMD group was higher in blood than in the LPS group, but not in the exudates. The CXCR4 antagonist further increased neutrophil and monocyte/macrophage populations in the blood, but did not alter the levels in the periodontal tissue and exudates in mice with periodontitis and LPS-injected air pouches. These results suggest that during inflammatory conditions such as periodontitis, CXCR4 is involved in the distribution of neutrophils and monocytes/macrophages in the blood, but not in inflamed peripheral tissues., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The strong bonding at the interface between the metal and the support, which can inhibit the undesirable aggregation of metal nanoparticles and carbon deposition from reforming of hydrocarbon, is well known as the classical strong metal-support interaction (SMSI). SMSI of nanocatalysts was significantly affected by heat treatment and reducing conditions during catalyst preparation.the heat treatment and reduction conditions during catalyst preparation. SMSI can be weakened by the decrement of metal-doped sites in the supporting oxide and can often deactivate catalysts by the encapsulation of active sites through these processes. To retain SMSI near the active sites and to enhance the catalytic activity of the nanocatalyst, it is essential to increase the number of surficial metal-doped sites between nanometal and the support. Herein, we propose a mild reduction process using dry methane (CH 4 /CO 2 ) gas that suppresses the aggregation of nanoparticles and increases the exposed interface between the metal and support, Ni and cerium oxide. The effects of mild reduction on the chemical state of Ni-cerium oxide nanocatalysts were specifically investigated in this study. As a result, mild reduction led to form large amounts of the Ni 3+ phase at the catalyst surface of which SMSI was significantly enhanced. It can be easily fabricated while the dry reforming of methane (DRM) reaction is on stream. The superior performance of the catalyst achieved a considerably high CH 4 conversion rate of approximately 60% and stable operation up to 550 h at a low temperature, 600 °C.

SignificanceYeiE has been identified as a master virulence factor of Cronobacter sakazakii . In this study, we determined the crystal structures of the regulatory domain of YeiE in complex with its physiological ligand sulfite ion (SO 3 2- ). The structure provides the basis for the molecular mechanisms for sulfite sensing and the ligand-dependent conformational changes of the regulatory domain. The genes under the control of YeiE in response to sulfite were investigated to reveal the functional roles of YeiE in the sulfite tolerance of the bacteria. We propose the molecular mechanism underlying the ability of gram-negative pathogens to defend against the innate immune response involving sulfite, thus providing a strategy to control the pathogenesis of bacteria.

Although cancer immunotherapy has emerged as a novel cancer treatment modality, it still suffers from low therapeutic efficacy in clinics due to the presence of a low number of activated immune cells and immunosuppressive factors in the tumor microenvironment (TME). Immunomodulatory ribonucleic acids (RNAs) have been developed to improve the therapeutic efficacy of cancer immunotherapy through either regulating target cell functions [i.e., messenger RNA (mRNA) or small interfering RNA (siRNA)] or stimulating immune cells [i.e., toll-like receptors (TLRs) or cytosolic retinoic acid-inducible gene I (RIG-I) agonist]. However, RNA-based therapeutics face many biological barriers, including ineffective delivery to target cells, degradation by ribonucleases (RNases), and difficulties in passing through the cellular membranes. In this review, we discuss nanoparticle-based delivery strategies that can overcome these hurdles to enhance RNA-based immunomodulation in cancer immunotherapy. Various nanoparticle-based delivery has been reported to increase the delivery efficacy of RNAs, by improving cellular uptake, RNA stability, and accumulation at the desired sites (target cells and intracellular compartments). The nanoparticle-based delivery of multifaceted immunomodulatory RNAs could enhance cancer immunotherapy through the regulating functions of immune cells, tumor cells, and immunosuppressive factors as well as stimulating the immune cells by recognition of endosomal TLRs and cytosolic RIG-I. Nanotechnology-assisted RNA-based therapeutics are expected to offer tremendous potential and advances for treating cancer, viral infections, and other diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the effect of the emergence of coronavirus disease-19 (COVID-19) on pediatric intussusception., Materials and Methods: Patients (< 18 years) who were diagnosed with intussusception and received enema reduction from 2011 to 2020 were included. We reviewed the demographics, yearly/monthly/seasonal incidence of intussusception, method and failure rate of enema reduction, recurrence rate of intussusception, surgical record, and pathologic report. Subsequently, we investigated the differences in mean age, failure rate of enema reduction, and recurrence rate of intussusception between the cases in 2020 and those in the period from 2011 to 2019., Results: A total of 859 enema reductions were performed during the past decade, more in males and in the age < 1 year (mean age, 22.2 months). The yearly incidence was highest in 2014 and lowest in 2020, and the monthly incidence was highest on December and September. The cases in 2020 ( n = 27) had a lower mean age (18.1 months vs. 22.8 months), higher failure rate of enema reduction (7.4% vs. 2.4%), and higher recurrence rate of intussusception (14.8% vs 7.3%) compared with those that occurred between 2011 and 2019 ( n = 832). However, these results did not show statistical significance ( p = 0.07, p = 0.15, p = 0.14, respectively)., Conclusion: With the emergence of COVID-19, the number of enema reductions was remarkably decreased with a lower mean age, higher failure rate, and higher recurrence rate., Competing Interests: Conflicts of Interest: The authors have no potential conflicts of interest to disclose., (Copyrights © 2022 The Korean Society of Radiology.)

Objective: The purpose of the study is to evaluate the relationship between HbA1c and severity of coronavirus disease 2019 (COVID-19) outcomes in patients with type 2 diabetes (T2D) with acute COVID-19 infection., Research Design and Methods: We conducted a retrospective study using observational data from the National COVID Cohort Collaborative (N3C), a longitudinal, multicenter U.S. cohort of patients with COVID-19 infection. Patients were ≥18 years old with T2D and confirmed COVID-19 infection by laboratory testing or diagnosis code. The primary outcome was 30-day mortality following the date of COVID-19 diagnosis. Secondary outcomes included need for invasive ventilation or extracorporeal membrane oxygenation (ECMO), hospitalization within 7 days before or 30 days after COVID-19 diagnosis, and length of stay (LOS) for patients who were hospitalized., Results: The study included 39,616 patients (50.9% female, 55.4% White, 26.4% Black or African American, and 16.1% Hispanic or Latino, with mean ± SD age 62.1 ± 13.9 years and mean ± SD HbA1c 7.6% ± 2.0). There was an increasing risk of hospitalization with incrementally higher HbA1c levels, but risk of death plateaued at HbA1c >8%, and risk of invasive ventilation or ECMO plateaued >9%. There was no significant difference in LOS across HbA1c levels., Conclusions: In a large, multicenter cohort of patients in the U.S. with T2D and COVID-19 infection, risk of hospitalization increased with incrementally higher HbA1c levels. Risk of death and invasive ventilation also increased but plateaued at different levels of glycemic control., (© 2022 by the American Diabetes Association.)

Return of spontaneous circulation (ROSC) through cardiopulmonary resuscitation (CPR) after cardiac arrest (CA) causes post-cardiac arrest syndrome (PCAS) due to dysfunction in various organs, which provokes acute kidney injury because of renal ischemia-reperfusion injury. Therapeutic hypothermia (TH) can reduce PCAS after CA and ROSC. However, it needs to be more sophisticated and effective. Hence, we aimed to elucidate the protective effects of olanzapine-induced TH against renal injury in asphyxial CA-induced rats. Every rat's body temperature was maintained at 33 °C for 6 h after administering olanzapine post-CA and ROSC. Olanzapine-induced TH dramatically increased the survival rate of the rats and ameliorated renal tissue damage. Moreover, it suppressed oxidative stress responses through preservation of mitochondrial function and endoplasmic reticulum stress as the main contributor of oxidative stress. Notably, these actions of olanzapine-induced TH were mediated through the Sirt3-related signaling pathway, including the maintenance of Sirt3 and FOXO3a protein expression and the activation of AMPKα and superoxide dismutase 1 (SOD2, a mitochondrial antioxidant). This study is the first to disclose the protective effects of olanzapine-induced TH against renal injury after CA and ROSC, suggesting that olanzapine-induced TH could be utilized for treating CA followed by ROSC.

Importance: Understanding of SARS-CoV-2 infection in US children has been limited by the lack of large, multicenter studies with granular data., Objective: To examine the characteristics, changes over time, outcomes, and severity risk factors of children with SARS-CoV-2 within the National COVID Cohort Collaborative (N3C)., Design, Setting, and Participants: A prospective cohort study of encounters with end dates before September 24, 2021, was conducted at 56 N3C facilities throughout the US. Participants included children younger than 19 years at initial SARS-CoV-2 testing., Main Outcomes and Measures: Case incidence and severity over time, demographic and comorbidity severity risk factors, vital sign and laboratory trajectories, clinical outcomes, and acute COVID-19 vs multisystem inflammatory syndrome in children (MIS-C), and Delta vs pre-Delta variant differences for children with SARS-CoV-2., Results: A total of 1 068 410 children were tested for SARS-CoV-2 and 167 262 test results (15.6%) were positive (82 882 [49.6%] girls; median age, 11.9 [IQR, 6.0-16.1] years). Among the 10 245 children (6.1%) who were hospitalized, 1423 (13.9%) met the criteria for severe disease: mechanical ventilation (796 [7.8%]), vasopressor-inotropic support (868 [8.5%]), extracorporeal membrane oxygenation (42 [0.4%]), or death (131 [1.3%]). Male sex (odds ratio [OR], 1.37; 95% CI, 1.21-1.56), Black/African American race (OR, 1.25; 95% CI, 1.06-1.47), obesity (OR, 1.19; 95% CI, 1.01-1.41), and several pediatric complex chronic condition (PCCC) subcategories were associated with higher severity disease. Vital signs and many laboratory test values from the day of admission were predictive of peak disease severity. Variables associated with increased odds for MIS-C vs acute COVID-19 included male sex (OR, 1.59; 95% CI, 1.33-1.90), Black/African American race (OR, 1.44; 95% CI, 1.17-1.77), younger than 12 years (OR, 1.81; 95% CI, 1.51-2.18), obesity (OR, 1.76; 95% CI, 1.40-2.22), and not having a pediatric complex chronic condition (OR, 0.72; 95% CI, 0.65-0.80). The children with MIS-C had a more inflammatory laboratory profile and severe clinical phenotype, with higher rates of invasive ventilation (117 of 707 [16.5%] vs 514 of 8241 [6.2%]; P < .001) and need for vasoactive-inotropic support (191 of 707 [27.0%] vs 426 of 8241 [5.2%]; P < .001) compared with those who had acute COVID-19. Comparing children during the Delta vs pre-Delta eras, there was no significant change in hospitalization rate (1738 [6.0%] vs 8507 [6.2%]; P = .18) and lower odds for severe disease (179 [10.3%] vs 1242 [14.6%]) (decreased by a factor of 0.67; 95% CI, 0.57-0.79; P < .001)., Conclusions and Relevance: In this cohort study of US children with SARS-CoV-2, there were observed differences in demographic characteristics, preexisting comorbidities, and initial vital sign and laboratory values between severity subgroups. Taken together, these results suggest that early identification of children likely to progress to severe disease could be achieved using readily available data elements from the day of admission. Further work is needed to translate this knowledge into improved outcomes.

Controlling the line shape of Fano resonance has continued to attract significant research attention in recent years owing to its practical applications such as lasing, biosensing, and slow-light devices. However, controllable Fano resonances always require stringent alignment of complex symmetry-breaking structures; therefore, the manipulation can only be performed with limited degrees of freedom and a narrow tuning range. This work demonstrates dark-mode excitation tuning independent of the bright mode for the first time, to the authors' knowledge, in asymmetric Fano metamaterials. Metallic subwavelength slits are arranged to form asymmetric unit cells and generate a broad and bright (radiative) Fabry-Perot mode and a sharp and dark (non-radiative) surface mode. The introduction of the independent radial and angular asymmetries realizes independent control of the Fano phase (q) and quality factor (Q). This tunability provides a dynamic phase shift while maintaining a high-quality factor, enabling switching between nearly perfect transmission and absorption, which is confirmed both numerically and experimentally. The proposed scheme for fully controlled Fano systems can aid practical applications such as phase-sensitive switching devices.

(1) Background: scoliosis is highly prevalent in children with neurological disorders, however, studies predicting the progression and affecting the direction of scoliosis have been insufficient. We investigated the factors associated with the progression and direction of scoliosis in children with neurological disorders. (2) Method: retrospectively, 518 whole spine radiographs from 116 patients were used for analysis. Factors affecting the progression of scoliosis over time were analyzed using linear mixed-effects model. Factors associated with the apex direction of the scoliosis were analyzed. (3) Results: pelvic obliquity (PO) ≥ 2.5°, gross motor function classification system level V, vertebral rotation, and female sex significantly affect the progression of scoliosis ( p = 0.04, <0.001, <0.001, 0.005, respectively). The higher side of PO and the apex side of scoliosis were interrelated (χ² = 14.58, p < 0.001), but the asymmetrical neurological upper extremity involvement was not. (4) Conclusions: severely impaired gross motor function, PO, vertebral rotation, and female sex were significantly related to the progression of scoliosis. The higher side of PO was opposite to the apex side of scoliosis. By identifying the factors that influence the progression of scoliosis, patients at high risk could be more actively intervened to minimize the severe complications.

Background: Children with cerebral palsy (CP) are less physically active than their typically developing peers. The effects of decreased physical activity on children's quality of life (QOL) or caregiver's lives are not well understood. This study aimed to investigate the association between physical activity, QOL, and parenting stress in children with CP., Methods: A prospective cross-sectional study was done in children with CP. Daily physical activity was measured over 7 days using an accelerometer (ActiGraph™). Caregivers completed the Child Health Questionnaire - Parent Form 50 and Parenting Stress Index - Short Form. Multiple regression analysis was used., Results: In total, data from 65 children with Gross Motor Function Classification System (GMFCS) levels I-V, aged 4-13 years, were analyzed. Non-ambulatory (GMFCS IV-V) children had significantly lower activity counts and moderate to vigorous physical activity (MVPA) in comparison with ambulatory (GMFCS I-II) and marginally ambulatory (GMFCS III) children. The ambulatory group had better physical QOL than the non-ambulatory group. Caregivers of the non-ambulatory or marginally ambulatory children with CP reported higher parenting stress levels than those of the ambulatory group. Time spent in MVPA and activity counts were positively associated with physical QOL in children with CP. Low activity counts and low amounts of MVPA of children with CP were significant predictors of high parenting stress., Conclusions: Physical activity in children with CP is associated with children's QOL and parenting stress. These results suggest that clinicians should conduct physical activity assessment and counseling to promote physical activity., (© 2022 Japan Pediatric Society.)

Ubiquitination has been shown to provide an essential regulatory role in modulating the duration and amplitude of the signaling activity in angiogenesis. While successive enzymatic reactions mediated by three distinct types of enzymes commonly known as E1, E2, and E3 are required for ubiquitination, the role of E3s which govern the final step of ubiquitination has been extensively analyzed in angiogenesis. In contrast, the role of E2s, which determine the context and functional consequences of ubiquitination, remains largely unknown with respect to angiogenesis. To better elucidate the role of E2s in modulating endothelial behaviors during angiogenesis, we first systematically analyze the expression pattern of E2s in endothelial cells (ECs) using previously published scRNA-seq data and identify ubiquitin-conjugating enzyme variant 1 (UBE2V1), an unconventional E2 without innate catalytic activity, as one of the most abundantly expressed E2s in ECs. While ubiquitously expressed in diverse cell types, abrogation of UBE2V1 significantly impairs proliferation and viability of human umbilical vein endothelial cells (HUVECs) without affecting other cell types, suggesting that UBE2V1 is likely to possess nonredundant functions in ECs. Consistent with this idea, UBE2V1 appears to be critical for morphogenesis and migration of ECs during angiogenesis. Interestingly, we find that UBE2V1 is essential for fibroblast growth factor 2 (FGF2)-induced angiogenesis, but appears to have minor effects on vascular endothelial growth factor-A-induced angiogenesis in vitro as well as in vivo. Therefore, it seems that UBE2V1 could enable ECs to distinguish two related yet distinct angiogenic cues. Mechanistically, we show that UBE2V1 promotes ubiquitination of MEK kinase 1, a key mediator of FGF2 signaling, to enhance phosphorylation of extracellular signal-regulated kinase 1/2 in HUVECs. Taken together, our results illustrate the unique role of UBE2V1 as a key modulator for angiogenic behaviors in ECs., (© 2021 Federation of American Societies for Experimental Biology.)

Although multi‑organ dysfunction is associated with the survival rate following cardiac arrest (CA), the majority of studies to date have focused on hearts and brains, and few studies have considered renal failure. The objective of the present study, therefore, was to examine the effects of therapeutic hypothermia on the survival rate, pathophysiology and antioxidant enzymes in rat kidneys following asphyxial CA. Rats were sacrificed one day following CA. The survival rate, which was estimated using Kaplan‑Meier analysis, was 42.9% one day following CA. However, hypothermia, which was induced following CA, significantly increased the survival rate (71.4%). In normothermia rats with CA, the serum blood urea nitrogen level was significantly increased one day post‑CA. In addition, the serum creatinine level was significantly increased one day post‑CA. However, in CA rats exposed to hypothermia, the levels of urea nitrogen and creatinine significantly decreased following CA. Histochemical staining revealed a significant temporal increase in renal injury after the normothermia group was subjected to CA. However, renal injury was significantly decreased in the hypothermia group. Immunohistochemical analysis of the kidney revealed a significant decrease in antioxidant enzymes (copper‑zinc superoxide dismutase, manganese superoxide dismutase, glutathione peroxidase and catalase) with time in the normothermia group. However, in the hypothermia group, these enzymes were significantly elevated following CA. Collectively, the results revealed that renal dysfunction following asphyxial CA was strongly associated with the early survival rate and therapeutic hypothermia reduced renal injury via effective antioxidant mechanisms.

Objective: This study aimed to characterize Neolithic human maxillary molars from archeological remains at the Jiaojia site, Shandong, China, and compare their ultrastructural features with sex and age-matched modern locals., Design: Maxillary first (n = 86) and second (n = 80) molars in 5000-year-old individuals (n = 50) from the Jiaojia site were scanned by cone-beam computed tomography (CBCT). Sex and age-matched control groups were assigned from oral surgical patients at Shandong University. Images were analyzed for crown size, root length, root morphology, canal inter-orifice distances, mesiobuccal canal morphology, and second mesiobuccal (MB2) canal prevalence and location. Neolithic and modern values were compared statistically using Chi-squared and Mann-Whitney test at p < .05., Results: Crown and root size were smaller, and canal inter-orifice distances were shorter in Neolithic maxillary molars than their modern counterparts. For mesiobuccal roots, Weine's Type I single canals were the most prevalent in Neolithic and modern first and second molars. MB2 canal prevalence were not significantly different (p > .05) in Neolithic (53.3%) or modern (60.5%) first molars, and Neolithic (11.3%) or modern (21.3%) second molars. But, MB2 prevalence was significantly higher for modern than ancient male first (p = .032) and second (p = .005) molars. Additionally, MB2 were located more mesially and closer to MB1 in Neolithic than modern molars., Conclusions: Maxillary molar root and canal morphology of ancient 5000-year-old remains at the Jiaojia site resemble that of local patients. A trend towards larger tooth size, and more dispersed MB2 canals over this short evolutionary period warrants additional investigation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Endo-1,4-β-xylanase is one of the most important enzymes employed in biorefineries for obtaining fermentable sugars from hemicellulosic components. Herein, we aimed to improve the catalytic performance of Bacillus circulans xylanase (Bcx) using a structure-guided rational design. A systematic analysis of flexible motions revealed that the R49 component of Bcx (i) constrains the global conformational changes essential for substrate binding and (ii) is involved in modulating flexible motion. Site-saturated mutagenesis of the R49 residue led to the engineering of the active mutants with the trade-off between flexibility and rigidity. The most active mutant R49N improved the catalytic performance, including its catalytic efficiency (7.51-fold), conformational stability (0.7 °C improvement), and production of xylose oligomers (2.18-fold higher xylobiose and 1.72-fold higher xylotriose). The results discussed herein can be applied to enhance the catalytic performance of industrially important enzymes by controlling flexibility., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The deficiency of antigen-specific T cells and the induction of various treatment-induced immunosuppressions still limits the clinical benefit of cancer immunotherapy. Although the chemo-immunotherapy adjuvanted with Toll-like receptor 7/8 agonist (TLR 7/8a) induces immunogenic cell death (ICD) and in situ vaccination effect, indoleamine 2,3-dioxygenase (IDO) is also significantly increased in the tumor microenvironment (TME) and tumor-draining lymph node (TDLN), which offsets the activated antitumor immunity. To address the treatment-induced immunosuppression, an assemblable immune modulating suspension (AIMS) containing ICD inducer (paclitaxel) and supra-adjuvant (immune booster; R848 as a TLR 7/8a, immunosuppression reliever; epacadostat as an IDO inhibitor) is suggested and shows that it increases cytotoxic T lymphocytes and relieves the IDO-related immunosuppression (TGF-β, IL-10, myeloid-derived suppressor cells, and regulatory T cells) in both TME and TDLN, by the formation of in situ depot in tumor bed as well as by the efficient migration into TDLN. Local administration of AIMS increases T cell infiltration in both local and distant tumors and significantly inhibits the metastasis of tumors to the lung. Reverting treatment-induced secondary immunosuppression and reshaping "cold tumor" into "hot tumor" by AIMS also increases the response rate of immune checkpoint blockade therapy, which promises a new nanotheranostic strategy in cancer immunotherapy., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Given that lipase is an enzyme applicable in various industrial fields and water-miscible organic solvents are important reaction media for developing industrial-scale biocatalysis, a structure-based strategy was explored to stabilize lipase A from Bacillus subtilis in a water-ethanol cosolvent. Site-directed mutagenesis of ethanol-interacting sites resulted in 4 mutants, i.e., Ser16Gly, Ala38Gly, Ala38Thr, and Leu108Asn, which were stable in 50% ethanol and had up to 1.8-fold higher stability than the wild-type. In addition, Leu108Asn was more thermostable at 45 °C than the wild type. The results discussed in this study not only provide insights into strategies for enzyme engineering to improve organic solvent resistance but also suggest perspectives on pioneering routes for constructing enzyme-based biorefineries to produce value-added fuels and chemicals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To investigate the efficacy of a nickel-titanium (NiTi) file with an automated computerized numerical control (CNC) system for root canal shaping., Methods: The movement of the automated device and the insertion angle were investigated. In Experiment 1, simulated resin root canals were randomly divided into four groups (n = 20): manual downward movement using a handpiece (Group 1), vertical downward movement by CNC (Group 2), reciprocating up and down movement by CNC (Group 3), and spiral up and down movement by CNC (Group 4). In Experiment 2, five different insertion angles of the NiTi file were evaluated (n = 20). Four parameters were used to evaluate the shaping ability: change in the working length, central axis offset, curvature variation, and preparation time. Groups were compared using one-way analysis of variance (ANOVA) with significance was set at P < 0.05., Results: The change in central axis position in the curved part of the root canal was found to be smaller in Group 4 than in other groups (P < 0.05). The curvature changes and preparation time of Groups 1 and 4 were significantly reduced compared with Groups 2 and 3 (P < 0.05). The variation in working length and curvature in the 5° insertion angle group was significantly smaller than in the other groups (P < 0.05)., Conclusions: A spiral up and down movement, controlled by the CNC machine, and 5° insertion angle, maintained original root canal shape more precisely than other methods., (© 2021. The Author(s).)

Purpose: To investigate the safety and efficacy of hypofractionated radiation therapy (HFRT) in patients with non-small cell lung cancer who are unfit for surgery or stereotactic body radiation therapy (SBRT) at our institution., Materials and Methods: From May 2007 to December 2018, HFRT was used to treat 68 lesions in 64 patients who were unsuitable for SBRT because of central tumor location, large tumor size, or contiguity with the chest wall. The HFRT schedule included a dose of 50-70 Gy delivered in 10 fractions over 2 weeks. The primary outcome was freedom from local progression (FFLP), and the secondary endpoints included overall survival (OS), disease-free survival, and toxicities., Results: The median follow-up period was 25.5 months (range, 5.3 to 119.9 months). The FFLP rates were 79.8% and 67.8% at 1 and 2 years, respectively. The OS rates were 82.8% and 64.1% at 1 and 2 years, respectively. A larger planning target volume was associated with lower FFLP (p = 0.023). Dose escalation was not associated with FFLP (p = 0.964). Four patients (6.3%) experienced grade 3-5 pulmonary toxicities. Tumor location, central or peripheral, was not associated with either grade 3 or higher toxicity., Conclusion: HFRT with 50-70 Gy in 10 fractions demonstrated acceptable toxicity; however, the local control rate can be improved compared with the results of SBRT. More studies are required in patients who are unfit for SBRT to investigate the optimal fractionation scheme.

Background and Purpose: This study aimed to determine the equivalence between definitive chemoradiotherapy (DCRT) and radical esophagectomy in clinical T1bN0M0 esophageal squamous cell carcinoma (ESCC)., Materials and Methods: Among 282 patients with cT1bN0M0 ESCC, 238 underwent radical esophagectomy and 44 underwent DCRT. Both treatments were retrospectively compared overall survival (OS), progression-free survival (PFS), and complications., Results: The DCRT group exhibited poorer patient characteristics than the surgery group, especially with mean age (73 vs. 63 years), Eastern Cooperative Oncology Group (ECOG) status, and Charlson Comorbidity Index (p < 0.001, each). The median follow-up duration was 49.5 (range, 0.4-97.0) and 45.5 months (range, 5.0-112.0) in the surgery and DCRT groups, respectively. In the DCRT group, clinical complete response was achieved in 43 patients (97.7%) at 1 month after treatment. The 5-year OS rates were 75.8% and 68.8% (p = 0.135) and the 5-year PFS were 63.8% and 57.8% (p = 0.637) for the surgery and DCRT groups, respectively. Local recurrence rates were identical between the two groups (11.4% and 11.4%), but the distant metastasis rate was lower in the DCRT group (n = 1, 2.27% vs. n = 29, 12.15%). Grade 3-4 hematologic toxicities were observed in 11 patients (25%) of the DCRT group, and 56 patients (23.5%) in the surgery group showed grade 3-5 surgical complications, including mortality (n = 5)., Conclusion: Based on the non-inferior survival rates, recurrence patterns, and complication rates without critical surgical mortality, DCRT was comparable to esophagectomy for cT1bN0 esophageal squamous cell carcinoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

The present study aimed to investigate the renoprotective effect of therapeutic hypothermia (TH) on renal ischemia-reperfusion injury (RI/RI) induced by asphyxial cardiac arrest (CA) in rats. A total of 48 male rats were randomly divided into five groups: i) Sham (n=6); ii) Normothermia + CA (Normo.) (n=14); iii) Normo. and 2 h of TH after return of spontaneous circulation (ROSC) (n=12); iv) Normo. and 4 h of TH after ROSC (n=9); and v) Normo. and 6 h of TH after ROSC (n=7). All rats except the Sham group underwent asphyxia CA and were sacrificed 1 day after ROSC. The survival rate increased from 42.8% in the Normo. group to 50, 66.6 and 85.7% in the groups with 2, 4 and 6 h of TH after CA, respectively. TH attenuated the histopathological changes of the renal tissues following ROSC and the levels of blood urea nitrogen, serum creatinine and malondialdehyde in renal tissues. On immunohistochemistry, the relative optical density of nuclear erythroid-related factor-2 (Nrf2) and heme oxygenase (HO-1) expression in renal tissues increased in the Normo. group compared with that in the Sham group and exhibited further significant increases at 6 h of TH after ROSC. In conclusion, TH attenuated renal injury and increased the expression of Nrf2 and HO-1 in a TH treatment time-dependent manner., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Jawad et al.)

Introduction: This study aimed to investigate microbiota and the histopathology of infected immature teeth microenvironments after disinfection with calcium hydroxide, triple antibiotic paste, and a synthetic antimicrobial peptide (synthetic human beta-defensin-3-C15) for regenerative endodontic procedures (REPs). The null hypothesis was that there is no difference among intracanal medications on disinfection in REPs., Methods: Pulp necrosis and periapical lesions were induced in immature beagle dog premolars. Block randomized teeth were uninfected (negative control, n = 6), left infected (positive control, n = 6), or medicated with a disinfectant (n = 6/group). After disinfection (2 weeks), teeth were reaccessed, irrigated with 17% EDTA, blood clot induced, sealed with ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK), and restored with resin-modified glass ionomer. Animals were monitored radiographically and euthanized (12 weeks) for histopathologic and metagenomic analyses., Results: REP-treated roots showed radiographic repair of periapical radiolucency (67.65%, 23/34), continued root development (73.53%, 25/34), and apical closure (70.59%, 24/34) regardless of the disinfectant used (P > .05). Canal microenvironments histologically devoid of bacteria contained new mineralized and pulp-like tissues in characteristic patterns that varied by disinfectant. Next-generation sequencing (16S ribosomal RNA) identified Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes as dominant phyla of microbiota in immature teeth. Infection-induced teeth showed changes in diversity and richness of microbiota from negative controls. Compared with positive controls, all treated teeth exhibited depleted operational taxonomic units, with lower phylogenic diversity from synthetic human beta-defensin-3-C15-treated teeth., Conclusions: There were no differences among the medicaments investigated in radiologic treatment outcomes, but disinfectants in REPs showed altered microbiota from normal and diseased immature teeth with different histologic patterns of regeneration., (Copyright © 2021 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Importance: SARS-CoV-2., Objective: To determine the characteristics, changes over time, outcomes, and severity risk factors of SARS-CoV-2 affected children within the National COVID Cohort Collaborative (N3C)., Design: Prospective cohort study of patient encounters with end dates before May 27th, 2021., Setting: 45 N3C institutions., Participants: Children <19-years-old at initial SARS-CoV-2 testing., Main Outcomes and Measures: Case incidence and severity over time, demographic and comorbidity severity risk factors, vital sign and laboratory trajectories, clinical outcomes, and acute COVID-19 vs MIS-C contrasts for children infected with SARS-CoV-2., Results: 728,047 children in the N3C were tested for SARS-CoV-2; of these, 91,865 (12.6%) were positive. Among the 5,213 (6%) hospitalized children, 685 (13%) met criteria for severe disease: mechanical ventilation (7%), vasopressor/inotropic support (7%), ECMO (0.6%), or death/discharge to hospice (1.1%). Male gender, African American race, older age, and several pediatric complex chronic condition (PCCC) subcategories were associated with higher clinical severity (p ≤ 0.05). Vital signs (all p≤0.002) and many laboratory tests from the first day of hospitalization were predictive of peak disease severity. Children with severe (vs moderate) disease were more likely to receive antimicrobials (71% vs 32%, p<0.001) and immunomodulatory medications (53% vs 16%, p<0.001). Compared to those with acute COVID-19, children with MIS-C were more likely to be male, Black/African American, 1-to-12-years-old, and less likely to have asthma, diabetes, or a PCCC (p < 0.04). MIS-C cases demonstrated a more inflammatory laboratory profile and more severe clinical phenotype with higher rates of invasive ventilation (12% vs 6%) and need for vasoactive-inotropic support (31% vs 6%) compared to acute COVID-19 cases, respectively (p<0.03)., Conclusions: In the largest U.S. SARS-CoV-2-positive pediatric cohort to date, we observed differences in demographics, pre-existing comorbidities, and initial vital sign and laboratory test values between severity subgroups. Taken together, these results suggest that early identification of children likely to progress to severe disease could be achieved using readily available data elements from the day of admission. Further work is needed to translate this knowledge into improved outcomes.

Purpose: To investigate the role of Nrf2/HO-1 in renal histopathological ailments time-dependently in asphyxial cardiac arrest (CA) rat model., Methods: Eighty-eight Sprague Dawley male rats were divided into five groups of eight rats each. Asphyxial CA was induced in all the experimental rats except for the sham group. The rats were sacrificed at 6 hours, 12 hours, one day and two days post-CA. Serum blood urea nitrogen (BUN), creatinine (Crtn) and malondialdehyde from the renal tissues were evaluated. Hematoxylin and eosin and periodic acid-Schiff staining were done to evaluate the renal histopathological changes in the renal cortex. Furthermore, Nrf2/HO-1 immunohistochemistry (ihc) and western blot analysis were performed after CA., Results: The survival rate of rats decreased in a time-dependent manner: 66.6% at 6 hours, 50% at 12 hours, 38.1% in one day, and 25.8% in two days. BUN and serum Crtn markedly increased in CA-operated groups. Histopathological ailments of the renal cortical tissues increased significantly from 6 hours until two days post-CA. Furthermore, Nrf2/HO-1 expression level significantly increased at 6 hours, 12 hours, and one day., Conclusions: The survival rate decreased time-dependently, and Nrf/HO-1 expression increased from 6 hours with the peak times at 12 hours, and one day post-CA.

Background and Objectives : Endovascular thrombectomy (EVT is an emerging gold standard treatment for acute cerebral infarction and may allow functional improvement after subacute cerebral infarction. However, the long-term functional benefits of EVT in patients with moderate to severe disability remain unclear. We investigated the effects of EVT on the activities of daily living (ADL), handicap, gait, and eating in patients with middle cerebral artery (MCA) occlusion who exhibited moderate to severe disability (score of 3-5 on the modified Rankin scale (mRS)) due to stroke, up to six months after onset. Materials and Methods : This retrospective longitudinal case-control study assessed 45 patients with MCA occlusion who exhibited moderate to severe disability (mRS score ≥ 3): 15 underwent EVT and 30 served as controls. Clinical assessments were conducted at two weeks (12-16 days), four weeks (26-30 days), and six months (180-210 days) after stroke onset. Functional assessments comprised the Korean version of the modified Barthel index (MBI), mRS, functional ambulation category (FAC), and dysphagia outcome severity scale (DOSS) to assess disability, handicap, gait, and eating. Results : The MBI, mRS, FAC, and DOSS scores all improved significantly (all p < 0.05) in the EVT group, compared to the controls. Conclusions : EVT has favorable effects on performing routine ADL, the handicap itself, walking, and eating. Therefore, EVT is recommended for patients with acute MCA occlusion, including those with severe disability at the initial assessment.

A stroke may be followed by central post-stroke pain (CPSP), which is characterized by chronic neuropathic pain. The exact mechanism has not yet been fully uncovered. We investigated alterations in the white matters in patients with CPSP, compared with stroke patients without CPSP and normal controls. Our retrospective cross-sectional, case-control study participants were assigned to three groups: CPSP (stroke patients with CPSP ( n = 17)); stroke control (stroke patients without CPSP ( n = 26)); and normal control (normal subjects ( n = 34)). The investigation of white matter for CPSP was focused on the values of fiber numbers (FN) and fractional anisotrophy (FA) for spinothalamic tract (STT), anterior thalamic radiation (ATR), superior thalamic radiation (STR) and posterior thalamic radiation (PTR), and corticospinal tract (CST) was measured. The FA for the STT and STR of the CPSP group were lower than those for the stroke control and normal control groups. The FA of CST and ATR did not differ between the CPSP and stroke groups, but both differed from the normal control. The FA of PTR in the stroke control group differed from the normal control group, but not from the CPSP group. The FN of CST, STT, ATR, and STR for the CPSP and stroke control groups did not differ from each other, but both differed from those of normal controls. FN of PTR did not differ between the CPSP and normal control groups. The alterations in the spinothalamic tract and superior thalamic radiation after stroke would play a role in the pathogenesis of CPSP.

We have compared the diagnostic ability of different concentrations of 0.125% and 0.0625% dilute pilocarpine for detecting denervation supersensitivity in unilateral Adie's tonic pupil. This retrospective, observational, case-control study involved 117 subjects, consisting of 56 patients with unilateral Adie's tonic pupil and 61 controls with other causes of unilateral dilated pupils. Subjects underwent the dilute pilocarpine test with one of the two concentrations, 0.125% or 0.0625%. Pupillary light reflex was recorded with a dynamic pupillometer at baseline and at 30-40 min after instilling one of the two concentrations of dilute pilocarpine. Diagnostic accuracy of two different concentrations of the dilute pilocarpine test, 0.125% group versus 0.0625% group, were compared by area under the receiver operating characteristic curve (AUC). Diagnostic ability of the dilute pilocarpine test for detecting denervation supersensitivity in unilateral Adie's tonic pupil was significantly better in the 0.0625% group than in the 0.125% group (AUC = 0.954 vs. 0.840, respectively, P = 0.047). In the 0.0625% group, the change in maximal pupil diameter of ≥ 0.5 mm after topical pilocarpine instillation showed 100% sensitivity and 82.8% specificity for detecting Adie's tonic pupil. This study confirmed that pupillary constriction with 0.0625% pilocarpine is better than 0.125% pilocarpine for detecting denervation supersensitivity in Adie's tonic pupil. Digital pupillometry is a reliable method for assessing denervation supersensitivity in Adie's tonic pupil.

Atopic dermatitis (AD) is a T helper (Th)2-biased disease with elevated expression of Th2 cytokines that responds to Th2 signaling blockade. TRIM32 is an E3 ubiquitin ligase with innate antiviral activity. In our previous studies, we showed that Trim32 null mice developed Th2-biased skin inflammation in response to imiquimod and associated a low level of TRIM32 with AD. In this study, we provide evidence that TRIM32 deficiency contributes to enhanced Th2 cell differentiation in vitro. Analysis of TRIM32-associated proteins from public databases identified protein kinase C (PKC)ζ as a TRIM32-associated protein that contributes to the regulation of Th2 signaling. We demonstrated that PKCζ was specifically ubiquitinated by TRIM32 and, further, that PKCζ stability tended to be increased in Th2 cells with a Trim32 null background. Furthermore, Prkcz null mice showed compromised AD-like phenotypes in the MC903 AD model. Consistently, a high PKCζ and low TRIM32 ratio was associated with CD4+ cells in AD human skin compared with those in healthy controls. Taken together, these findings suggest that TRIM32 functions as a regulator of PKCζ that controls the differentiation of Th2 cells important for AD pathogenesis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Potent antiviral agents effectively reduce liver-related events in patients with chronic hepatitis B. This study aimed to determine whether alanine aminotransferase normalization using potent antiviral agents was related to hepatocellular carcinoma development. From 2007 to 2017, we included 610 patients with chronic hepatitis B who received entecavir or tenofovir disoproxil fumarate. The patients were divided into the alanine aminotransferase normalization group (Gr.1) and non-normalization group (Gr.2) within a year of potent antiviral treatment. Liver-related events included hepatic encephalopathy, variceal bleeding, and ascites. The mortality rate and hepatocellular carcinoma incidence were investigated for each group. The patients who showed ALT normalization at 1 year of treatment were 397 (65.1%) of 610. During a median follow-up period of 86 months, 65 (10.7%) patients developed hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly lower in Gr.1 than in Gr.2 ( p < 0.001). Risk factors for alanine aminotransferase non-normalization were body mass index, cholesterol, and liver cirrhosis at baseline. Male sex, age, platelet level, alcohol use, presence of cirrhosis at baseline, and non-normalization after 1 year of treatment were independent risk factors for hepatocellular carcinoma. Alanine aminotransferase normalization within 1 year of initiating antiviral agents reduces the risk of hepatocellular carcinoma development.

Introduction. Antipathogenic or antivirulence strategy is to target a virulence pathway that is dispensable for growth, in the hope to mitigate the selection for drug resistance. Hypothesis/Gap Statment. Peroxide stress responses are one of the conserved virulence pathways in bacterial pathogens and thus good targets for antipathogenic strategy. Aim. This study aims to identify a new chemical compound that targets OxyR, the peroxide sensor required for the full virulence of the opportunistic human pathogen, Pseudomonas aeruginosa . Methodology. Computer-based virtual screening under consideration of the 'eNTRy' rules and molecular docking were conducted on the reduced form of the OxyR regulatory domain (RD). Selected hits were validated by their ability to phenocopy the oxyR null mutant and modulate the redox cycle of OxyR. Results. We first isolated three robust chemical hits that inhibit OxyR without affecting prototrophic growth or viability. One (compound 1) of those affected the redox cycle of OxyR in response to H 2 O 2 treatment, in a way to impair its function. Compound 1 displayed selective antibacterial efficacy against P. aeruginosa in Drosophila infection model, without antibacterial activity against Staphylococcus aureus . Conclusion. These results suggest that compound 1 could be an antipathogenic hit inhibiting the P. aeruginosa OxyR. More importantly, our study provides an insight into the computer-based discovery of new-paradigm selective antibacterials to treat Gram-negative bacterial infections presumably with few concerns of drug resistance.

This retrospective study investigated the effect of mineral trioxide aggregate (MTA) plug location on treatment outcome and root maturation after regenerative endodontic procedures (REP) in immature permanent teeth. Thirty-three roots (n = 33) in cohort that underwent REP consistently according to AAE guideline were included to trace radiographic changes for the root and canal dimensions. Based on intraoral radiographs, roots were divided into two groups depending on the location of MTA plug within whole root length: coronal group (n = 14), within the upper half; apical group (n = 19), within the lower half. Periapical radiographs were standardized to assess treatment outcomes and root maturation including root development stages and digital measurements on the change ratios of root length, apex width, radiographic root area (RRA), modified RRA (mRRA), and periapical rarefaction area. The data were statistically analysed using the Mann-Whitney test. The patients' average age was 11 years and 10 months, with no significant between-group difference in sex. Premolars were the most prevalent tooth type (62.1%), followed by incisiors and molars. Pre-existing symptoms and signs subsided within 6 months in all cases. The teeth showed similar radiographic root development in both groups (P > 0.05). However, mRRA increase ratio was significantly higher in apical group than that in coronal group at early (< 6 months) and late (< 24 months) periods of follow-up (P < 0.05). Significant changes of root development stage were observed at early period for apical group and at late period for coronal group (P < 0.05). All the observed cases showed continuing root development after REP. Significant changes in root developments occurred at different follow-up periods according to the location of MTA plugs.

Lateropulsion (pusher syndrome) is an important barrier to standing and gait after stroke. Although several studies have attempted to elucidate the relationship between brain lesions and lateropulsion, the effects of specific brain lesions on the development of lateropulsion remain unclear. Thus, the present study investigated the effects of stroke lesion location and size on lateropulsion in right hemisphere stroke patients. The present retrospective cross-sectional observational study assessed 50 right hemisphere stroke patients. Lateropulsion was diagnosed and evaluated using the Scale for Contraversive Pushing (SCP). Voxel-based lesion symptom mapping (VLSM) analysis with 3T-MRI was used to identify the culprit lesion for SCP. We also performed VLSM controlling for lesion volume as a nuisance covariate, in a multivariate model that also controlled for other factors contributing to pusher behavior. VLSM, combined with statistical non-parametric mapping (SnPM), identified the specific region with SCP. Lesion size was associated with lateropulsion. The precentral gyrus, postcentral gyrus, inferior frontal gyrus, insula and subgyral parietal lobe of the right hemisphere seemed to be associated with the lateropulsion; however, after adjusting for lesion volume as a nuisance covariate, no lesion areas were associated with the SCP scores. The size of the right hemisphere lesion was the only factor most strongly associated with lateropulsion in patients with stroke. These results may be useful for planning rehabilitation strategies of restoring vertical posture and understanding the pathophysiology of lateropulsion in stroke patients.

Background: The majority of U.S. reports of COVID-19 clinical characteristics, disease course, and treatments are from single health systems or focused on one domain. Here we report the creation of the National COVID Cohort Collaborative (N3C), a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative U.S. cohort of COVID-19 cases and controls to date. This multi-center dataset supports robust evidence-based development of predictive and diagnostic tools and informs critical care and policy., Methods and Findings: In a retrospective cohort study of 1,926,526 patients from 34 medical centers nationwide, we stratified patients using a World Health Organization COVID-19 severity scale and demographics; we then evaluated differences between groups over time using multivariable logistic regression. We established vital signs and laboratory values among COVID-19 patients with different severities, providing the foundation for predictive analytics. The cohort included 174,568 adults with severe acute respiratory syndrome associated with SARS-CoV-2 (PCR >99% or antigen <1%) as well as 1,133,848 adult patients that served as lab-negative controls. Among 32,472 hospitalized patients, mortality was 11.6% overall and decreased from 16.4% in March/April 2020 to 8.6% in September/October 2020 (p = 0.002 monthly trend). In a multivariable logistic regression model, age, male sex, liver disease, dementia, African-American and Asian race, and obesity were independently associated with higher clinical severity. To demonstrate the utility of the N3C cohort for analytics, we used machine learning (ML) to predict clinical severity and risk factors over time. Using 64 inputs available on the first hospital day, we predicted a severe clinical course (death, discharge to hospice, invasive ventilation, or extracorporeal membrane oxygenation) using random forest and XGBoost models (AUROC 0.86 and 0.87 respectively) that were stable over time. The most powerful predictors in these models are patient age and widely available vital sign and laboratory values. The established expected trajectories for many vital signs and laboratory values among patients with different clinical severities validates observations from smaller studies, and provides comprehensive insight into COVID-19 characterization in U.S. patients., Conclusions: This is the first description of an ongoing longitudinal observational study of patients seen in diverse clinical settings and geographical regions and is the largest COVID-19 cohort in the United States. Such data are the foundation for ML models that can be the basis for generalizable clinical decision support tools. The N3C Data Enclave is unique in providing transparent, reproducible, easily shared, versioned, and fully auditable data and analytic provenance for national-scale patient-level EHR data. The N3C is built for intensive ML analyses by academic, industry, and citizen scientists internationally. Many observational correlations can inform trial designs and care guidelines for this new disease., Competing Interests: Declaration of interests Benjamin Amor, Katie Rebecca Bradwell, Andrew T. Girvin, Amin Manna, and Nabeel Qureshi: employee of Palantir Technologies; Brian T. Garibaldi: Member of the FDA Pulmonary-Allergy Drugs Advisory Committee (PADAC); Matvey B. Palchuk: employee of TriNetX; Kristin Kostka: employee of IQVIA Inc.; Julie A. McMurry: and Melissa A. Haendel Cofounders of Pryzm Health; Chris P. Austin and Ken R. Gersing, employees of the National Institutes of Health. No conflicts of interest reported for all other authors.

Increases of neutrophils and osteoclasts are pathological changes of periodontitis. RANKL is an osteoclast differentiation factor. The effect of periodontopathogen LPS on RANKL-expressing neutrophils has not been clarified yet. We evaluated numerical changes of RANKL-expressing neutrophils in air pouches of mice injected with LPSs of Fusobacterium nucleatum and Porphyromonas gingivalis. Mice with air pouches were assigned into saline (C)-, E. coli LPS- (Ec LPS)-, F. nucleatum LPS (Fn LPS)-, P. gingivalis LPS (Pg LPS)-, and Fn LPS and Pg LPS (Fn + Pg LPS)-injected groups. CD11b + Ly6G + neutrophils and CD11b + Ly6G + RANKL + neutrophils in blood and air pouch exudates were determined by flow cytometry. In blood, compared to the C group, the Fn LPS group showed increases of CD11b + Ly6G + neutrophils and CD11b + Ly6G + RANKL + neutrophils whereas the Pg LPS group showed no significant differences. These increases in the Fn LPS group were not different to those in the Ec LPS group. In exudates, Fn LPS and Pg LPS groups showed increases of CD11b + Ly6G + neutrophils and CD11b + Ly6G + RANKL + neutrophils compared to the C group. Increased levels in the Fn LPS group were not different to those in the Ec LPS group, but Pg LPS group was lower than those in the Ec LPS group. In blood and exudates, the Fn + Pg LPS group showed no difference in levels of these neutrophils compared to the Ec LPS group. LPSs of F. nucleatum and P. gingivalis increased RANKL-expressing neutrophils although the degrees of increases were different. These suggest that periodontopathogen LPS can act as a stimulant to increase RANKL-expressing neutrophils.

We evaluated changes in the pupillary light reflex (PLR) of ethambutol (EMB)-induced optic neuropathy and analyzed the correlations between PLR parameters and other structural changes in EMB-induced optic neuropathy. This retrospective, observational, case-control study involved thirty-two eyes of 17 patients with EMB-induced optic neuropathy (EON group), sixty eyes of 60 patients without EMB-induced optic neuropathy (non-EON group) while taking ethambutol, and forty-five eyes of 45 normal controls. PLR was measured by digital pupillometry. The clinical characteristics, optical coherence tomography measurements and PLR parameters including pupil diameter, constriction latency, constriction ratio/velocity, and dilation velocity were noted. The differences in PLR measurements were compared among the three groups. Correlations between PLR parameters and other structural parameters in EMB-induced optic neuropathy were evaluated. The pupillary constriction ratio, constriction and dilation velocities were significantly reduced in the EON group compared to the non-EON group and controls (all P < 0.05). In EMB-induced optic neuropathy, average outer macular ganglion cell layer (mGCL) thickness showed a significant correlation with the pupillary constriction ratio (ß = 4.14, P = 0.003) and maximal constriction velocity (ß = 1.08, P < 0.001). This study confirmed that pupillary constriction and dilation velocities were significantly decreased in patients with EMB-induced optic neuropathy, compared to normal controls. Digital pupillometry may be a useful tool in the evaluation of EMB-induced optic neuropathy.

Cardiac arrest (CA) is a leading cause of mortality worldwide. Most of post-resuscitation related deaths are due to post-cardiac arrest syndrome (PCAS). After cardiopulmonary resuscitation (CPR), return of spontaneous circulation (ROSC) leads to renal ischemia-reperfusion injury, also known as PCAS. Many studies have focused on brain and heart injuries after ROSC, but renal failure has largely been ignored. Therefore, we investigated the protective effects of therapeutic hypothermia (TH) on asphyxial CA-induced renal injury in rats. Thirty rats were randomly divided into five groups: 1) the control group (sham); 2) the normothermic CA (nor.); 3) a normothermic CA group that received TH immediately within 2 h after CPR (Hypo. 2 hrs); 4) a normothermic CA group that received TH within 4 h after CPR (Hypo. 4 hrs); and 5) a normothermia CA group that received TH within 6 h after CPR (Hypo. 6 h). One day after CPR, all rats were sacrificed. Compared with the normothermic CA group, the TH groups demonstrated significantly increased survival rate (P < 0.05); decreased serum blood urea nitrogen, creatinine, and lactate dehydrogenase levels; and lower histological damage degree and malondialdehyde concentration in their renal tissue. Terminal deoxynucleotidyl transferase dUTP nick end labeling stain revealed that the number of apoptotic cells significantly decreased after 4 h and 6 h of TH compared to the results seen in the normothermic CA group. Moreover, TH downregulated the expression of cyclooxygenase-2 in the renal cortex compared to the normothermic CA group one day after CPR. These results suggest that TH exerts anti-apoptotic, anti-inflammatory, and anti-oxidative effects immediately after ROSC that protect against renal injury., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study aimed to investigate the real-time nanoleakage and flow characteristics of calcium silicate-based (Ca-Si) root canal filling materials. Extracted human teeth (n = 30) were decoronated and standardized in their inner and outer dimensions. After root canal enlargement, the roots were filled with gutta-percha (GP) and AH26 sealer, GP and EndoSeal MTA sealer, or Biodentine. The roots were connected to a Nanoflow device (IB Systems) under hydrostatic pressure (40 cm∙H 2 O) and fluid flow was traced through the filled roots. Data were detected at the nanoscale twice per second and automatically recorded in units of nL/s. Leakage was quantified as the mean slope until the curve plateaued over time, and all static flow intervals lasting longer than 1 s were analyzed to identify any increase in flow and duration. Data were statistically analyzed using the Kruskal-Wallis test. The calculated leakage values were 0.0670 ± 0.0516 nL/s for GP/AH26, 0.1397 ± 0.1579 nL/s for GP/EndoSeal MTA, and 0.0358 ± 0.0538 nL/s for Biodentine, with no statistically significant differences among the root filling materials (P > 0.05). An analysis of real-time flow data for 1000 s to identify spot trends and the overall tendency of flow until a plateau was reached revealed a stepwise increase in the roots filled with Ca-Si material, whereas the GP/AH26-filled roots showed a linear increase. Real-time measurements under hydrostatic pressure with the Nanoflow device enabled precise fluid flow tracing through the root canal filling material. In terms of nanoleakage, the tested root canal filling materials showed no significant differences, while the real-time flow patterns of roots filled with Ca-Si material showed different characteristics from those of GP/AH26-filled roots., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: We retrospectively evaluated the prognostic significance of lymph node ratio (LNR) in patients with esophageal squamous cell carcinoma who underwent neoadjuvant concurrent chemoradiation therapy (NCRT) followed by surgery., Materials and Methods: In total, 270 patients who underwent NCRT followed by surgery between August 2005 and December 2015 were included. They were divided into three groups: LNR 0 (n = 196), LNR low (0 < LNR ≤ 0.1; n = 63), and LNR high (>0.1; n = 11). The primary endpoint was overall survival (OS), and the secondary endpoints were freedom from local recurrence (FFLR), distant metastasis-free survival (DMFS), and disease-free survival (DFS)., Results: The median number of retrieved lymph nodes per patient was 33. Pathologically, 74 patients had positive lymph nodes. The median follow-up duration was 36.1 months, and the median survival period was 68.4 months. There was a significant correlation between LNR and the number of positive lymph nodes (correlation coefficient = 0.763, p < 0.001). There was a substantial difference in the OS among the LNR groups, with 2-year survival rates of 79.0%, 54.0%, and 9.1% in the LNR 0, LNR low, and LNR high groups, respectively (p < 0.001). A marked decrease in FFLP, DMFS, and DFS was observed with the increasing LNR. In subgroup analysis, the survival results of patients with clinically positive lymph node were similar from those of entire cohort., Conclusion: LNR is a significant prognostic factor in patients with esophageal squamous cell carcinoma who underwent NCRT followed by surgery. Additional treatment and closer follow-up would be necessary for patients with a high LNR.

Backgrounds and Objective: Increased neutrophil infiltration and osteoclast formation are key characteristics of periodontitis. The effect of these neutrophils on osteoclast formation in periodontitis remains unclear. Therefore, we investigated the effects of neutrophils on osteoclast formation in a neutrophil-deficient mouse model of periodontitis., Methods: Anti-Ly6G antibody (Ab) was used for neutrophil depletion in two mouse models: periodontitis and air pouch. In the periodontitis experiments, mice were divided into PBS-administered control (C), control Ab-administered periodontitis (P), and anti-Ly6G Ab-administered periodontitis (P + Ly6G) groups. Periodontitis was induced by ligature of mandibular first molars. In the air pouch experiments, mice were divided into PBS-administered (C), LPS and control Ab-administered (LPS), and LPS and anti-Ly6G Ab-administered (LPS + Ly6G) groups. Neutrophil migration into air pouches was induced by LPS injection. Flow cytometry was used to examine CD11b + Ly6G + neutrophils in the blood of periodontitis mice and CD11b + Ly6G + RANKL + neutrophils in exudates of air pouch mice. In periodontal tissue, Ly6G + neutrophil and RANKL + cell numbers in periodontal ligament and alveolar bone areas were estimated using immunohistochemistry, osteoclast numbers were measured using TRAP assay, and alveolar bone loss was determined by H&E staining., Results: In blood, CD11b + Ly6G + neutrophils were found in greater percentage in the P group than in the C group on days 3 and 7. However, the percentage of neutrophils was lower in the P + Ly6G group than in the C and P groups. In periodontal tissue, the numbers of Ly6G + neutrophils and RANKL + cells were lower in the P + Ly6G group than in the P group on day 3. Ly6G + neutrophil numbers decreased more in the P + Ly6G group than in the P group on day 7, but RANKL + cell numbers did not decrease in the P + Ly6G group. In exudates, the number of CD11b + Ly6G + RANKL + neutrophils was greater in the LPS group than in the C and LPS + Ly6G groups. On days 3 and 7, the numbers of osteoclasts and alveolar bone loss were greater in periodontal tissue in the P and P + Ly6G groups than in the C group. Interestingly, there were fewer osteoclasts in the P + Ly6G group than in the P group on day 3., Conclusion: Neutrophil deficiency caused a reduction in numbers of both RANKL + cells and osteoclasts in periodontitis-induced tissues only on day 3. Furthermore, in the LPS-injected air pouch model, neutrophil deficiency reduced the influx of RANKL + neutrophils. These findings suggest that the presence of neutrophils induces RANKL expression and could induce osteoclast formation in the early stages of periodontitis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Strain distribution was investigated to assess the occlusal resistance alterations in immature teeth under different occlusal force., Methods: In vitro apexification models of teeth with a funnel-shaped immature apex were obturated with mineral trioxide aggregate (MTA; ProRoot MTA) using different combinations of core materials (10/group): group 1, full-length orthograde obturation of MTA; group 2, a 5-mm MTA apical plug with a composite core; group 3, a 5-mm MTA apical plug and back-filling with warm gutta-percha. Teeth with calcium hydroxide (CH)-medicated canals and untreated teeth with normal apices were tested as controls. The teeth were arranged between two adjacent normal-apex teeth, embedded in a resin mold with a simulated periodontal ligament space. Strain data were recorded from the 3-unit teeth assembly under static compressive occlusal forces (50, 100, 200, and 300 N). Measurements were repeated 20 times for each condition, and the data were statistically analyzed., Results: The immature teeth showed altered occlusal force resistance, placing increased strain on adjacent teeth. Teeth with CH-medicated canals showed significantly inferior occlusal resistance under all tested forces (P < 0.05). Application of an MTA plug with deep composite resin core resulted in significantly better stress-bearing capacity especially under forces of 50 and 300 N (P < 0.05)., Conclusions: The pattern of occlusal force distribution in immature teeth differed according to the canal obturation materials used for apexification. Immature teeth with an MTA apical plug showed more favorable occlusal force resistance than those with CH-medicated canals.

Objectives: To obtain radicular measurements of two separate mesiobuccal (MB) root canals in maxillary first molars using micro-computed tomography (μCT) with customized software., Materials and Methods: Human maxillary first molar MB roots (N = 36) with two separate canals (MB1, MB2) and apical foramina were scanned by μCT and analyzed with Kappa2 software to reconstruct three-dimensional (3D) surface models of roots and canals. These models were sectioned at 0.1 mm intervals perpendicular to the central axis of each canal. Canal widths, 3D curvatures, and surrounding dentine thicknesses were measured concurrently on each section. Dentine thicknesses were analyzed statistically for differences between each direction and the different levels of both canals., Results: Dentine walls around MB1 were thicker than MB2 (p < 0.05). Thinnest dentine was most often located at disto-inside direction in both canals. Canal widths were significantly smaller in MB2 than MB1 (p < 0.01). Apical constrictions were smaller (p < 0.05) and further (p < 0.05) from the apex in MB2 than MB1. Canal curvatures were greatest in the apical third of both canals (p < 0.001), and they were greater in MB2 than MB1 (p < 0.05)., Conclusions: MB2 canals had shorter lengths, smaller widths, and more severe curvatures and were surrounded by thinner dentine walls. In MB2, apical constrictions were between 1 and 2 mm from the apex, compared to about 1 mm for MB1., Clinical Relevance: These detailed measurements and in-depth 3D analyses of maxillary first molar MB roots with two separate canals and apical foramina provide morphologic references for root canal therapy.

Background/aims: The controlled attenuation parameter (CAP), based on transient elastography, is widely used for noninvasive assessment of the degree of hepatic steatosis (HS). We investigated the correlation of the degree HS between CAP and ultrasound (US) in patients with HS., Methods: In total, 986 patients with US-based HS who underwent transient elastography within 1 month were evaluated. The US-based grade of HS was categorized as mild (grade 1), moderate (grade 2), or severe (grade 3)., Results: The CAP was significantly correlated with the US-based grade of HS (r = 0.458, p < 0.001). The median CAP value of each US-based HS grade showed a positive correlation with grade (271.1, 303.7, and 326.7 dB/m for grades 1, 2, and 3). In a multivariate analysis, the US-based HS grade, body mass index, serum albumin, alanine aminotransferase, and total cholesterol, and liver stiffness were all significantly correlated with the CAP value (all p < 0.05). The areas under the receiver operating characteristic curves for grade 2 to 3 and grade 3 HS were 0.749 (95% confidence interval [CI], 0.714 to 0.784) and 0.738 (95% CI, 0.704 to 0.772). The optimal cut-off CAP values to maximize the sum of the sensitivity and specificity for grade 2 to 3 and grade 3 HS were 284.5 dB/m (sensitivity 78.6%, specificity 61.7%) and 298.5 dB/m (sensitivity 84.6%, specificity 55.6%)., Conclusion: The correlation of the degree of HS between CAP and US was significantly high in patients with HS, and the optimal cut-off CAP values for grade 2 to 3 and grade 3 HS were 284.5 and 298.5 dB/m.

Background: Ocular coloboma is an excavation of ocular structures that occurs due to abnormal fusion of the embryonic optic fissure. Further, cleft lip/palate (CL/P), a congenital midline abnormality, is caused by a defect in the fusion of the frontonasal, maxillary, and mandibular prominences. No study has reported the association between these two phenotypes in the absence of other systemic abnormalities. We present a case of ocular coloboma along with CL/P and without other neurological abnormalities., Case Presentation: A 5-year-old Asian boy presented with decreased visual acuity in his right eye. Physical examination revealed no abnormal findings except CL/P, which was surgically corrected at the age of 9 months. Best-corrected visual acuity was 20/60 in the right eye and 20/25 in the left eye. Anterior segment examination revealed iris coloboma in the inferior quadrant of his right eye as well as a large inferonasal optic disc and chorioretinal coloboma in the same eye. He was prescribed glasses based on his cycloplegic refractive errors and part-time occlusion of the left eye was recommended. After 3 months, best-corrected visual acuity improved to 20/30 in the right eye., Conclusion: The association of ocular coloboma should be kept in mind when encountering a patient with CL/P without other neurological or systemic abnormalities.

Background and Purpose: The findings of ophthalmic examinations have not been systematically investigated in visual snow syndrome. This study reviewed the abnormal neuro-ophthalmologic findings in a patient cohort with symptoms of visual snow syndrome., Methods: We retrospectively reviewed 28 patients who were referred for symptoms of visual snow to a tertiary referral hospital from November 2016 to October 2019. We defined the findings of best corrected visual acuity (BCVA), visual field testing, pupillary light reflex, contrast sensitivity, full-field and multifocal electroretinography, and optical coherence tomography., Results: Twenty patients (71%) were finally diagnosed as visual snow syndrome. Their additional visual symptoms included illusionary palinopsia (61%), enhanced entoptic phenomenon (65%), disturbance of night vision (44%), and photophobia (65%). A history of migraine was identified in ten patients (50%). The mean BCVA was less than 0.1 logarithm of the minimum angle of resolution, and electrophysiology showed normal retinal function in all patients. Contrast sensitivity was decreased in two of the seven patients tested. Medical treatment was applied to five patients which all turned out to be ineffective. Among the eight patients who were excluded, one was diagnosed with rod-cone dystrophy and another with idiopathic intracranial hypertension., Conclusions: Neuro-ophthalmologic findings are mostly normal in patients with visual snow syndrome. Retinal or neurological diseases must be excluded as possible causes of visual snow., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2020 Korean Neurological Association.)

Purpose: We sought to establish normative ranges of the ganglion cell-inner plexiform layer (GCIPL) thickness using spectral-domain optical coherence tomography in Korean elderly individuals and to identify factors that influence GCIPL thickness., Methods: We conducted a retrospective, observational study of 114 healthy subjects (75 years old or older) who underwent comprehensive ophthalmic examinations at a single institution. GCIPL thickness was measured with the Cirrus spectral-domain optical coherence tomography system and automatic segmentation. Subjects were divided into two age groups: those younger than 80 years and those 80 years or older, respectively. A cross-sectional analysis was adopted to evaluate associations of GCIPL thickness with sex, age, intraocular pressure, optic disc rim area, axial length, spherical equivalent (SE) refractive errors, astigmatism, and body mass index., Results: The average and minimum GCIPL thicknesses were 80.3 ± 5.6 µm and 76.3 ± 5.9 µm, respectively. The GCIPL thickness was significantly lower in the older group than in the younger group in the inferior, inferonasal, and inferotemporal segments (all p &lt; 0.01). A thinner average GCIPL thickness was strongly associated with increasing age (β = -2.87, p = 0.021) and thinner circumpapillary retinal nerve fiber layer thickness (β = 2.87, p &lt; 0.001) in all segments., Conclusions: GCIPL thickness decreased with age globally and in all segments, even after 75 years of age. Thinner GCIPL was associated with older age and thinner circumpapillary retinal nerve fiber layer. Age-related changes should be considered when using GCIPL thickness to assess glaucoma and other optic neuropathies characterized by retinal ganglion cell loss.