Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

Effect of Secondary Phase on Passivation Layer of Super Duplex Stainless Steel UNS S 32750: Advanced Safety of Li-Ion Battery Case Materials.

Aluminum, traditionally the primary material for battery casings, is increasingly being replaced by UNS S 30400 for enhanced safety. UNS S 30400 offers superior strength and corrosion resistance compared to aluminum; however, it undergoes a phase transformation owing to stress during processing and a lower high-temperature strength. Duplex stainless steel UNS S 32750, consisting of both austenite and ferrite phases, exhibits excellent strength and corrosion resistance. However, it also precipitates secondary phases at high temperatures, which are known to form through the segregation of Cr and Mo. Various studies have investigated the corrosion resistance of UNS S 32750; however, discrepancies exist regarding the formation and thickness of the passivation layer. This study analyzed the oxygen layer on the surface of UNS S 32750 after secondary-phase precipitation. The microstructure, volume fraction, chemical composition, and depth of O after the precipitation of the secondary phases in UNS S 32750 was examined using FE-SEM, EDS, EPMA and XRD, and the surface chemical composition and passivation layer thickness were analyzed using electron probe microanalysis and glow-discharge spectroscopy. This study demonstrated the segregation of alloy elements and a reduction in the passivation-layer thickness after precipitation from 25 µm to 20 µm. The findings of the analysis aid in elucidating the impact of secondary-phase precipitation on the passivation layer.

Clinical and molecular characteristics of Korean patients with Kabuki syndrome.

INTRODUCTION: Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. METHODS: This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. RESULTS: The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. CONCLUSION: This study enhances the understanding of the clinical and genetic characteristics of KS.

Study of Precipitated Secondary Phase at 700 °C on the Electrochemical Properties of Super Duplex Stainless Steel AISI2507: Advanced High-Temperature Safety of a Lithium-Ion Battery Case.

Super duplex stainless steel (SDSS) is a suitable structural material for various engineering applications due to its outstanding strength and corrosion resistance. In particular, its high-temperature strength can enhance the safety of electronic products and cars. SDSS AISI2507, known for its excellent strength and high corrosion resistance, was analyzed for its microstructure and electrochemical behavior at the ignition temperature of Li-ion batteries, 700 °C. At 700 °C, AISI2507 exhibited secondary phase precipitation values of 1% and 8% after 5 and 10 h, respectively. Secondary phase precipitation was initiated by the expansion of austenite, forming sigma, chi, and CrN phases. The electrochemical behavior varied with the fraction of secondary phases. Secondary phase precipitation reduced the potential (From -0.25 V to -0.31 V) and increased the current density (From 8 × 10-6 A/cm2 to 3 × 10-6 A/cm2) owing to galvanic corrosion by sigma and chi. As the fraction of secondary phases increased (From 0.0% to 8.1%), the open circuit potential decreased (From -0.25 V to -0.32 V). Secondary phase precipitation is a crucial factor in reducing the corrosion resistance of SDSS AISI2507 and occurs after 1 h of exposure at 700 °C.

Effect of Secondary Phase on Electroless Ni Plating Behaviour of Super Duplex Stainless Steel SAF2507 for Advanced Li-Ion Battery Case.

The development of Li-ion battery cases requires superior electrical conductivity, strength, and corrosion resistance for both cathode and anode to enhance safety and performance. Among the various battery case materials, super duplex stainless steel (SDSS), which is composed of austenite and ferrite as two-phase stainless steel, exhibits outstanding strength and corrosion resistance. However, stainless steel, which is an iron-based material, tends to have lower electrical conductivity. Nevertheless, nickel-plating SDSS can achieve excellent electrical conductivity, making it suitable for Li-ion battery cases. Therefore, this study analysed the plating behaviour of SDSS plates after nickel plating to leverage their exceptional strength and corrosion resistance. Electroless Ni plating was performed to analyse the plating behaviour, and the plating behaviour was studied with reference to different plating durations. Heat treatment was conducted at 1000 °C for one hour, followed by cooling at 50 °C/s. Post-heat treatment, the analysis of phases was executed using FE-SEM, EDS, and EPMA. Electroless Ni plating was performed at 60-300 s. The plating duration after the heat treatment was up to 300 s, and the behaviour of the materials was observed using FE-SEM. The phase analysis concerning different plating durations was conducted using XRD. Post-heat treatment, the precipitated secondary phases in SAF2507 were identified as Sigma, Chi, and CrN, approximating a 13% distribution. During the electroless Ni plating, the secondary phase exhibited a plating rate equivalent to that of ferrite, entirely plating at around 180 s. Further increments in plating time displayed growth of the plating layer from the austenite direction towards the ferrite, accompanied by a reduced influence from the substrate. Despite the differences in composition, both the secondary phase and austenite demonstrated comparable plating rates, showing that electroless Ni plating on SDSS was primarily influenced by the substrate, a finding which was primarily confirmed through phase analysis.

Right lower lung midline herniation as a rare complication in an infant with heart-lung transplantation: A case report.

BACKGROUND: Lung herniation is a rare complication of heart-lung transplantation that can be fatal owing to vascular compromise and airway obstruction. To date, only five cases of lung herniation related to heart-lung transplantation have been reported in the literature; however, to the best of our knowledge, this is the first worldwide report of heart-lung transplantation-related lung herniation in an infant. METHODS: We describe the case of lung herniation as a rare heart-lung transplantation-related complication in an infant. A 12-month-old female baby developed severe bronchopulmonary dysplasia with severe pulmonary hypertension, and she underwent extracorporeal membrane oxygenation for cardiac collapse and lung support. Then, we performed heart-lung transplantation to manage the irreversible deterioration of her lung function. After the heart-lung transplantation, we found the radiological abnormalities persisted on follow-up chest radiographs until the 13th postoperative day diagnosed as lung herniation of the right lower lobe on chest computed tomography. RESULTS: After the relocation of the herniated lung, the clinical condition of the patient improved, and the patient is currently growing without any respiratory symptoms. CONCLUSIONS: In this case report, we emphasize that clinical awareness and high suspicion of this rare complication are needed for early diagnosis and proper treatment to prevent post-transplantation morbidity and mortality related to potential ischemic injury.

mRNA-HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV-mediated cancers via subcutaneous immunization.

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

ß-Asarone Alleviates High-Glucose-Induced Oxidative Damage via Inhibition of ROS Generation and Inactivation of the NF-κB/NLRP3 Inflammasome Pathway in Human Retinal Pigment Epithelial Cells.

Diabetic retinopathy (DR) is the leading cause of vision loss and a major complication of diabetes. Hyperglycemia-induced accumulation of reactive oxygen species (ROS) is an important risk factor for DR. ß-asarone, a major component of volatile oil extracted from Acori graminei Rhizoma, exerts antioxidant effects; however, its efficacy in DR remains unknown. In this study, we investigated whether ß-asarone inhibits high-glucose (HG)-induced oxidative damage in human retinal pigment epithelial (RPE) ARPE-19 cells. We found that ß-asarone significantly alleviated cytotoxicity, apoptosis, and DNA damage in HG-treated ARPE-19 cells via scavenging of ROS generation. ß-Asarone also significantly attenuated the excessive accumulation of lactate dehydrogenase and mitochondrial ROS by increasing the manganese superoxide dismutase and glutathione activities. HG conditions markedly increased the release of interleukin (IL)-1ß and IL-18 and upregulated their protein expression and activation of the nuclear factor-kappa B (NF-κB) signaling pathway, whereas ß-asarone reversed these effects. Moreover, expression levels of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome multiprotein complex molecules, including thioredoxin-interacting protein, NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain, and cysteinyl aspartate-specific proteinase-1, were increased in ARPE-19 cells under HG conditions. However, their expression levels remained similar to those in the control group in the presence of ß-asarone. Therefore, ß-asarone protects RPE cells from HG-induced injury by blocking ROS generation and NF-κB/NLRP3 inflammasome activation, indicating its potential as a therapeutic agent for DR treatment.

Repercussion of extracellular polymeric removal by low-temperature calcium peroxide pretreatment on bacterial fragmentation for enhancing biohydrogen production.

This study envisioned attaining the percipience of effective biohydrogen production from paper mill waste-activated sludge through low-temperature calcium peroxide-mediated bacterial pretreatment (TCP-BP). Floc dissociation with limited cell destruction was attained at a calcium peroxide dosage of 0.05 g/g suspended solids (SS) at 70 °C temperature. This TCP-BP method improves bacterial fragmentation, and very high SS solubilization was achieved at 42 h, with the solubilization and solid reduction of 18.6% and 14.1%, respectively. BP-only pretreatment shows lower solubilization efficiency of 9.4% than TCP-BP pretreatment due to the presence of flocs, which inhibit the enzymatic action during bacterial fragmentation. A biohydrogen test shows a high biohydrogen potential of 94.1 mL H2/gCOD for the TCP-BP sample, which is higher than that of the BP-only and control samples. According to the findings, low-temperature calcium peroxide-mediated bacterial fragmentation is validated to be an efficient process for sludge degradation and biohydrogen production.

A paradigm shift: AMPK negatively regulates ULK1 activity.

In glucose-starved cells, macroautophagy (hereafter referred to as autophagy) is considered to serve as an energy-generating process contributing to cell survival. AMPK (adenosine monophosphate-activated protein kinase) is the primary cellular energy sensor that is activated during glucose starvation. According to the current paradigm in the field, AMPK promotes autophagy in response to energy deprivation by binding and phosphorylating ULK1 (UNC-51 like kinase 1), the protein kinase responsible for autophagy initiation. However, conflicting findings have been reported casting doubts about the current established model. In our recent study, we have thoroughly reevaluated the role of AMPK in autophagy. Contrary to the current paradigm, our study revealed that AMPK functions as a negative regulator of ULK1 activity. The study has elucidated the underlying mechanism and demonstrated the significance of the negative role in controlling autophagy and maintaining cellular resilience during energy depletion.Abbreviations: AMPK: adenosine monophosphate-activated protein kinase; ULK1: UNC-51 like kinase 1; MTORC1: mechanistic target of rapamycin complex 1; ATG14: autophagy-related protein 14; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; ATP: adenosine triphosphate; VPS34: vacuolar protein sorting 34; BECN1: Beclin 1; AMPKα: AMPK catalytic subunit α; LKB1: liver kinase B1; PIK3R4: phosphatidylinositol 3-kinase regulatory subunit 4.

Molecular mechanisms underlying the vulnerability of Pacific abalone (Haliotis discus hannai) to Vibrio harveyi infection at higher water temperature.

Climate change is one of the most important threats to farmed abalone worldwide. Although abalone is more susceptible to vibriosis at higher water temperatures, the molecular mode of action underlying this has not been fully elucidated. Therefore, this study aimed to address the high susceptibility of Halitotis discus hannai to V. harveyi infection using abalone hemocytes exposed to low and high temperatures. Abalone hemocytes were divided into four groups, 20C, 20 V, 25C, and 25 V, depending on co-culture with (V)/without (C) V. harveyi (MOI = 12.8) and incubation temperature (20 °C or 25 °C). After 3 h of incubation, hemocyte viability and phagocytic activity were measured, and RNA sequencing was performed using Illumina Novaseq. The expression of several virulence-related genes in V. harveyi was analyzed using real-time PCR. The viability of hemocytes was significantly decreased in the 25 V group compared to cells in the other groups, whereas phagocytic activity at 25 °C was significantly higher than at 20 °C. Although a number of immune-associated genes were commonly upregulated in abalone hemocyte exposed to V. harveyi, regardless of temperature, pathways and genes regarding pro-inflammatory responses (interleukin-17 and tumor necrosis factor) and apoptosis were significantly overexpressed in the 25 V group compared to the 25C group. Notably, in the apoptosis pathway, genes encoding executor caspases (casp3 and casp7) and pro-apoptotic factor, bax were significantly up-regulated only in the 25 V group, while the apoptosis inhibitor, bcl2L1 was significantly up-regulated only in the 20 V group compared to the control group at the respective temperatures. The co-culture of V. harveyi with abalone hemocytes at 25 °C up-regulated several virulence-related genes involved in quorum sensing (luxS), antioxidant activity (katA, katB, and sodC), motility (flgI), and adherence/invasion (ompU) compared to those at 20 °C. Therefore, our results showed that H. discus hannai hemocytes exposed to V. harveyi at 25 °C were highly stressed by vigorously activated inflammatory responses and that the bacterial pathogen overexpressed several virulence-related genes at the high temperature tested. The transcriptomic profile of both abalone hemocytes and V. harveyi in the present study provide insight into differential host-pathogen interactions depending on the temperature conditions and the molecular backgrounds related to increased abalone vulnerability upon global warming.

Ophthalmologic clinical features of ocular myasthenia gravis.

To investigate the clinical features of ocular myasthenia gravis (OMG) in ophthalmology. A total of 28 patients with ptosis or diplopia who were followed for at least 6 months between March 2016 and February 2022 were included in this study. The clinical symptoms of the patients and test results were analyzed. According to the positivity of serologic or electrophysiologic test, these patients were divided into 2 groups (positive and negative OMG results) and according to the clinical symptoms of diplopia or ptosis for comparison. Ptosis, diplopia, and both ptosis and diplopia were present in 6 (21.43%), 14 (50.0%), and 8 (28.57%) patients, respectively. Acetylcholine receptor auto-antibody (AchR Ab) was positive in 16 (57.14%) of 28 patients and the ice test was positive in 13 (92.86%) of 14 patients with ptosis. Abnormal thymic lesions were presented in 7 (25.0%) patients, and a definite improvement in response to pyridostigmine was observed in 27 (100.0%) patients. Both ptosis and diplopia were significantly higher in the group with positive results than that in the negative results group (P = .025). In addition, both horizontal and vertical diplopia was significantly higher in the group with AchR Ab titer > 5.0 than that in the group with AchR Ab titer < 5.0 (P = .041). After excluding cranial nerve palsy, if there is ptosis and diplopia, especially vertical diplopia, the possibility of OMG should be considered.

A 17-Year-Old Girl Diagnosed With STING-Associated Vasculopathy With Onset in Infancy (SAVI) After Lung Transplantation.

CASE PRESENTATION: A 17-year-old girl received lung transplantation after chronic respiratory failure. She developed a fever (> 38 °C) once or twice weekly starting 2 months after surgery, and multiple papulopustules on the skin waxed and waned for 4 months. She then developed blood-tinged sputum. She had been treated with triple immunosuppressants, including prednisolone, tacrolimus, and mycophenolate mofetil after lung transplantation, and her symptoms appeared during prednisolone dose reduction.

Prognostic impact of preoperative respiratory colonization on early-onset pneumonia after lung transplantation.

Background: The number of lung transplantation procedures is rapidly increasing worldwide. Little is known about the effect of perioperative respiratory microbial colonization on pneumonia during lung transplantation. We evaluated the microbiome composition and incidence of early pneumonia in patients undergoing lung transplantation. We investigated factors related to post-transplant pneumonia (PTP) after lung transplantation. Methods: A retrospective analysis of patients subjected to lung transplantation between May 2013 and December 2019 was performed. Perioperative microbial colonization, and its relationship with early pneumonia, were examined in specimens from bronchial washing, bronchoalveolar lavage, and sputum aspiration before and after surgery. One-year mortality, as the primary outcome, was analyzed using the Kaplan-Meier curve model. Results: Among 76 patients who underwent lung transplantation, 34 donors (44.7%) and 28 recipients (36.8%) showed positive respiratory cultures with respect to preoperative respiratory colonization. A separate analysis of donors and recipients showed that 42 donors and 48 recipients were in respiratory non-colonized state, and 28 (53.8%) donors and 36 (69.2%) recipients survived 1 year after lung transplantation. Acinectobacter baumannii was the most common respiratory multidrug-resistant (MDR) pathogen. PTP was significantly lower in the survivor group (38.5% vs. 70.8%, P=0.009). Out of the recipients with preoperative respiratory colonization, 57.1% survived 1 year after lung transplantation. Patients with PTP had significantly higher 1-year mortality than those without PTP (P=0.009). Preoperative respiratory colonization of the recipients (P=0.010) and PTP patients (P=0.005) was associated with high 1-year mortality rate. Perioperative respiratory colonization of donors was not associated with the incidence of PTP and 1-year survival. Conclusions: Perioperative colonization of recipients was a powerful predictive factor for PTP, which was associated with 1-year mortality in patients subjected to lung transplantation. Our results suggest that donor acceptance criteria may change to better address potential shortages in organ donation.

Red sea bream interleukin (IL)-1ß and IL-8 expression, subcellular localization, and antiviral activity against red sea bream iridovirus (RSIV).

Interleukin-1 beta (IL-1ß) is transcribed by monocytes, macrophages, and dendritic cells in response to activation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) or cytokine signalling and causes a rapid inflammatory response to infection. IL-8, also known as chemokine C-X-C motif ligand (CXCL)-8, is regulated by IL-1ß and affects the chemotaxis of macrophages and neutrophils upon pathogen infection. In healthy red sea bream, rsbIL-1ß is most highly distributed in the liver, and rsbIL-8 is most highly distributed in the head kidney. In response to RSIV infection, rsbIL-1ß and rsbIL-8 mRNA are significantly upregulated in the kidney and spleen. This may be because the primary infection targets of RSIV are the kidney and spleen. In the gills, both genes were significantly upregulated at 7 days after RSIV infection and may be accompanied by a cytokine storm. In the liver, both genes were significantly downregulated at most observation points, which may be because the immune cells such as macrophages and dendritic cells expressing rsbIL-1ß or rsbIL-8 migrated to other tissues because the degree of RSIV infection was relatively low. Using a GFP fusion protein, it was confirmed that rsbIL-1ß and rsbIL-8 were localized to the cytoplasm of Pagrus major fin (PMF) cells. RsbIL-1ß overexpression induced the expression of interferon gamma (IFN-γ), myxovirus-resistance protein (Mx) 1, IL-8, IL-10, TNF-α, and MyD88, while rsbIL-8 overexpression induced the expression of IFN-γ, Mx1, rsbIL-1ß and TNF-α. In addition, overexpression of both genes significantly reduced the genome copies of RSIV and significantly reduced the viral titers. Therefore, rsbIL-1ß and rsbIL-8 in red sea bream play an antiviral role against RSIV through their normal signalling.

Identification and characterization of warm temperature acclimation proteins (Wap65s) in rainbow trout (Oncorhynchus mykiss).

Hemopexin is a vital glycoprotein for processing excessive iron in blood and functions as an iron scavenger in mammals. Teleosts however, unlike mammals, have two known hemopexin paralogs called warm temperature acclimation-related 65 kDa protein (Wap65-1 and Wap65-2, collectively termed Wap65s). Although Wap65s in rainbow trout have been considered notable biomarkers with significantly higher and/or lower expression under conditions of stress or disease, the individual roles, similarities and differences between the two paralogs are not well known. The aim of this study was to gain an understanding of the characteristics and functions of trout Wap65s from the perspective of iron-metabolism, physiological roles, and relevant immunological responses. The expression of Wap65-1 and -2 in this study was determined in the face of challenges by Aeromonas salmonicida, infectious hematopoietic necrosis virus (IHNV), and iron-dextran. Immuno-histochemistry (IHC) was employed to localize the major cell types for Wap65-2 expression, and trout leukocytes were isolated and incubated with LPS and OxLDL for comprehending the immunological characteristics of Wap65-2. We demonstrate that Wap65-1 is expressed only in the liver but Wap65-2 is systemically expressed in most organs and tissues. Interestingly, Wap65-1 expression was not significantly changed under A. salmonicida and iron-dextran administration, but was significantly decreased under IHNV. In contrast, Wap65-2 was up-regulated in all challenged groups, however with different expression patterns in the blood and liver. These results suggested that the two paralogs may participate in different biological roles. IHC showed that Wap65-2 antibody had high affinity for leukocyte-like cells, and macrophages but not lymphocytes significantly increased expression under LPS and OxLDL stimulation. These results support the conclusion that trout Wap65-2, not Wap65-1 may have conventional hemopexin functions such as reported in mammals including effects on iron metabolism, inflammation, and acute-phase protein.

Impact of the Coronavirus Disease Pandemic on Patients with Head Injuries in South Korea.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic is affecting the characteristics of patients with head injuries. This study aimed to evaluate the effect of the COVID-19 pandemic on patients with head injuries at a regional emergency medical center in South Korea. METHODS: From April 2019 to November 2020, 350 patients with head injuries were admitted to our hospital. The study period was divided into the pre-COVID-19 (n=169) and COVID-19 (n=181) eras (10 months each). Patients with severe head injuries requiring surgery (n=74) were categorized into those who underwent surgery (n=41) and those who refused surgery (n=33). RESULTS: Head injuries in pediatric patients (<3 years) were more frequent in the COVID-19 era than in the pre-COVID-19 era (8.8% vs. 3.6%, p=0.048). More patients refused surgery in the COVID-19 era than in the pre-COVID-19 era (57.9% vs. 30.6%, p=0.021). Refusal of surgery was associated with old age (67.7±14.5 vs. 52.4±19.1, p<0.001), marital status (married, 84.8% vs. 61.0%, p=0.037), unemployment (42.4% vs. 68.3%, p=0.034), COVID-19 era (66.7% vs. 39.0%, p=0.021), and lower Glasgow coma scale scores (6.12±3.08 vs. 10.6±3.80, p<0.001). Multivariable logistic regression analysis revealed that refusal of surgery was independently associated with old age (adjusted odds ratio [OR], 1.084; 95% confidence interval [CI], 1.030-1.140; p=0.002), COVID-19 era (adjusted OR, 6.869; 95% CI, 1.624-29.054; p=0.009), and lower Glasgow coma scale scores (adjusted OR, 0.694; 95% CI, 0.568-0.848; p<0.001). CONCLUSION: We observed an increased prevalence of head injuries in pediatric patients (<3 years) during the COVID-19 pandemic. Additionally, among patients with severe head injuries requiring surgery, more patients refused to undergo surgery during the COVID-19 pandemic.

Successful Lung Transplantation From a Donor Who Had Recovered From Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia.

During the present coronavirus disease 2019 (COVID-19) pandemic, transplantation of donor lungs using patients with a history of COVID-19 infection is a critical issue. Donor-derived virus infection and graft dysfunction are possible after transplantation. However use of such lungs could save the lives of patients requiring emergency transplantation. We successfully transplanted lungs from a brain-dead donor who had recovered from severe acute respiratory syndrome coronavirus 2 into a severe respiratory failure patient supported with extracorporeal membrane oxygenation who needed an emergency transplant. At the 3-month follow-up our patient showed no evidence of COVID-19 transmission or graft dysfunction.

Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies.

Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (α-DG). Mutations in FKRP are associated with muscular dystrophies (MD) ranging from limb-girdle LGMDR9 to Walker-Warburg Syndrome (WWS), a severe type of congenital MD. Although hypoglycosylation of α-DG is the main hallmark of this group of diseases, a full understanding of the underlying pathophysiology is still missing. Here, we investigated molecular mechanisms impaired by FKRP mutations in pluripotent stem (PS) cell-derived myotubes. FKRP-deficient myotubes show transcriptome alterations in genes involved in extracellular matrix receptor interactions, calcium signaling, PI3K-Akt pathway, and lysosomal function. Accordingly, using a panel of patient-specific LGMDR9 and WWS induced PS cell-derived myotubes, we found a significant reduction in the autophagy-lysosome pathway for both disease phenotypes. In addition, we show that WWS myotubes display decreased ERK1/2 activity and increased apoptosis, which were restored in gene edited myotubes. Our results suggest the autophagy-lysosome pathway and apoptosis may contribute to the FKRP-associated MD pathogenesis.

Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma.

Ferroptosis is caused by the iron-mediated accumulation of lipid peroxidation, which is distinct from apoptosis and necroptosis. Necrostatin-1 inhibits receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to initiate necroptosis; it also inhibits indoleamine 2,3-dioxygenase (IDO) to regulate tumor immunity. However, few studies have examined the off-target effect of necrostatin-1 on the ferroptosis pathway. The present study examined whether necrostatin-1 could interrupt ferroptosis induced by system xc- inhibitors (sulfasalazine and erastin) and a glutathione peroxidase 4 inhibitor (RSL3) in Huh7 and SK-HEP-1 cells. Necrostatin-1 completely prevented decreases in cell viability induced by sulfasalazine and erastin; it partially blunted decreases in cell viability induced by RSL3. Necrostatin-1, ferrostatin-1, and deferoxamine repressed sulfasalazine-provoked membrane permeabilization, as detected by 7-aminoactinomycin D staining and lipid peroxidation measured using a C11-BODIPY probe. However, other RIPK1 inhibitors (necrostatin-1s and GSK2982772) and an IDO inhibitor (1-methyl-D-tryptophan) did not recover the decrease in cell viability induced by sulfasalazine. Necrostatin-1 potentiated sulfasalazine-induced expression of xCT, a catalytic subunit of system xc- in these cells. These results demonstrated that necrostatin-1 blocked ferroptosis through a mechanism independent from RIPK1 and IDO inhibition in Huh7 and SK-HEP-1 cells, indicating that its antioxidant activity should be considered when using necrostatin-1 as a RIPK1 inhibitor.