Efficacy of the Stripped AFX Aortic Cuff as a Scaffolding Bare Stent to Facilitate the Expansion of the Thoracoabdominal and Visceral Aorta during Thoracic Endovascular Aortic Repair for Complicated Stanford Type B Aortic Dissection.

Purpose: During thoracic endovascular aortic repair for complicated Stanford type B aortic dissection, large bare stent placement for the abdominal aorta is sometimes necessary. In smaller abdominal aortic diameter cases, we used the stripped AFX aortic cuff as a scaffolding bare stent rather than the Zenith Dissection Endovascular Stent, which is a commercially available, large bare stent. In this study, we evaluated the feasibility of the stripped AFX aortic cuff and experiments were conducted to compare the stripped AFX and the Zenith Dissection Endovascular Stent. Material and Method: The type B aortic dissection patients treated with thoracic endovascular aortic repair using stripped AFX at three institutions between January 2014 and December 2017 were retrospectively reviewed. Clinical data, including technical success, perioperative complication, and overall survival, were evaluated. The experiment assessed the chronic outward force that reflected the load acting on the artery wall from the stent. Result: Eight cases (seven males) were reviewed. The median (interquartile range, IQR) age of the patients was 60 years (46.3-70.3). The technical success rate was 100%, and no perioperative complications were observed. The median (IQR) follow-up period was 28.9 months (17.5-31.5). During the follow-up, one patient died of septic shock unrelated to aortic events. The median (IQR) diameter of the stripped AFX on the last follow-up CT was 23.5 mm (21.9-25.0). The chronic outward force of the Zenith Dissection Endovascular Stent was two to three times that of the stripped AFX. Conclusions: The stripped AFX aortic cuff is feasible and safe as a scaffolding stent during thoracic endovascular aortic repair for Stanford Type B aortic dissection.

A Novel Characteristic Gastric Mucus Named "Web-like Mucus" Potentially Induced by Vonoprazan.

Background: In the absence of Helicobacter pylori (HP) infection, a characteristic gastric mucus adhesion may appear during the use of vonoprazan. We named this novel characteristic mucus "web-like mucus" (WLM). This study aimed to determine the incidence and risk factors for WLM. Methods: Between January 2017 and January 2022, 5665 patients were enrolled in this study. The patients were divided into a proton-pump inhibitor (PPI)-prescribed group (n = 2000), a vonoprazan-prescribed group (n = 268), and a no-PPI/vonoprazan-prescribed (n = 3397) group, and the presence of WLM was examined. After excluding four patients with autoimmune gastritis, the remaining 264 patients in the vonoprazan group were divided into WLM and non-WLM groups, and their clinical features were analyzed. Results: A total of 55 (21%) patients had WLM, all in the vonoprazan-prescribed group. There were no significant differences in factors such as, sex, age, chronic kidney disease, diabetes mellitus, HP eradication history, smoking, or alcohol consumption between the WLM and non-WLM groups. The median duration from the start of vonoprazan administration to the endoscopic detection of WLM was 2 (1-24) months. Conclusions: WLM appears to be a characteristic feature in patients treated with vonoprazan.

Activation of STING in pancreatic cancer-associated fibroblasts exerts an antitumor effect by enhancing tumor immunity.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate; therefore, the development of effective treatments is a priority. The stimulator of interferon genes (STING) pathway enhances tumor immunity by inducing the production of type 1 interferon (IFN) and proinflammatory cytokines and chemokines and promoting the infiltration of cytotoxic T cells. To assess the function of STING on pancreatic tumorigenesis, Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP mice (KPC mice) and Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP/STING-/- mice (KPCS mice) were generated. However, STING deletion did not affect pancreatic tumorigenesis in mice. Because STING is expressed not only in immune cells but also in cancer-associated fibroblasts (CAFs), we evaluated the STING function in PDAC CAFs. A mouse STING agonist 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA) was administered to KPC mice and CAFs from KPC mice and the resulting immune response was evaluated. DMXAA activated STING in PDAC CAFs in KPC mice, promoting cytotoxic T cell infiltration by secreting proinflammatory cytokines and enhancing tumor immunity. We next generated STING-deficient PDAC cells and subcutaneous tumors in which STING was expressed only in CAFs by performing bone marrow transplantation and assessed the antitumor effect of STING-activated CAFs. The administration of DMXAA to subcutaneous tumors expressing STING only in CAFs sustained the antitumor effect of DMXAA. About half of human PDACs lacked STING expression in the cancer stroma, suggesting that STING activation in PDAC CAFs exerts an antitumor effect, and STING agonists can be more effective in tumors with high than in those with low STING expression in the stroma.

Potential indication of chemotherapy for hypodipsia and arginine vasopressin deficiency secondary to hypothalamic-pituitary Langerhans cell histiocytosis: a case report and literature review.

Hypothalamic-pituitary Langerhans cell histiocytosis (HP-LCH) is often associated with arginine vasopressin deficiency (AVD). Patients with AVD caused by HP-LCH rarely develop an impaired osmotic threshold for thirst (OTT). Improvement in OTT among such patients has not been reported in the literature. To our knowledge, here we report the first case of AVD due to HP-LCH in which hypodipsia resolved during chemotherapy. A nine-year-old Japanese girl presented with polydipsia, polyuria, anorexia, and hypernatremia (149.8 mEq/L) and was diagnosed with AVD secondary to HP-LCH. Visual analog scale examination showed a reduced OTT following the water deprivation test. During chemotherapy for Langerhans cell histiocytosis (LCH), serum sodium concentrations became stable between 138.9 and 142.9 mEq/L under the replacement of desmopressin. Repeated visual analog scale examinations showed that she experienced a sense of thirst at a serum sodium concentration of 142.3-144.6 mEq/L, at which she did not experience any thirst prior to the initiation of chemotherapy. These data suggest that chemotherapy directly improved the OTT in our patient. Improved mechanical compression or infiltration of the hypothalamus related to OTT may lead to the recovery of the sense of thirst. This report highlights the potential role of chemotherapy for solitary HP-LCH in patients with hypodipsia and AVD.

Characteristic external genitalia in male neonates with 5α-reductase deficiency.

There have been no reports comparing neonatal external genitalia of 5α-reductase deficiency (5αRD) with those of other 46,XY differences of sex differentiation (DSD). This study enrolled 31 Japanese cases of 46,XY DSD whose external genitalia was examined during the neonatal period; four were diagnosed as 5αRD and 15 were defined as non-5αRD by genetic analysis of SRD5A2 or urinary steroid metabolites. We compared the following characteristics between 5αRD and non-5αRD groups, adjusting the severity of undermasculinization of the external genitalia: stretched penile length (SPL), glans width, location of the external urethral opening, and proportion of undescended testis. The external genitalia of all the 5αRD cases were Quigley classification grade 2 or 3. We compared the phenotypes between the four 5αRD cases and 11 non-5αRD cases with grade 2 or 3. The median (range) of SPL in the 5αRD group (14 mm [11-16]) was significantly lower than that in the non-5αRD group (22 mm [15-29]) (p = 0.003). An SPL cut-off value of <15 mm yielded a sensitivity of 50% (95% confidence interval [CI]; 7-93%) and specificity of 100% (95% CI, 72-100%) for discriminating between the groups. The median glans width, location of the external urethral opening, and proportion of undescended testis were not significantly different between the groups. The SPL of 5αRD in Quigley classification grade 2 or 3 was significantly shorter than that of other 46,XY DSDs with the equivalent grade.

Identification of amino acids in transmembrane domains of mutated cytokine receptor-like factor 2 and interleukin-7 receptor α required for constitutive signal transduction.

Cytokine receptor-like factor 2 (CRLF2) and interleukin-7 receptor α (IL-7Rα) form a receptor for thymic stromal lymphopoietin (TSLP). A somatic mutation consisting of the substitution of five amino acids (SLLLL) in the transmembrane domain of CRLF2 with three amino acids, including glutamic acid, isoleucine, and methionine (insEIM), which has been identified in acute lymphocytic leukemia, causes the TSLP-independent dimerization with IL-7Rα and activation. However, the dimerization mechanism remains unclear. In this study, we examined the involvement of the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα in TSLP-independent activation. HEK293 cells were transfected with vectors encoding CRLF2 and IL-7Rα, or their mutants, in which the amino acid of the transmembrane domain was replaced with alanine. STAT5 phosphorylation was detected using western blotting, and receptor dimerization was analyzed using the NanoBiT assay. The substitution of glutamic acid within the insEIM mutation for alanine failed to cause the STAT5 phosphorylation in the absence of TSLP. Moreover, the alanine substation of the specific leucine residues in the transmembrane domains of both CRLF2 and IL-7Rα abrogated the TSLP-independent signal transduction and dimerization. The mutation of IL-7Rα W264 partially reduced the phosphorylation of STAT5 without affecting receptor dimerization. These results suggest that the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα play at least three possible functions: interaction through hydrogen bonds, hydrophobic interaction, and signal transduction. Our findings contribute to a better understanding of the function of the transmembrane domains of cytokine receptors in their dimerization and signal transduction.

Effects of Short-Term Lenvatinib Administration Prior to Transarterial Chemoembolization for Hepatocellular Carcinoma.

AIM: Transarterial chemoembolization (TACE) combined with lenvatinib, employing a 4-day lenvatinib administration followed by TACE without an interval (short-term LEN-TACE), was performed for hepatocellular carcinoma (HCC). The aim was to assess tumor hemodynamics following the 4-day lenvatinib and to evaluate the treatment outcomes after the short-term LEN-TACE. METHODS: 25 unresectable HCC patients received this combined therapy. Lenvatinib (4-12 mg) was administrated for 4 days prior to TACE. Perfusion CT scans were obtained before and after the lenvatinib administration. Either cTACE (76%) or DEB-TACE (24%) were performed. RESULTS: intra-tumor blood flow significantly decreased after the 4-day lenvatinib (p < 0.05). The TACE procedure was successful with no severe adverse events in all patients. The overall complete response (CR) rate was 75% (cTACE 84%, DEB-TACE 40%). The lipiodol-washout ratio between 1 week and 4 months after cTACE correlated with the arterial flow reduction ratio by lenvatinib prior to TACE (r = -0.55). The 12-month progression-free survival (PFS) rate was 75.0%. CONCLUSIONS: The short-term LEN-TACE is feasible and safe, demonstrating promising outcomes with a high CR ratio, contributing to lipiodol retention in the tumor after cTACE, and extended PFS. To confirm the advantages of this treatment protocol, a prospective clinical trial is mandatory.

Machine Learning to Improve Accuracy of Transcutaneous Bilirubinometry.

INTRODUCTION: This study aimed to develop models for predicting total serum bilirubin by correcting errors of transcutaneous bilirubin using machine learning based on neonatal biomarkers that could affect spectrophotometric measurements of tissue bilirubin. METHODS: This retrospective study included infants born at our hospital (≥36 weeks old, ≥2,000 g) between January 2020 and December 2022. Infants without a phototherapy history were included. Robust linear regression, gradient boosting tree, and neural networks were used for machine learning models. A neural network, inspired by the structure of the human brain, was designed comprising three layers: input, intermediate, and output. RESULTS: Totally, 683 infants were included. The mean (minimum-maximum) gestational age, birth weight, participant age, total serum bilirubin, and transcutaneous bilirubin were 39.0 (36.0-42.0) weeks, 3,004 (2,004-4,484) g, 2.8 (1-6) days of age, 8.50 (2.67-18.12) mg/dL, and 7.8 (1.1-18.1) mg/dL, respectively. The neural network model had a root mean square error of 1.03 mg/dL and a mean absolute error of 0.80 mg/dL in cross-validation data. These values were 0.37 mg/dL and 0.28 mg/dL, smaller compared to transcutaneous bilirubin, respectively. The 95% limit of agreement between the neural network estimation and total serum bilirubin was -2.01 to 2.01 mg/dL. Unnecessary blood draws could be reduced by up to 78%. CONCLUSION: Using machine learning with transcutaneous bilirubin, total serum bilirubin estimation error was reduced by 25%. This integration could increase accuracy, lessen infant discomfort, and simplify procedures, offering a smart alternative to blood draws by accurately estimating phototherapy thresholds.

Cytochrome c oxidase subunit I gene in Thalassiosira nordenskioeldii strains inhabiting in cold and warm sea waters.

From the biota beneath the sea ice in Lake Saroma, which is adjacent to Sea of Okhotsk, a diatom culture of Saroma 16 was isolated. Strutted processes and a labiate process in Saroma 16 were characteristic of those in Thalassiosira nordenskioeldii. Similarity search analysis showed that the 826-bp rbcL-3P region sequence of this strain was 100% identical to multiple sequences registered as T. nordenskioeldii in a public database. The 4305-bp PCR-amplified mitochondrial cytochrome c oxidase subunit I (COI) gene (COI)-5P region of Saroma 16 included a 1060-bp open reading frame (ORF), which was interrupted by 934-bp and 2311-bp introns that included frame-shifted ORFs encoding reverse-transcriptase (RTase)-like proteins. Previous reports showed that a strain of the same species, CNS00052, originating from the East China Sea included no introns in the COI, whereas North Atlantic Ocean strains of the same species, such as CCMP992, CCMP993, and CCMP997, included a 2.3-kb intron in the same position as Saroma 16.

Implementation of the Time-Dependent Complete-Active-Space Self-Consistent-Field Method for Diatomic Molecules.

We present a computational approach that implements the time-dependent complete-active-space self-consistent-field method, as introduced in [Phys. Rev. A 88, 023402 (2013)]. Our implementation addresses the challenge of diatomic molecules subjected to an intense laser pulse by considering the full dimensionality of the problem using prolate spheroidal coordinates. The method incorporates the gauge-invariant frozen-core approximation, boosts the evaluation of the electron-electron interaction term using finite-element discrete-variable representation with Neumann expansion, and utilizes an exponential time differencing scheme tailored for the stable propagation of the stiff nonlinear orbital functions. We have successfully applied this methodology to study high-harmonic generation in diatomic molecules such as H2, LiH, and N2, shedding light on the impact of electron correlations in these systems.

DHX37 Variant is One of Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome / Partial Gonadal Dysgenesis without Müllerian Derivatives.

INTRODUCTION: The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. The clinical phenotype of TRS often overlaps with that of partial gonadal dysgenesis (PGD). Previous studies have demonstrated a causal association between TRS/PGD and heterozygous missense variants of DHX37. METHODS: We enrolled 11 Japanese 46,XY individuals (from 10 families) with TRS/PGD who exhibited undetected or hypoplastic testes, Müllerian duct regression, and low serum testosterone or anti-Müllerian hormone levels. The subjects underwent targeted sequencing of 36 known causative genes for DSD, PCR-based Sanger sequencing of DHX37, or whole exome sequencing. RESULTS: Previously described pathogenic variants or novel nonsense variants (SRY, NR5A1, and DMRT1) were observed in four out of 10 families. Additionally, we identified two heterozygous rare variants of DHX37 in four families: a previously reported pathogenic variant (c.923G>A, p.Arg308Gln) in three and a novel likely pathogenic variant (c.1882A>C, p.Thr628Pro) in one. The external genitalia of patients with the DHX37 variants varied from female-type to male-type without micropenis. Eighty percent of Japanese patients with TRS/PGD had monogenic disorders including DHX37 variant being the most commonly identified (40%). The external or internal genital phenotype of TRS/PGD overlaps between DHX37 variant carriers and others. CONCLUSIONS: DHX37 variant is one of common genetic causes in Japanese patients with TRS/PGD without Müllerian derivatives. Genetic test is helpful in detecting DHX37-related TRS/PGD, because of the phenotypic diversity of the external genitalia in this disorder.

RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review.

Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset growth failure, metaphyseal dysplasia, hair hypoplasia, immunodeficiency, and other extraskeletal manifestations. Herein, we report six Japanese individuals with CHH from four families. All probands presented with moderate short stature with mild metaphyseal dysplasia or brachydactyly. One of them had hair hypoplasia and the other immunodeficiency. By contrast, the affected siblings of two families showed only mild short stature. We also reviewed all previously reported 13 Japanese individuals. No n.71A > G allele was detected. The proportions of Japanese versus Finnish individuals were 0% versus 70% for birth length < -2.0 SD, 84% versus 100% for metaphyseal dysplasia and 26% versus 88% for hair hypoplasia. Milder manifestations in the Japanese individuals may be related to the difference of genotypes. The mildest form of CHH phenotypes is mild short stature without overt skeletal alteration or extraskeletal manifestation and can be termed "RMRP-related short stature".

Suppressed pediatric asthma hospitalizations during the COVID-19 pandemic in Japan, from a national survey.

BACKGROUND: Acute asthma exacerbation in children is often caused by respiratory infections. In this study, a coordinated national surveillance system for acute asthma hospitalizations and causative respiratory infections was established. We herein report recent trends in pediatric acute asthma hospitalizations since the COVID-19 pandemic in Japan. METHODS: Thirty-three sentinel hospitals in Japan registered all of their hospitalized pediatric asthma patients and their causal pathogens. The changes in acute asthma hospitalization in children before and after the onset of the COVID-19 pandemic and whether or not COVID-19 caused acute asthma exacerbation were investigated. RESULTS: From fiscal years 2010-2019, the median number of acute asthma hospitalizations per year was 3524 (2462-4570), but in fiscal years 2020, 2021, and 2022, the numbers were 820, 1,001, and 1,026, respectively (the fiscal year in Japan is April to March). This decrease was observed in all age groups with the exception of the 3- to 6-year group. SARS-CoV-2 was evaluated in 2094 patients from fiscal years 2020-2022, but the first positive case was not detected until February 2022. Since then, only 36 of them have been identified with SARS-CoV-2, none of which required mechanical ventilation. Influenza, RS virus, and human metapneumovirus infections also decreased in FY 2020. In contrast, 24% of patients had not been receiving long-term control medications before admission despite the severity of bronchial asthma. CONCLUSION: SARS-CoV-2 was hardly detected in children with acute asthma hospitalization during the COVID-19 pandemic. This result indicated that SARS-CoV-2 did not induce acute asthma exacerbation in children. Rather, infection control measures implemented against the pandemic may have consequently reduced other respiratory virus infections and thus acute asthma hospitalizations during this period. However, the fact that many hospitalized patients have not been receiving appropriate long-term control medications is a major problem that should be addressed.