Mechanism of action of adapalene for treating EGFR-TKI-induced skin disorder.

BACKGROUND: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. METHODS: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1ß. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. RESULTS: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. CONCLUSION: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.

Temporal Trend of the SARS-CoV-2 Omicron Variant and RSV in the Nasal Cavity and Accuracy of the Newly Developed Antigen-Detecting Rapid Diagnostic Test.

The aim of this work is to analyze the viral titers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) at the anterior nasal site (ANS) and nasopharyngeal site (NS), evaluate their virological dynamics, and validate the usefulness of a newly developed two-antigen-detecting rapid antigen diagnostic test (Ag-RDT) that simultaneously detects SARS-CoV-2 and RSV using clinical specimens. This study included 195 asymptomatic to severely ill patients. Overall, 668 specimens were collected simultaneously from the ANS and NS. The cycle threshold (Ct) values calculated from real-time polymerase chain reaction were used to analyze temporal changes in viral load and evaluate the sensitivity and specificity of the Ag-RDT. The mean Ct values for SARS-CoV-2-positive, ANS, and NS specimens were 28.8, 28.9, and 28.7, respectively. The mean Ct values for RSV-positive, ANS, and NS specimens were 28.7, 28.8, and 28.6, respectively. SARS-CoV-2 and RSV showed the same trend in viral load, although the viral load of NS was higher than that of ANS. The sensitivity and specificity of the newly developed Ag-RDT were excellent in specimens collected up to 10 days after the onset of SARS-CoV-2 infection and up to 6 days after the onset of RSV infection.

The first case of hemorrhagic shock and encephalopathy syndrome with fulminant hypercytokinemia associated with pediatric COVID-19.

BACKGROUND: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead not only to respiratory symptoms but also to neurologic symptoms with various levels of severity. After the worldwide prevalence of Omicron variant, severe neurological manifestations of coronavirus disease 2019 (COVID-19) such as febrile seizure, demyelinating disease, and cerebrovascular disease, have been reported. However, reports of acute encephalopathy in patients with COVID-19 are quite limited. Especially in terms of cytokine storm-inducing hemorrhagic shock and encephalopathy syndrome (HSES), there is no case reported related to COVID-19. CASE PRESENTATION: We describe the case of an 8-year-old girl who presented with fatal HSES associated with pediatric SARS-CoV-2 infection. Status epilepticus occurs after the onset of fever and diarrhea and lasted for at least an hour. Unconsciousness was followed by circulatory failure and ultimately leading to death within 2 days after the fever onset. Analysis of forty-eight cytokines and chemokines measured in three consecutive serum samples revealed that interferon (IFN)-γ, interleukin (IL)-6, IL-10, IL-17A, tumor necrosis factor (TNF)-a, IL-8, Interferon gamma inducible protein (IP)-10, and Monocyte chemoattractant protein (MCP)-1, were increased within an hour after the onset of impaired consciousness. CONCLUSION: Here, we describe a case of fatal fulminant encephalopathy with rapid progression because of HSES associated with COVID-19. High levels of cytokines and chemokines observed in this case may be because of the SARS-CoV-2-associated cytokine storm. This study is the first COVID-19-associated case of HSES.

Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2022.

The members of the Japanese Society for Pediatric Infectious Diseases and the Japanese Society of Pediatric Pulmonology have developed Guidelines for the Management of Respiratory Infectious Diseases in Children with the objective of facilitating appropriate diagnosis, treatment and prevention of respiratory infections in children. The first edition was published in 2004 and the fifth edition was published in 2022. The Guideline 2022 consists of 2 parts, clinical questions and commentary, and includes general respiratory infections and specific infections in children with underlying diseases and severe infections. This executive summary outlines the clinical questions in the Guidelines 2022, with reference to the Japanese Medical Information Distribution Service Manual. All recommendations are supported by a systematic search for relevant evidence and are followed by the strength of the recommendation and the quality of the evidence statements.

Donor Foot Morbidity Following Nonvascularized Toe Phalanx Transfer Utilizing a New Reconstruction Technique.

BACKGROUNDS: Nonvascularized toe phalanx transfer is an accepted surgical option for short and hypoplastic digits in congenital hand abnormalities. However, one of the criticisms of this technique is the donor site morbidity. The purpose of this study was to evaluate donor foot morbidity after nonvascularized toe phalanx transfer using a new donor site reconstruction technique. METHODS: We retrospectively reviewed 116 nonvascularized toe phalanx transfers in 69 children between 2001 and 2020 in whom the donor foot was reconstructed with a new technique using iliac osteochondral bone graft with periosteum. Feet treated with an isolated donor proximal phalanx of the fourth toe were selected and morbidity was assessed both subjectively and objectively at a minimum of 2 years after surgery. Motion, stability, and alignment of the metatarsophalangeal joint were clinically evaluated. The relative length of the fourth toe to the third toe was measured on a roentgenogram. The satisfaction of the parents for overall function and appearance was evaluated using a visual analog scale. RESULTS: Ninety-four operated feet in 65 patients, including 43 boys and 22 girls, were included. The right foot was evaluated in 52 patients and the left foot in 42 patients. The mean age at operation was 2 years and the mean follow-up period was 7.6 years. Motion at the metatarsophalangeal joint was good at 69% with an average extension of 45 degrees and flexion of 25 degrees. Stability and alignment were good at 95% and 84%, respectively. Only 4 toes had gross instability and 4 toes with poor alignment required revision surgery. Sixty-two toes (66%) maintained proportional length and 9 toes were graded as short. Parental satisfaction was high for appearance as well as function. CONCLUSIONS: This newly described technique of using iliac osteochondral bone graft with periosteum to reconstruct toe phalanx donors provided satisfactory results. The function and appearance of the donor foot after a nonvascularized toe phalanx transfer was well preserved. LEVEL OF EVIDENCE: Level IV; therapeutic.

Impact of the omicron phase on a highly advanced medical facility in Japan.

Background: Eight waves of the coronavirus disease 2019 (COVID-19) epidemic have been observed in Japan. This retrospective study was conducted to clarify the clinical characteristics of pediatric COVID-19 patients. Methods: We studied 121 patients admitted to the Jichi Children's Medical Center Tochigi between April 2020 and March 2023. Incidence of pediatric COVID-19 in Tochigi Prefecture was used to examine hospitalization and severe illness rates. Results: The mean age of the patients was 3 years and 8 months. One hundred and eleven patients (91.7%) were hospitalized after January 2022 (after the 6th wave), when the Omicron strain became endemic in Japan. Convulsions occurred in 30 patients (24.8%), all of whom were admitted after the 6th wave. Twenty-three of the 30 patients had no underlying disease. Eleven patients (9.1%) were diagnosed with acute encephalopathy. One patient died due to hemorrhagic shock and encephalopathy syndrome and two had sequelae after the 6th wave. The patient who died due to encephalopathy had hypercytokinemia. In the Tochigi Prefecture, the number of pediatric COVID-19 patients increased after the 6th wave, but the hospitalization rate declined. The rate of severe illness did not change before the end of 5th and after the 6th wave. Conclusion: Although the rate of severe illness in patients with pediatric COVID-19 did not increase after the 6th wave, some patients had complicated critical illnesses. Systemic inflammatory reaction was considered to have been associated with the severe encephalopathy.

Distribution of cervical intraepithelial neoplasia is closely associated with HPV status and uterine position.

Although cervical intraepithelial neoplasia (CIN) lesions are considered to be not randomly distributed across the cervix, but predominantly in the anterior wall, the clinicopathological etiology remains unknown. Herein, we aimed to elucidate the relationship between quantitatively measured area of CIN2/3 and cervical cancer associated factors by retrospective cohort study. We analyzed 235 consecutive therapeutic conization specimens dissected as a single intact section to determine CIN2/3 area and its correlation with both clinical risk factors including human papillomavirus (HPV) status (single or multiple infection) and uterine position defined by transvaginal ultrasound. Cervical wall was classified into three groups: anterior: (11, 12, 1, and 2 o'clock), posterior (5, 6, 7, and 8 o'clock) and lateral (3, 4, 9, and 10 o'clock). Multiple regression revealed that younger age and HPV16 status were significantly correlated with CIN2/3 area (p = 0.0224 and p = 0.0075, respectively). The Jonckheere-Terpstra test showed a significant trend: CIN2/3 area was highest in the single HPV16 group, followed by the multiple HPV16 group and the non-HPV16 group (p < 0.0001). CIN2/3 area in the anterior wall was statistically significantly larger than the posterior and lateral wall (p = 0.0059 and p = 0.0107, respectively). CIN2/3 area in the anterior wall was significantly greater with anteversion-anteflexion than retroversion-retroflexion (p = 0.0485), whereas CIN2/3 area in the posterior wall was significantly larger with retroversion-retroflexion than anteversion-anteflexion (p = 0.0394). In conclusion, the topographical distribution of CIN2/3 area is closely associated with patient age, high-risk HPV status, especially single HPV16 infection and uterine position.

Diagnostic accuracy of a novel SARS CoV-2 rapid antigen test and usefulness of specimens collected from the anterior nasal cavity.

OBJECTIVES: We aimed to validate a newly developed antigen-detecting rapid diagnostic test (Ag-RDT) for SARS-CoV-2 using anterior nasal specimens. METHODS: Between February 12 and September 30, 2021, 16 patients (age range, <1 month-76 years) were enrolled, and samples were collected simultaneously from anterior nasal and nasopharyngeal sites continuously during hospitalization. The primary end points were the diagnostic accuracy of the Ag-RDT and utility of anterior nasal specimens. RESULTS: In total, 226 sets of paired samples were obtained. In 88.2% of specimens, the viral load was high at the nasopharyngeal site. The mean cycle threshold values for the anterior nasal and nasopharyngeal sites were 32.4 and 29.9, respectively. Using the real-time polymerase chain reaction results as a reference, the Ag-RDT showed a 100% sensitivity up to day 6 of the illness, using specimens with moderate or high viral load (cycle threshold <30) from either site. From day 7, the sensitivity was 70.4-90.6% and 83.9-84.6% for the anterior nasal and nasopharyngeal sites, respectively. The specificity remained at 100%. CONCLUSION: Our novel Ag-RDT meets the World Health Organization criteria and provides stable sensitivity and specificity and accurate results with anterior nasal specimens.

Acute Perimyocarditis in an Adolescent Japanese Male after a Booster Dose of the BNT162b2 COVID-19 Vaccine.

Perimyocarditis is a rare and serious cardiac complication following COVID-19 vaccination. Young males are most at risk after the second dose. With the introduction of the booster (third) dose, some reports have focused on the risk of perimyocarditis after a booster dose. However, no currently available report in Japan has comprehensively described this phenomenon. A healthy 14-year-old Japanese male, who had completed a two-dose primary series of the BNT162b2 (Pfizer-BioNTech) vaccine six months prior, developed fever and chest pain within 24 hours after a homologous booster dose. He was transferred to our institute because of worsening chest pain. A multiplex PCR test showed no evidence of active viral infections, including SARS-CoV-2. Electrocardiography revealed ST-segment elevation in almost all leads, suggesting pericarditis. Echocardiography showed normal systolic function. Laboratory data demonstrated C-reactive protein levels of 8.8 mg/dL and elevated cardiac damage markers (troponin T, 1.9 ng/mL; creatine phosphokinase, 1527 U/L; MB isoenzyme, 120 U/L), suggesting myocarditis. He was diagnosed with perimyocarditis associated with the booster dose, which was confirmed by cardiac magnetic resonance imaging four days after initial symptoms. Chest pain improved spontaneously along with a resolution of electrocardiographic findings and laboratory data within several days. He was discharged eight days after admission. Perimyocarditis is less frequent after a booster dose than after primary doses. In this case, the patient with booster-dose-associated perimyocarditis showed favorable clinical course without severe sequelae. The patient's clinical course was consistent with findings on previous large-scale reports on primary-dose-associated perimyocarditis and case series on booster-dose-associated perimyocarditis.

Case Report: Anterior Scleritis Presenting as a Primary Ocular Manifestation in Multisystem Inflammatory Syndrome in Children With COVID-19.

Multisystem inflammatory syndrome in children (MIS-C) is a newly defined hyperinflammatory disease linked to antecedent coronavirus disease 2019. Patients with MIS-C present with various symptoms, and ocular findings such as mild bilateral conjunctivitis are relatively common. However, detailed descriptions of severe ocular reports associated with MIS-C are scarce in the current literature. Here we report a case of MIS-C in a Japanese boy, with severe eye manifestations in the form of anterior scleritis as the primary MIS-C symptom. Detailed ocular examinations by ophthalmologists may be key for clarifying the pathophysiology of MIS-C.

Perinatal Management in a Pregnant Woman with Ureteropelvic Junction Obstruction: Case Report and Literature Review.

Although giant hydronephrosis (GH) associated with ureteropelvic junction obstruction (UPJO) is extremely rarely detected in pregnant women, diagnostic methods, therapeutic approaches, and perinatal management have not been established. A 31-year-old Japanese primipara had a 15 cm × 12 cm multi-cystic mass in the right abdomen detected by transabdominal ultrasound at gestational week 26. Magnetic resonance imaging revealed that the mass was right renal GH. She underwent serial ultrasound-guided transretroperitoneal drainage as conservative treatment. She delivered vaginally at gestational week 36. Since she had flank pain and a documented non-functional right kidney, laparoscopic nephrectomy was conducted 22 months after delivery. UPJO with fewer smooth muscle cells and fibrosis was histologically diagnosed in the surgical specimen. Her postpartum and postoperative courses were uneventful for 10 months. We performed a literature review of diagnostic methods, clinical characteristics, and perinatal management in pregnant women with GH due to UPJO.

Diagnosis and treatment of influenza based on health insurance claims between the 2010-2011 and 2019-2020 influenza seasons in Japan.

Medical practices for influenza virus infection vary among countries. In Japan, treatment with anti-influenza drugs is recommended for patients diagnosed with influenza. This health claims database study provides quantitative information aimed at describing the actual medical practices, including diagnostic testing and medication use, for managing influenza in Japan. Most patients diagnosed with influenza underwent diagnostic tests and were prescribed anti-influenza drugs. Meanwhile, the majority of patients prescribed anti-influenza drugs had undergone diagnostic testing. However, an increase in the percentage of anti-influenza prescriptions without diagnostic testing was observed during the 2019-2020 influenza season, which may be associated with the COVID-19 pandemic.

Comparison of Inconvenience Costs Between Influenza Antivirals for Japanese Pediatric Patients: A Conjoint Analysis of Parental Responses.

INTRODUCTION: Certain drug characteristics, including dosage and form, are associated with either convenience or inconvenience for the patients taking them, and any inconvenience can be considered as a "cost" in disease treatment. Multiple antivirals are available for influenza in Japan, with various dosages and forms. This study evaluated the inconvenience costs associated with influenza antivirals for pediatric patients by using conjoint analysis on responses from their parents. METHODS: An online survey (May 2021) was conducted for parents whose child took antivirals for influenza at 6-11 years during the 3 years until March 2021. Attributes of the conjoint analysis were administration routes and formulation (tablet, capsule, dry syrup, or inhalant), duration of administration, frequency of administration per day, and out-of-pocket expenses. We assumed the efficacy and safety to be equivalent among the antivirals. A logistic regression model was applied to the analysis. We also asked parents about their recent experiences with antiviral treatment for their child. RESULTS: We collected responses from 3161 eligible individuals. The mean age (standard deviation) of the children when taking the antivirals and percentage of female children were 8.27 (1.63) years old and 53.2%, respectively. The tablet was the most preferred formulation; the inconvenience costs for each administration route and formulation, relative to the tablet as zero, were Japanese yen (JPY) 515 (US dollar 4.61, as of October 2021) for the inhalant, JPY 775 for the capsule, and JPY 804 for the dry syrup. The inconvenience costs for 5 days relative to 1 day and for twice a day relative to once a day were JPY 2150 and JPY 399, respectively. CONCLUSION: Based on the conjoint analysis, a single-dose tablet antiviral was suggested to have the lowest inconvenience cost for pediatric patients. TRIAL REGISTRATION: UMIN000044243.

Severe Abdominal Recurrence of Low-grade Endometrial Stromal Sarcoma After Hysteroscopic Surgery.

BACKGROUND: Low-grade endometrial stromal sarcoma (LG-ESS) is an indolent tumor harboring gene fusion involving polycomb family genes. While early LG-ESS has a good clinical course, some tumors have pelvic recurrence. The etiology and genetic alterations involved in the process remain unknown. CASE REPORT: A 44-year-old nulliparous woman underwent hysteroscopic surgery for a 2.5 cm submucosal uterine tumor with negative endometrial cytology. Pathological evaluation revealed LG-ESS. On the 31st day, total laparoscopic hysterectomy was indicated. She was diagnosed with stage IA (pT1aNXM0) LG-ESS without lymphovascular invasion. At 4 years, positron-emission tomography showed multiple pelvic masses. Secondary debulking surgery was performed, which revealed severe intra-abdominal recurrence of LG-ESS with JAZF1-SUZ12 fusion. CONCLUSION: Hysteroscopic surgery is a convenient tool for benign uterine submucosal diseases. However, intrauterine morcellation with fluid can lead to unexpected recurrence of occult LG-ESS. It is important when seeking consent for surgery to inform patients about the possible risk of dissemination of uterine mesenchymal tumors.

Effect of Bronchial Thermoplasty on Air Trapping Assessed by Xenon Ventilation Computed Tomography.

Objective Bronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe asthma. Although it has been suggested that BT works by reducing airway smooth muscle, the detailed mechanism underlying its effects is still unknown. Methods We performed xenon ventilation computed tomography (Xe-CT) before each BT procedure and six weeks after the third treatment to assess the improvement in lung ventilation at each separate lung region. The air trapping index in each lobe was defined as the mean trapping value (0: none, 1: mild, 2: moderate, and 3: severe) of the included segments. Patients and Materials Four patients were included. Results Asthma symptoms were improved after BT. The comparison of the scores at baseline with those after the third treatment showed that the air trapping index was improved in both the treated and untreated regions. However, neither the pulmonary function nor the exhaled nitric oxide was improved. Conclusion Using Xe-CT, we successfully evaluated the air trapping in patients who underwent BT. The improvement in asthma symptoms by BT may be related to the amelioration of peripheral lung ventilation in both the treated and untreated regions.

Visual Field Test With Gaze Check Tasks: Application in a Homonymous Hemianopic Patient Unaware of the Visual Defects.

Gaze control is required for applying visual stimuli to a particular area of the visual field. We developed a visual field test with gaze check tasks to investigate hemianopia. In this test, participants must report the presence or absence of visual stimuli when a small object at the fixation point vibrates. Trials in the absence of visual stimuli were used as gaze check tasks, since the vibration could be observed only when the gaze was directed at the fixation point. We evaluated the efficacy of our test in four control participants and one patient with homonymous hemianopia who was unaware of the defects in the left visual field. This patient presented hemianopia in the test with gaze check tasks, but not when the gaze check tasks were omitted. The patient showed spontaneous gaze movements from the fixation point to the upper left direction, as well as scanning of the left visual field during the test without gaze check tasks. Thus, we concluded that the visual defects in this patient were compensated in daily life by spontaneous eye movements coordinated with visual information processing. The present results show the usefulness of the visual field test with gaze check tasks.

Lack of persisting antibody in a post-transplant patient after vaccine-strain varicella.

BACKGROUND: LAVV have historically been avoided in children after solid organ transplantation. However, it has been reported that post-transplant, children without severe immunosuppression can generate anti-varicella antibody after immunization but the duration of the response is not clear. Furthermore, the origin of the varicella virus in immunosuppressed patients who develop varicella after vaccination is often unclear. CLINICAL PROGRESS: A female child received LAVV 30 months after a living donor liver transplant at the age of 2 months. Varicella rash appeared on the trunk 16 days after vaccination and gradually spread over the body. The patient was treated with intravenous acyclovir followed by oral therapy and recovered fully. The virus detected in blisters was derived from the vaccine-type strain. Paired sera before and after the onset of varicella showed an increase in antibody titer. However, 2 years after onset, the antibody titer decreased to undetectable again. CONCLUSIONS: This was an informative case of varicella due to vaccine strain attenuated virus. Antibody levels were not maintained over many years. Although varicella was caused by the vaccine-type strain, repeated vaccinations may be necessary for post-transplant patients who develop varicella.