Successful treatment of erythema nodosum with salazosulfapyridine in a 9-year-old patient with chronic non-bacterial osteomyelitis.

We report a 9-year-old Japanese girl with chronic non-bacterial osteomyelitis (CNO) accompanied by recurrent erythema nodosum (EN) which was successfully treated with salazosulfapyridine (SASP). She was referred to our hospital because of recurrent erythema on her lower extremities and persistent knee and ankle arthralgia, which had been present for approximately one year. Although naproxen, a nonsteroidal anti-inflammatory drug (NSAID), was initiated, her symptoms frequently recurred. Magnetic resonance imaging demonstrated multiple distinct high-intensity signals in the talus bones suggestive of multiple bone edemas. Additionally, a histological examination of erythematous lesions was consistent with the histopathological findings of EN. She was diagnosed as having CNO complicated by EN, and received 250 mg/day of SASP as a second-line treatment, which showed partial response of both skin and bone lesions. Following increase in the dose of SASP to 500 mg/day resulted in complete remission of her skin and bone lesions. In conclusion, our findings suggest that SASP is effective not only for CNO bone lesions but also for EN. SASP could serve as a second-line therapeutic option at least for some cases of CNO complicated by EN refractory to NSAIDs.

A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome.

OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis.

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.

Epidemiology conduction of paediatric rheumatic diseases based on the registry database of the Pediatric Rheumatology Association of Japan.

OBJECTIVES: Although epidemiological surveys of paediatric rheumatic diseases in Japan have been conducted, they were single surveys with no continuity. This is the first report of the Pediatric Rheumatology Association of Japan registry database, which was established to continuously collect data for paediatric rheumatic diseases. METHODS: Pediatric Rheumatology International Collaborate Unit Registry version 2 (PRICUREv2) is a registry database established by the Pediatric Rheumatology Association of Japan. The registry data were analysed for the age of onset, time to diagnosis, sex differences, seasonality, and other factors. RESULTS: Our data showed the same trend regarding rates of paediatric rheumatic diseases reported in Japan and other countries. The age of onset was lower in juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis and higher in systemic lupus erythematosus and Sjögren's syndrome. The time to diagnosis was relatively short in JIA and systemic lupus erythematosus but longer in juvenile dermatomyositis and Sjögren's syndrome. Rheumatoid factor-positive polyarticular JIA showed a seasonality cluster with regard to onset. CONCLUSION: PRICUREv2 aided the retrieval and evaluation of current epidemiological information on patients with paediatric rheumatic diseases. It is expected that the data collection will be continued and will be useful for expanding research in Japan.

Spatio-temporal categorization for first-person-view videos using a convolutional variational autoencoder and Gaussian processes.

In this study, HcVGH, a method that learns spatio-temporal categories by segmenting first-person-view (FPV) videos captured by mobile robots, is proposed. Humans perceive continuous high-dimensional information by dividing and categorizing it into significant segments. This unsupervised segmentation capability is considered important for mobile robots to learn spatial knowledge. The proposed HcVGH combines a convolutional variational autoencoder (cVAE) with HVGH, a past method, which follows the hierarchical Dirichlet process-variational autoencoder-Gaussian process-hidden semi-Markov model comprising deep generative and statistical models. In the experiment, FPV videos of an agent were used in a simulated maze environment. FPV videos contain spatial information, and spatial knowledge can be learned by segmenting them. Using the FPV-video dataset, the segmentation performance of the proposed model was compared with previous models: HVGH and hierarchical recurrent state space model. The average segmentation F-measure achieved by HcVGH was 0.77; therefore, HcVGH outperformed the baseline methods. Furthermore, the experimental results showed that the parameters that represent the movability of the maze environment can be learned.

Risk Factors for Stoma Outlet Obstruction: Preventing This Complication after Construction of Diverting Ileostomy during Laparoscopic Colorectal Surgery.

Introduction: Bowel obstruction at the outlet of the stoma, also referred to as "stoma outlet obstruction" (SOO), has been noted to be more common after laparoscopic colorectal surgery with diverting ileostomy than after laparotomy. Thus, the aim of this study is to identify the risk factors for SOO and to evaluate the effectiveness of a modified ileostomy procedure for reducing its incidence. Methods: The medical records of 63 patients who underwent laparoscopic colorectal surgery with diverting ileostomy between January 2014 and July 2021 were retrospectively reviewed. We analyzed the risk factors for SOO using computed tomography findings. Results: In total, 34 patients underwent surgery before modification of the ileostomy procedure (LSa group), and 29 patients underwent surgery after modification (LSb group). In the LSa group, 6 patients have reportedly developed SOO (SOO group), whereas 28 patients did not (non-SOO group). No patients in the LSb group developed SOO. The thickness of the abdominal rectus muscle (ThM) in the SOO group and the non-SOO group was 13.4 mm and 9.6 mm, respectively (p = 0.005). The angle between the ileostomy and the abdominal wall (AIW) was 95.8° in the non-SOO group and 82.2° in the SOO group (p = 0.033). The AIW was 93.4° in the LSa group and 99.7° in the LSb group (p = 0.043). Conclusions: As per our findings, a thick abdominal rectus muscle is predictive of SOO. Correction of the AIW (eliminating medial inclination) by modifying the operative technique has eliminated the occurrence of SOO in our patient population.

Genetic analysis of human parechovirus type 5 isolated from children in Sapporo, Japan in the summer of 2018.

Human parechovirus (HPeV) types 1 and 3 are frequently detected in Japan, but HPeV5 is not detected. HPeV5 was isolated for the first time in Japan from seven clinical samples collected from children in Sapporo as part of the National Epidemiological Surveillance of Infectious Diseases from July to August in 2018. Seven HPeV5 strains that were detected in Sapporo (HPeV5 Sa) were analyzed in the VP1 region by direct sequencing using Sanger sequencing methods. Whole genome sequence of these strains was determined by next-generation sequencing. The VP1 region of HPeV5 Sa was closely related to HPeV5 strains detected in Belarus and Germany in 2018, and to those detected in Australia in 2019. The 3D polymerase region of HPeV5 Sa strains showed a high nucleotide identity to HPeV3 strain detected in Australia in 2013. These findings suggest that HPeV5 Sa is a recombinant virus of HPeV5 and HPeV3, and HPeV5 strains that are genetically closely related to each other may have circulated in Europe, Japan, and Australia between 2018 and 2019.

Successful treatment of IgA vasculitis with prolonged cutaneous manifestation with colchicine in a 10-year-old boy.

We report a 10-year-old boy with immunoglobulin (Ig)A vasculitis (IgAV) with prolonged cutaneous manifestations who was successfully treated with colchicine. At the age of 9 years, he was diagnosed as having IgAV by typical purpura, abdominal pain, and haematochezia. Initially, his severe gastrointestinal manifestation subsided by prednisolone 60 mg/day and intravenous methylprednisolone pulse therapy. However, his gastrointestinal manifestation was glucocorticoid-dependent and refractory to factor XIII concentrate, intravenous IgG, and mycophenolate mofetil. His abdominal pain and haematochezia responded to the combination therapy with dapsone and low dose of prednisolone 5 mg/day and did not relapse even after discontinuation of dapsone. On the other hand, the effect of dapsone on his cutaneous manifestation was dose-dependent as well as dapsone had no glucocorticoid-sparing effect. Approximately 12 months after onset, colchicine treatment was started, which resulted in remission of his chronic cutaneous manifestation. After prednisolone was tapered off, his cutaneous manifestation is currently well-controlled on colchicine 0.5 mg/day without adverse events. He had never complicated kidney involvements. In conclusion, it is observed that colchicine treatment exerts a beneficial effect in IgAV patients with prolonged cutaneous manifestation refractory to multiple drugs.

Development of Graves' disease during drug-free remission of juvenile dermatomyositis.

We report a Japanese boy with Graves' disease (GD) which developed during drug-free remission of juvenile dermatomyositis (JDM). He had been diagnosed with JDM at the age of 6 years by typical skin rashes, muscle weakness, elevated serum transaminase levels, and typical findings of both magnetic resonance imaging and muscle biopsy. Although anti-melanoma differentiation antigen 5 autoantibody was positive, there was no complication of interstitial lung disease. He showed good response to methylprednisolone pulse therapy followed by oral prednisolone in combination with weekly methotrexate (MTX) and achieved drug-free remission after 3.5 years of treatment. Nevertheless, serum levels of soluble interleukin-2 receptor (sIL-2R) gradually elevated to 3185 U/ml despite no signs of relapse or malignancy. Hyperactivity and attention deficit was also noted. One year and 3 months after the cessation of MTX, he presented with abdominal pain, tachycardia, and apparent goitre. Laboratory tests showed elevated free triiodothyronine, undetectable thyroid stimulating hormone (TSH), and positive anti-TSH receptor antibodies. 99mTc scintigraphy showed high levels of thyroid uptake. He was diagnosed with GD and treated with 15 mg/day of thiamazole. Although transient drug eruption was observed, his thyroid functions are currently well-controlled on 5 mg/day of thiamazole. In conclusion, to our knowledge, this is the first report in English literature describing complication of GD with JDM. Unexpected elevation of sIL-2R could be a clue to the diagnosis of GD during the follow-up of JDM.

A case of autoimmune enteropathy with CTLA4 haploinsufficiency.

Autoimmune enteropathy (AIE) is a rare disease, characterized by intractable diarrhea, villous atrophy of the small intestine, and the presence of circulating anti-enterocyte autoantibodies. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and mutations in FOXP3, which is a master gene of regulatory T cells (Tregs), are major causes of AIE. Recent studies have demonstrated that mutations in other Treg-associated genes, such as CD25 and CTLA4, show an IPEX-like phenotype. We present the case of a 13-year-old girl with CTLA4 haploinsufficiency, suffering from recurrent immune thrombocytopenic purpura and intractable diarrhea. We detected an autoantibody to the AIE-related 75 kDa antigen (AIE-75), a hallmark of the IPEX syndrome, in her serum. She responded well to a medium dose of prednisolone and a controlled dose of 6-mercaptopurine (6-MP), even after the cessation of prednisolone administration. Serum levels of the soluble interleukin-2 receptor and immunoglobulin G (IgG) were useful in monitoring disease activity during 6-MP therapy. In conclusion, autoimmune-mediated mechanisms, similar to the IPEX syndrome, may be involved in the development of enteropathy in CTLA4 haploinsufficiency. Treatment with 6-MP and monitoring of disease activity using serum levels of soluble interleukin-2 receptor and IgG is suggested for such cases.

A Serum Level of Squamous Cell Carcinoma Antigen as a Real-Time Biomarker of Atopic Dermatitis.

Background: Although serum levels of squamous cell carcinoma antigen (SCCA) are elevated in atopic dermatitis (AD), their clinical utility has not been fully elucidated. Methods: Thirty-three cases of AD who admitted to our hospital were analyzed. Results: Baseline characteristics on admission were as follows: median age 19 months [interquartile range (IQR), 12-52 months], median objective severity scoring of atopic dermatitis (O-SCORAD) 19.2 (IQR, 4.2-36.0), and median serum SCCA levels 3.2 ng/mL (IQR, 2.1-6.8 ng/mL). O-SCORAD significantly correlated with serum SCCA levels (rs = 0.865, P < 0.001). In 9 cases whose information before and after treatment was available (median interval, 3 days; IQR 2-5 days), median serum SCCA levels significantly decreased from 8.0 to 2.0 ng/mL (P = 0.008) after the treatment. Conclusions: Serum levels of total SCCA rapidly declined in response to the treatment and could be used as a real-time biomarker in childhood AD.

Primaquine plus clindamycin as a promising salvage therapy for Pneumocystis jirovecii pneumonia: A retrospective analysis in Japanese patients.

Treatment of intractable Pneumocystis jirovecii pneumonia (PCP) patients with primaquine (PQ) in combination with clindamycin (CLDM) was conducted by the Research Group on Chemotherapy of Tropical Diseases (RG-CTD), as a kind of compassionate use. Primaquine was not nationally licensed at the time but imported by RG-CTD for the use in a clinical research to investigate safety and efficacy in malaria treatment. Eighteen Japanese adult patients thus treated were analyzed. Prior to the treatment with PQ-CLDM, most of the patients had been treated with trimethoprim-sulfamethoxazole first, all of which being followed by pentamidine and/or atovaquone treatment. This combination regimen of PQ-CLDM was effective in 16 (89%) patients and developed adverse events (AEs) in five (28%) patients. AEs included skin lesions, methemoglobinemia, and hepatic dysfunction, though none of them were serious. As a second-line or salvage treatment for PCP, PQ-CLDM appears to be a better option than pentamidine or atovaquone. Currently in Japan, both PQ and CLDM are licensed drugs but neither of them is approved for treatment of PCP. Considering the potentially fatal nature of PCP, approval of PQ-CLDM for treating this illness should be urged.