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We observed a stellar occultation by (3200) Phaethon, which occurred in western Japan on 2021 October 3 (UTC). This observation was requested by the DESTINY+ mission team, which plans to conduct a flyby of asteroid Phaethon in 2028. Overall, this research effort contributes towards a large-scale observation campaign with a total of 72 observers observing from western Japan to southern Korea. 36 stations were established, and stellar occultation by the asteroid Phaethon was detected in 18 of them. This is the first time that this many multiple chord observations have been made for such a small asteroid (it has a diameter of 5–6 km). Observational reductions show that the apparent cross-section of Phaethon at the time of the occultation could be approximated using an ellipse with a major diameter of 6.12 ± 0.07 km and a minor diameter of 4.14 ± 0.07 km, and a position angle of 117.°4 ± 1.°5. As can be seen from the small error bars of the fitted ellipse, we have succeeded in estimating the shape and size of the asteroid with an extremely high degree of accuracy. Our observation results, together with other observations, will be used to create a 3D model of Phaethon and to improve its orbit. The instruments that we used for this observation are commonly used by many amateur astronomers in Japan for occultation observations and are not difficult to obtain. This paper describes the method and results of our observations using a CMOS camera and a GPS module, so that many people can participate in occultation observations in the future.

It is challenging to preserve the fertility of female patients with B-cell acute lymphoblastic leukemia (B-ALL) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) while maintaining treatment intensity. We report two cases of female patients with Philadelphia chromosome-negative (Ph -) B-ALL whose oocytes were retrieved after controlled ovarian stimulation during and after blinatumomab treatment. The first patient was a 30-year-old woman with relapsed Ph-B-ALL who received prednisolone (PSL) and cytoreductive chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by three courses of blinatumomab bridging to allo-HSCT. Ovarian stimulation was performed twice during blinatumomab administration, and two oocytes were retrieved during each course. The second patient was a 26-year-old woman with newly diagnosed Ph-B-ALL who received PSL, one course of conventional chemotherapy, and one course of high-dose methotrexate and cytarabine followed by two courses of blinatumomab bridging to allo-HSCT. Immediately after completion of the first course of blinatumomab, ovarian stimulation was performed, and three oocytes were retrieved. Use of a 2-week rest period enabled ovarian stimulation and oocyte retrieval to be performed without delaying treatment. Blinatumomab may be an option for preserving fertility while maintaining treatment intensity.

サイトカイン放出症候群の発症と重症化を予見する新たな指標 --キメラ抗原受容体T細胞療法における血清リン値が鍵--. 京都大学プレスリリース. 2022-10-19.

Cellular inhibitors of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-α underlies the immunopathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4+ DCs and percentages of cIAP1+ or cIAP2+ lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4.

Hereditary angioedema (HAE) is a potentially life-threatening rare disease, which is mainly caused by the deficiency or dysfunction of C1-esterase inhibitor, and characterized by spontaneous, recurrent episodes of edema in various parts of the body including internal organs and the laryngeal area. Delayed diagnosis and treatment increase the burdens and risks of this condition. The current study aimed to understand the burden of illness for HAE patients in Japan before and after diagnosis through a patient reported outcome survey. A survey instrument was distributed to 121 adult patients with HAE by a patient organization via HAE treating physicians between July and November in 2016. Seventy patients (57.9%) returned the questionnaire. Patients reported high levels of medical resource utilization, including emergency procedures and services. Episodes of receiving laparotomy were somewhat less after diagnosis with HAE than before, but no apparent difference in episodes of tracheotomy between before and after the diagnosis. The economic burden, including direct and indirect medical costs, was highest before diagnosis, but still perceived as substantial after diagnosis. Patients reported disruption of work and school life, with 40% reporting that they miss 10 or more days from work or education per year. Sixty percent of patients reported that HAE affected their daily activities. We concluded that HAE is associated with considerable physical, social, economic and psycho-social burdens even after diagnosis, and that higher attack frequency is associated with a heavy disease burden for patients in Japan.

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34+ , CD203c- , CD117+ , CD123dim+ ) and basophils (CD34- , CD203c+ , CD117± , CD123+ ) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33+ , CD34+ , CD123- ) and basophils (CD33+ , CD34+ , CD123+ ) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts.

Varicella zoster virus (VZV) reactivates more frequently in immunocompromised patients than immunocompetent subjects and is a significant cause of morbidity and mortality. Acyclovir is frequently used for treatment against VZV reactivation. However, long-term use of acyclovir can result in the emergence of VZV strain resistant to acyclovir. Here, we report a 67-year-old man with adult T-cell leukemia who suffered from herpes zoster with acyclovir-resistant VZV after long-term prophylaxis. The isolated viruses from his skin lesions were a mixture of acyclovir-resistant and acyclovir-susceptible strains. Sequence analysis showed the presence of thymidine kinase (TK) mutations in the resistant clones. Interestingly, oral administration of famciclovir, a prodrug form of penciclovir, resulted in resolution of his herpes zoster, although most acyclovir-resistant strains of VZV were reported to be resistant to penciclovir. This implied that a certain amount of susceptible VZV with wild-type viral TK gene was present in vivo, and that famciclovir could be phosphorylated intracellularly by the intact viral kinases. As famciclovir is more potent and longer-acting than acyclovir, the susceptible strains might have suppressed the generation and proliferation of the resistant in vivo. Even when VZV is developing resistance to acyclovir, famciclovir might be effective at least in the early resistant phase.

Background The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs. Methods A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016–2017. Responses were collected from 70 patients (57.9%) and subjected to analysis. Results The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min–max, 0–53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3–73) and at diagnosis 32.8 years (0–73). Patients reported an average of 15.7 (0–100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0–200) before diagnosis, but these declined to 4.3 (0–50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect. Conclusions There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by episodes of localized swelling, often of life-threatening severity. HAE due to C1 inhibitor (C1-INH) deficiency is common and is divided into types 1 and 2, but HAE with normal C1-INH is exceedingly rare. Herein, we describe the case of a patient with HAE with normal C1-INH undergoing orthognathic surgery. A 24-year-old woman came to our hospital with a diagnosed jaw deformity and commenced preoperative orthodontic treatment before scheduled orthognathic surgery. During the preoperative period, she experienced mild hoarseness. The hoarseness worsened, and computed tomography revealed mild laryngeal edema. Serum C1-INH, C3, C4, and CH50 levels were normal. Her younger sister had reportedly experienced a similar episode of lip edema previously. These findings supported a diagnosis of HAE with normal C1-INH. She underwent orthognathic surgery in close consultation with a hematologist and anesthesiologist at the age of 33 years. The surgery was completed without complications. She reported throat tightness 4 days after surgery, although her facial swelling was consistent with the procedure performed and was not remarkable. Concentrated C1-INH was administered, and the throat tightness slowly resolved within approximately 1 hour. Twenty-five days after surgery, she was discharged with reduced facial swelling. In the present case, orthognathic surgery was performed successfully in a patient with the exceedingly rare condition of HAE with normal C1-INH, in close consultation with a hematologist and an anesthesiologist. Postoperative throat tightness was successfully treated via the administration of concentrated C1-INH. Concentrated C1-INH administration can be considered in patients with HAE and normal C1-INH who experience angioedemic attack, keeping in mind that it may be slow to take effect.

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17-68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered.

Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn’s disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine–threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by down-regulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the down-regulation of TLR-mediated pro-inflammatory cytokine responses.

Benefit of high-dose cytarabine (HD-AraC) for acute myeloid leukemia (AML) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. We retrospectively analyzed data ...

The number of patients who are administered immunosuppressive agents has been increasing. Accordingly, more patients face higher risks for developing immunodeficiency-associated lymphoproliferative disorders (LPD). Although immunodeficiency-associated LPD are distinct from other lymphoid neoplasms in terms of their immunocompromised backgrounds, little is known about the impact of lymphopenia at diagnosis on survival in patients with these LPD. Seventy-one immunodeficiency-associated LPD in Kyoto University Hospital (post-transplant LPD (PTLD), n = 26; other iatrogenic immunodeficiency-associated LPD, n = 45) were reviewed and analyzed. The median age at diagnosis was 63 years (range, 3–83). Diffuse large B cell lymphoma was the most common subtype (n = 33), followed by Hodgkin lymphoma (n = 12), B cell monomorphic LPD not specified (n = 11), and polymorphic LPD or early-phase diseases (n = 15). The median follow-up period for survivors was 2.5 years and overall survival (OS) and progression-free survival (PFS) at 2.5 years were 75% and 67%, respectively. Multivariate analysis showed that lymphopenia (≤ 800/μL) at diagnosis predicted inferior OS (HR, 3.72; P = 0.043) and PFS (HR, 3.82; P = 0.012). Serum albumin values also strongly affected OS (> 3.18 g/dL vs. ≤ 3.18 g/dL; HR, 0.21; P = 0.010) and PFS (HR, 0.26; P = 0.013). Lymphopenia at diagnosis is suggested to predict inferior OS and PFS in patients with immunodeficiency-associated LPDs. Immunocompromised status might affect disease progression in these distinct lymphoid neoplasms growing under immunocompromised backgrounds.

High-pressure torsion (HPT) is one of the most promising methods employed to fabricate ultra-fine grained (UFG) materials for use in industrial applications. The aim of this work is to investigate the tribological behavior of UFG carbon steels produced by an HPT. In cases where the counter ball material was tungsten and cobalt cemented carbide (WC-Co), the wear rate (0.2~2.0x10-7 mm2/N) decreased with increasing the Vickers hardness (Hv200~650) for both HPT processed and quenched-tempered (QT) steels. On the other hand, in cases where the counter ball material was high carbon-chromium bearing steel (SUJ2), the wear rate of HPT (1.0~2.5x10-6 mm2/N) increased with increasing the hardness, which was an abnormal wear behavior. There was a tendency that the wear rate increased with an increase of the coefficient of friction, and that the coefficient of friction of HPT was 13-18 % higher than that of QT. Moreover, the adhesion force of HPT was 6-7 times higher than that of QT. Thus we have concluded that the high wear rate of HPT steels in the case of the SUJ2 ball wear tests were due to the high coefficient of friction as a result of the high adhesion force, which was caused by the high density of the grain boundaries in the UFG materials.

Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified. Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients. IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP. These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.

The combination of calcineurin inhibitors and short-term methotrexate has been used as a standard graft-versus-host-disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation. Mini-dose methotrexate (mini-MTX), consisting of 5 mg/m

Viral infection is one of the lethal adverse events after cord blood transplantation (CBT). Human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) ligand divergences can increase the risk of viral infection due to conflicting interactions between virus-infected cells and immune cells. However, the relationship between these disparities and the frequency of viral infection after CBT remains to be evaluated. Herein, we have conducted a retrospective multicenter study to assess the effect of HLA and KIR ligand mismatches on viral infections after CBT. The study included 429 patients, among which 126 viral infections occurred before day 100. Viral infection was significantly associated with poorer overall survival (OS; hazard ratio [HR] 1.74, p 0.01). Patients harboring ≥3 mismatches in the HLA allele and inhibitory KIR ligand mismatches (HLAKIR mismatches) had a significantly greater prevalence of viral infection (HR 1.66, p = 0.04). Thus, patients with HLAKIR mismatches had poorer outcomes in terms of non-relapse mortality (HR 1.61, p = 0.05). Our study demonstrates the unfavorable impacts of HLAKIR mismatches on viral infections and non-relapse mortality after CBT. Evaluating the viral infection risk and performance of an appropriate and early intervention in high-risk patients and optimizing the graft selection algorithm could improve the outcome of CBTs.

Viral infection is a serious complication that can greatly affect patient mortality and morbidity after allogenic hematopoietic stem cell transplantation (allo-HSCT). For the early identification of patients at high risk for viral infection, we evaluated the impact of lymphocyte area under the curve (AUC) value as a new predictive factor for early immune reconstitution after allo-HSCT against viral infection. This study included 286 patients who underwent their first allo-HSCT at Kyoto University Hospital between 2005 and 2017. Lymphocyte AUC from day 0 to day +15 was calculated in the analysis of human herpesvirus 6 (HHV-6), and lymphocyte AUC from day 0 to day +30 was calculated in the analysis of other viruses (cytomegalovirus [CMV], adenovirus, BK virus, JC virus, and varicella zoster virus). The risk factors for each viral reactivation/infection were assessed by multivariate analysis. The median age at transplantation was 51 years (range, 17 to 68 years). The median lymphocyte AUC was 63/μL (range, 0 to 5620/μL) at day +15 and 3880 (range, 0 to 118, 260/μL) at day +30. An increase in lymphocyte AUC was significantly associated with a high frequency of HHV-6 reactivation (P = .033) and a low frequency of CMV antigenemia (P = .014). No apparent association was found between lymphocyte AUC and reactivation/infection of other viruses. Aplastic anemia as a primary disease (hazard ratio [HR], 5.34; P < .001) and cord blood as a donor source (HR, 3.05; P = .006) were other risk factors for HHV-6 reactivation. Other risk factors for CMV antigenemia included the occurrence of acute graft-versus-host disease (HR 2.21; P < .001) and recipient age (HR 1.55; P = .017). Higher lymphocyte AUC at day +30 was significantly associated with low treatment-related mortality (HR, .47; P = .045). Lymphocyte AUC may be a good predictive factor for immune reconstitution against CMV reactivation. It also provides valuable information for predicting HHV-6 reactivation and treatment-related mortality.

Background Tonsilloliths are related clinically to halitosis and tonsillar abscess. However, the dynamics of tonsilloliths over time are unknown. The aim of the study was to evaluate change in the characteristics of tonsilloliths in a time-dependent fashion by follow-up computed tomography (CT). Methods Tonsilloliths were analyzed in 326 CT scan pair sets of initial and at least two follow-up CT examinations of patients with whole palatine tonsils and various diseases of the oral and maxillofacial regions. Results Over the follow-up period, 12.1% of tonsilloliths disappeared. Approximately 26.1% of tonsilloliths changed in size during follow-up, mostly increasing in size. In tonsilloliths that showed enlargement, the mean (± standard deviation) growth rate was 0.61 ± 0.41 mm per year. Approximately 37.3% of tonsilloliths changed position during the follow-up period; of these, movement was toward the respiratory tract in 92% at a mean rate of − 1.38 ± 1.59 mm per year. The calcification levels of almost all tonsilloliths showed dynamic change: HU number increased in 84.3% and decreased in 12.7% of tonsilloliths over the follow-up period. The mean rate of HU increase was 63.8 ± 96.3 HU/year, and the mean rate of HU decrease was − 38.4 ± 66.8 HU/year. Conclusions The calcification levels of all tonsilloliths showed dynamic fluctuation, and a tendency for excretion of tonsilloliths from the body. Their dynamics over time suggest that tonsilloliths may be in a permanently active phase which functions to remove foreign matter.

Background: Hereditary angioedema (HAE) is a rare but life-threatening condition. HAE types I and II (HAE-1/2) result from C1-inhibitor (C1–INH) deficiency. However, recent genetic analysis has established a new type of HAE with normal C1–INH (HAEnC1-INH). The mutations of factor XII, plasminogen, angiopoietin 1, and kininogen 1 genes may be the cause of HAEnC1-INH. Nevertheless, other causative molecules (HAE-unknown) may be involved. The Japanese therapeutic environment for HAE has been improving owing to the self-subcutaneous injection of icatibant, which was approved for the treatment of acute attack and enables early therapy. Erythema marginatum (EM) is a visible prodromal symptom which occasionally occurs prior to an angioedema attack; hence, recognizing the risk of an acute attack is important for early treatment. However, the detailed characteristics of EM remain unclear. In this study, we first investigated the clinical manifestations of EM in Japanese patients with HAE. Methods: A 20-point survey was developed and distributed to 40 physicians to gather clinical data on EM from patients with HAE. Results: Data on 68 patients with HAE (58 patients with HAE-1/2 and 10 patients with HAE-unknown) were collected. Of the patients with HAE-1/2, 53.4% experienced EM, whereas 43.1% did not. The forearm was the most frequent area of EM (64.5%), followed by the abdomen (29.0%) and upper arm and precordium (19.3%). Of the HAE-1/2 patients with EM, 41.9% always had angioedema following EM, while 29.0% always had colocalization of EM with angioedema. Moreover, 3.2% showed a correlation between the awareness of EM and severity of an angioedema attack. In 60.9% of HAE-1/2 patients with EM, the interval between the awareness of EM and appearance of angioedema was

Viral infection is more frequently reported in cord blood transplantation (CBT) than in transplantation of other stem cell sources, but its precise mechanism related to antiviral host defenses has not been elucidated yet. To evaluate the effect of human leukocyte antigen (HLA) class I allele-level incompatibility on viral infection in CBT, we conducted a single-center retrospective study. Total 94 patients were included, and viral infections were detected in 32 patients (34%) within 100 days after CBT. HLA-C mismatches in graft-versus-host direction showed a significantly higher incidence of viral infection (hazard ratio (HR), 3.67; p = 0.01), while mismatches in HLA-A, -B, or -DRB1 were not significant. Overall HLA class I mismatch was also a significant risk factor and the predictor of post-CBT viral infection (≥ 3 mismatches, HR 2.38, p = 0.02), probably due to the insufficient cytotoxic T cell recognition and dendritic cell priming. Patients with viral infection had significantly worse overall survival (52.7% vs. 72.1%; p = 0.02), and higher non-relapse mortality (29.3% vs. 9.8%; p = 0.01) at 5 years. Our findings suggest that appropriate graft selection as well as prophylaxis and early intervention for viral infection in such high-risk patients with ≥ 3 HLA class I allele-level mismatches, including HLA-C, may improve CBT outcomes.

We read with great interest the article by Pouletty et al recently published in your journal.1 The authors described a series of 16 cases with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the Paris area. While the affected children exhibited, in a complete or incomplete form, clinical features of Kawasaki disease (KD), they also presented several features distinct from KD, such as an older age at onset and a higher frequency of myocarditis and/or pericarditis, and of resistance to first treatment with intravenous immunoglobulin (IVIG). Clusters of similar cases have been identified in the USA and other European countries since April 2020.2 3 However, it is still a matter of debate whether PIMS-TS and KD share aetiology and/or pathophysiology, or represent two distinct clinical entities. Herein, we explore the cause behind its outbreak in relation to neutrophil extracellular traps (NETs), a novel killing mechanism of neutrophils. KD is a multisystem vasculitis that primarily affects coronary arteries of young children, especially in Japan. Although the aetiology of KD remains unclear, it may be triggered by infectious agents, leading to exaggerated activation of immune systems in genetically susceptible children. We first investigated whether KD patients’ serum stimulates NET formation in human neutrophils. NETs are extracellular structures primarily composed of …

The intestinal microbiota plays an important role in the pathogenesis of acute graft-versus-host disease (aGVHD). During the course of hematopoietic stem cell transplantation (HSCT), the intestinal microbiota is influenced by the use of broad-spectrum antibiotics. However, the impact of the use and type of antibiotics on the microbiota composition and, subsequently, the onset of aGVHD remain poorly understood. We hypothesized that the use and type of antibiotics had an impact on the occurrence of aGVHD. We assessed 275 patients who underwent their first allogeneic HSCT between January 2005 and June 2015 at Kyoto University Hospital. We monitored the 6 most frequently administered antibiotics (fourth-generation cephalosporins, glycopeptides, piperacillin-tazobactam, carbapenems, aminoglycosides, and quinolones) administered between days –14 and +14 relative to HSCT and its duration. The primary endpoint was the cumulative incidence of grades II to IV aGVHD. The cumulative incidence of aGVHD was significantly higher in patients administered fourth-generation cephalosporins than in patients not receiving fourth-generation cephalosporins (grades II to IV: hazard ratio, 1.98; 95% confidence interval, 1.19 to 3.29; P = .0087; grades III to IV: hazard ratio, 8.03; 95% confidence interval, 1.07 to 60.51; P = .043). In contrast, there was no significant association between administration of other antibiotics and aGVHD incidence. As for organ-specific aGVHD, the cumulative incidence of gut aGVHD was significantly higher in patients who received fourth-generation cephalosporins than in those who did not (31% versus 16%, P = .018). In conclusion, we demonstrated that the administration of fourth-generation cephalosporins had a strong impact on the development of aGVHD.