start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=12 article-no= start-page=e095428 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effectiveness of education programme to increase competency of health cadres in Indonesia: a cluster non-randomised controlled trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objectives Health cadres, who assist midwives in supporting pregnant women in community settings, need to enhance their competencies in identifying risk factors and referring high-risk pregnant women to midwives for further care. Since the capabilities of these health cadres are influenced by maternal complications, an educational programme was implemented to strengthen their skills. Therefore, this study aimed to evaluate the competency of health cadres by providing a researcher-developed educational programme.
Design An open-label, cluster non-randomised controlled trial.
Setting and participants Health cadres with at least 1 year of work experience were recruited at six public health centres (PHCs) in Banjarnegara Regency, Indonesia.
Interventions Six PHCs were selected and allocated into intervention group (IG=3 PHCs) and control group (CG=3 PHCs) groups. A total of 133 female health cadres were enrolled across the selected PHCs. At each PHC, a systematic random sampling method was used to select the participants. The researchers and health professionals provided a 3-week period of theoretical and scenario-based simulations to the IG, while the CG received no education.
Outcome measures Researcher-developed questionnaires and checklists were used to assess the knowledge, skills (health assessment, communication, attitude) and confidence. The primary endpoint was competency, a total score of knowledge and skills. The outcome domains were compared between the two groups, and a linear mixed-effect model was used to account for cluster-level variation.
Results A total of 130 (97.7%) completed the study (IG:64, CG:66). The competency score showed significant improvement at endline (CG=49.5?and IG=52.5; p=0.002). The median scores for health assessment skills (CG=12?vs IG=14; p<0.001) and communication skills (CG=7?vs IG=8; p<0.001) were increased in the IG compared with the CG. Mixed-effect model indicated that groups (ƒÀ (95%?CI) 2.49 (0.57 to 4.41), p=0.012), baseline knowledge (ƒÀ(95%?CI) 0.73 (0.54 to 0.92), p<0.001) and midline health assessment skills (ƒÀ (95%?CI) 0.54 (0.25 to 0.82), p<0.001) were significant positive predictors, while age was negatively associated with competency (ƒÀ (95%?CI) ?0.20 (?0.30 to ?0.10), p<0.001)).
Conclusion Education effectively increased the competency of health cadres. A well-structured education programme is necessary for health cadres to improve and maintain their competencies in monitoring high-risk pregnant women.
Trial registration number NCT06134518. en-copyright= kn-copyright= en-aut-name=SulistyoriniDewie en-aut-sei=Sulistyorini en-aut-mei=Dewie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HuqK A T M Ehsanul en-aut-sei=Huq en-aut-mei=K A T M Ehsanul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=BabaitaAbdulfatai Olamilekan en-aut-sei=Babaita en-aut-mei=Abdulfatai Olamilekan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AiveySadia A en-aut-sei=Aivey en-aut-mei=Sadia A kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HuiyingGao en-aut-sei=Huiying en-aut-mei=Gao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KazawaKana en-aut-sei=Kazawa en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FukushimaYasuko en-aut-sei=Fukushima en-aut-mei=Yasuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KakoMayumi en-aut-sei=Kako en-aut-mei=Mayumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MoriyamaMichiko en-aut-sei=Moriyama en-aut-mei=Michiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=2 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=3 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=4 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=5 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=6 en-affil=Faculty of Health Sciences, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=8 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=9 en-affil=Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=2 article-no= start-page=129 end-page=130 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251231 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Exposure-induced mediator?outcome confounders in causal mediation: implications and visualisation en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=SuzukiEtsuji en-aut-sei=Suzuki en-aut-mei=Etsuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShinozakiTomohiro en-aut-sei=Shinozaki en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamamotoEiji en-aut-sei=Yamamoto en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Department of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Interfaculty Initiative in Information Studies, the University of Tokyo kn-affil= affil-num=3 en-affil=Okayama University of Science kn-affil= END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=6 article-no= start-page=e098532 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202506 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Protocol for a multicentre, open-label, dose-escalation phase I/II study evaluating the tolerability, safety, efficacy and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with aggressive natural killer cell leukaemia en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction Aggressive natural killer cell leukaemia (ANKL) is a rare form of NK cell lymphoma with a very low incidence and poor prognosis. While multi-agent chemotherapy including L-asparaginase has been used to treat ANKL patients, they often cannot receive adequate chemotherapy at diagnosis due to liver dysfunction. PPMX-T003, a fully human monoclonal antibody targeting the transferrin receptor 1, shows promise in treating ANKL by helping patients recover from fulminant clinical conditions, potentially enabling a transition to chemotherapy. This study aimed to evaluate the tolerability, safety, efficacy, and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with ANKL.
Methods and analysis This multicentre, open-label, dose-escalation phase I/II study will be conducted at nine hospitals in Japan. Patients diagnosed with ANKL (whether as a primary or recurrent disease) and exhibiting abnormal liver function or hepatomegaly due to the primary disease will be included. The primary endpoint is the tolerability and safety of repeated continuous intravenous administration of PPMX-T003 in the first course, based on adverse events and dose-limiting toxicities. PPMX-T003 will be administered as a continuous intravenous infusion every 24?hours for five consecutive days, followed by a 2-day break. Pretreatment will be provided to minimise the risk of infusion-related reactions. Initial doses of PPMX-T003 will be 0.5, 1.0 or 2.0 mg/kg, with subsequent dose increases determined by the Data and Safety Monitoring Committee. The sample size is set at seven participants, with enrolment increased to up to 12 participants if dose-limiting toxicities occur, based on feasibility due to the rarity of ANKL. Descriptive statistics will summarise data according to initial dose, and pharmacokinetic analysis will be conducted based on administered dose.
Ethics and dissemination This study was approved by the institutional review boards at participating hospitals. The results will be disseminated in peer-reviewed journals.
Trial registration number jRCT2061230008 (jRCT); NCT05863234 (ClinicalTrials.gov). en-copyright= kn-copyright= en-aut-name=FukuharaNoriko en-aut-sei=Fukuhara en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OnizukaMakoto en-aut-sei=Onizuka en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KandaJunya en-aut-sei=Kanda en-aut-mei=Junya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AndoKiyoshi en-aut-sei=Ando en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Hematology, Tohoku University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Tokai University School of Medicine Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=4 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=6 en-affil=Department of Hematology, Hiroshima University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=8 article-no= start-page=e101809 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202508 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Neurological outcomes with hypothermia versus normothermia in patients with moderate initial illness severity following resuscitation from out-of-hospital cardiac arrest: protocol for a multicentre randomised controlled trial (R-CAST OHCA) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction Temperature control is a fundamental intervention for neuroprotection following resuscitation from cardiac arrest. However, evidence regarding the efficacy of hypothermia in post-cardiac arrest syndrome (PCAS) remains unclear. Retrospective studies suggest that the clinical effectiveness of hypothermia may depend on the severity of PCAS. The R-CAST OHCA trial aims to compare the efficacy of hypothermia versus normothermia in improving 30-day neurological outcomes in patients with moderately severe PCAS following out-of-hospital cardiac arrest.
Methods and analysis The multicentre, single-blind, parallel-group, superiority, randomised controlled trial (RCT) is conducted with the participation of 35 emergency and critical care centres and/or intensive care units at academic and non-academic hospitals. The study enrols moderately severe PCAS patients, defined as those with a revised post-Cardiac Arrest Syndrome for induced Therapeutic Hypothermia score of 5.5?15.5. A target number of 380 participants will be enrolled. Participants are randomised to undergo either hypothermia or normothermia within 3?hours after return of spontaneous circulation. Patients in the hypothermia group are cooled and maintained at 34‹C until 28 hours post-randomisation, followed by rewarming to 37‹C at a rate of 0.25‹C/hour. Patients in the normothermia group are maintained at normothermia (36.5‹C?37.7‹C). Total periods of intervention, including the cooling, maintenance and rewarming phases, will occur 40 hours after randomisation. Other treatments for PCAS can be determined by the treating physicians. The primary outcome is a favourable neurological outcome, defined as Cerebral Performance Category 1 or 2 at 30 days after randomisation and compared using an intention-to-treat analysis.
Ethics and dissemination This study has been approved by the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, Ethics Committee (approval number: R2201-001). Written informed consent is obtained from all participants or their authorised surrogates. Results will be disseminated via publications and presentations.
Trial registration number jRCT1062220035. en-copyright= kn-copyright= en-aut-name=NaitoHiromichi en-aut-sei=Naito en-aut-mei=Hiromichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishikimiMitsuaki en-aut-sei=Nishikimi en-aut-mei=Mitsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OkadaYohei en-aut-sei=Okada en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MaeyamaHiroki en-aut-sei=Maeyama en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KiguchiTakeyuki en-aut-sei=Kiguchi en-aut-mei=Takeyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YorifujiTakashi en-aut-sei=Yorifuji en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishidaKazuki en-aut-sei=Nishida en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsuiShigeyuki en-aut-sei=Matsui en-aut-mei=Shigeyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KurodaYasuhiro en-aut-sei=Kuroda en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NishiyamaKei en-aut-sei=Nishiyama en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=IwamiTaku en-aut-sei=Iwami en-aut-mei=Taku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NakaoAtsunori en-aut-sei=Nakao en-aut-mei=Atsunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=JAAM R-CAST OHCA Trial Group en-aut-sei=JAAM R-CAST OHCA Trial Group en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=3 en-affil=Department of Preventive Services, School of Public Health, Graduate School of Medicine, Kyoto University kn-affil= affil-num=4 en-affil=Department of Emergency and Critical Care Medicine, Tsuyama Chuo Hospital kn-affil= affil-num=5 en-affil=Division of Trauma and Surgical Critical Care, Osaka General Medical Center kn-affil= affil-num=6 en-affil=Department of Epidemiology, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Biostatistics, School of Public Health, Graduate School of Medicine, Kyoto University kn-affil= affil-num=8 en-affil=Department of Biostatistics, School of Public Health, Graduate School of Medicine, Kyoto University kn-affil= affil-num=9 en-affil=Emergency and Critical Care Center, TMG Asaka Medical Center kn-affil= affil-num=10 en-affil=Division of Emergency and Critical Care Medicine, Niigata University Graduate School of Medical and Dental Science kn-affil= affil-num=11 en-affil=Department of Preventive Services, School of Public Health, Graduate School of Medicine, Kyoto University kn-affil= affil-num=12 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil= kn-affil= END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=1 article-no= start-page=e003250 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical impact of combined assessment of myocardial inflammation and fibrosis using myocardial biopsy in patients with dilated cardiomyopathy: a multicentre, retrospective cohort study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Among patients with dilated cardiomyopathy (DCM), myocardial inflammation and fibrosis are risk factors for poor clinical outcomes. Here, we investigated the combined prognostic value of these two factors, as evaluated using myocardial biopsy samples.
Methods This retrospective and multicentre study included patients with DCM?defined as LVEF of ?45% and left diastolic diameter of >112% of predicted value, without evidence of secondary or ischaemic cardiomyopathy. In myocardial biopsy samples, inflammatory cells were counted using immunohistochemistry, and Massonfs Trichrome staining was performed to quantify the myocardial fibrosis as collagen area fraction (CAF). Higher myocardial inflammation was defined as leucocytes of ?14/mm?, including ?4 monocytes/mm?, with CD3+ T lymphocytes of?7/mm?. Greater myocardial fibrosis was defined as CAF of>5.9% by the Youdenfs index. The primary endpoint was cardiac death or left ventricular assist device implantation.
Results A total of 255 DCM patients were enrolled (average age, 53.1 years; 78% males). Within this cohort, the mean LVEF was 28.0%, mean CAF was 10.7% and median CD3+ cell count was 8.3/mm2. During the median follow-up period of 2688 days, 46 patients met the primary endpoint. Multivariable Cox proportional hazard analyses revealed that CD3+ cell count and CAF were independent determinants of the primary endpoint. Kaplan?Meier analysis showed that patients with both higher myocardial inflammation and greater fibrosis had the worst prognosis (log-rank p<0.001). When myocardial inflammation was graded as one of three degrees: T lymphocytes of <13/mm? (low); 13 of 13.1?23.9/mm? (moderate); and T lymphocytes of ?24?/mm? (high), patients with moderate inflammation exhibited a superior survival rate when CAF was ?5.9%, but a worse survival rate when CAF was >5.9%.
Conclusions Having both biopsy-proven higher myocardial inflammation and greater fibrosis predicted the worst clinical prognosis in patients with DCM. en-copyright= kn-copyright= en-aut-name=NakayamaTakafumi en-aut-sei=Nakayama en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OgoKeiko Ohta en-aut-sei=Ogo en-aut-mei=Keiko Ohta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SuganoYasuo en-aut-sei=Sugano en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YokokawaTetsuro en-aut-sei=Yokokawa en-aut-mei=Tetsuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KanamoriHiromitsu en-aut-sei=Kanamori en-aut-mei=Hiromitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IkedaYoshihiko en-aut-sei=Ikeda en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HiroeMichiaki en-aut-sei=Hiroe en-aut-mei=Michiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HatakeyamaKinta en-aut-sei=Hatakeyama en-aut-mei=Kinta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=Ishibashi-UedaHatsue en-aut-sei=Ishibashi-Ueda en-aut-mei=Hatsue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NakamuraKazufumi en-aut-sei=Nakamura en-aut-mei=Kazufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=DohiKaoru en-aut-sei=Dohi en-aut-mei=Kaoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=AnzaiToshihisa en-aut-sei=Anzai en-aut-mei=Toshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SeoYoshihiro en-aut-sei=Seo en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=Imanaka-YoshidaKyoko en-aut-sei=Imanaka-Yoshida en-aut-mei=Kyoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Cardiology, Nagoya City University Graduate School of Medical Sciences kn-affil= affil-num=2 en-affil=Department of Pathology, National Cerebral and Cardiovascular Center kn-affil= affil-num=3 en-affil=Department of Cardiology, Keiyu Hospital kn-affil= affil-num=4 en-affil=Department of Cardiovascular Medicine, Fukushima Medical University kn-affil= affil-num=5 en-affil=Department of Cardiology, Gifu University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Pathology, National Cerebral and Cardiovascular Center kn-affil= affil-num=7 en-affil=Department of Cardiology, National Center for Global Health and Medicine kn-affil= affil-num=8 en-affil=Department of Pathology, National Cerebral and Cardiovascular Center kn-affil= affil-num=9 en-affil=Department of Pathology, National Cerebral and Cardiovascular Center kn-affil= affil-num=10 en-affil=Center for Advanced Heart Failure, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Cardiology and Nephrology, Mie University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine kn-affil= affil-num=13 en-affil=Department of Cardiology, Nagoya City University Graduate School of Medical Sciences kn-affil= affil-num=14 en-affil=Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine kn-affil= END start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue=1 article-no= start-page=e000923 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250427 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Reversible cerebral vasoconstriction syndrome in idiopathic multicentric Castleman disease under treatment with tocilizumab en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disorder characterised by systemic inflammation resulting from overproduction of interleukin 6 (IL-6). While iMCD primarily affects the lymph nodes and related tissues, it can also rarely involve the central nervous system.
Case presentation We report the case of a 58-year-old female patient with at least a 3-year history of iMCD, who experienced acute thunderclap headaches due to reversible cerebral vasoconstriction syndrome (RCVS). RCVS occurred 3?months after initiating treatment with tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody, and was accompanied by focal cortical subarachnoid haemorrhage (SAH). Elevated IL-6 levels were found in both serum and cerebrospinal fluid. MR angiography revealed multiple diffuse stenotic lesions in the bilateral middle and posterior cerebral arteries, which, along with bilateral cerebral oedema, resolved within 3?months. The diffuse nature of the cerebral vasospasm and the presence of bilateral brain oedema suggested that cerebral vasospasm was due to RCVS rather than SAH.
Conclusions In patients with Castleman disease, RCVS may occur due to IL-6-dependent chronic cerebral vascular inflammation, either as a primary condition or as a complication of tocilizumab treatment. en-copyright= kn-copyright= en-aut-name=KamimuraNaoya en-aut-sei=Kamimura en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=UedaNaohisa en-aut-sei=Ueda en-aut-mei=Naohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KimuraKatsuo en-aut-sei=Kimura en-aut-mei=Katsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishikoriAsami en-aut-sei=Nishikori en-aut-mei=Asami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SatoYasuharu en-aut-sei=Sato en-aut-mei=Yasuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KishidaHitaru en-aut-sei=Kishida en-aut-mei=Hitaru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TanakaFumiaki en-aut-sei=Tanaka en-aut-mei=Fumiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Neurology, Yokohama City University Medical Center kn-affil= affil-num=2 en-affil=Department of Neurology, Yokohama City University Medical Center kn-affil= affil-num=3 en-affil=Department of Neurology, Yokohama City University Medical Center kn-affil= affil-num=4 en-affil= kn-affil= affil-num=5 en-affil= kn-affil= affil-num=6 en-affil=Department of Neurology, Yokohama City University Medical Center kn-affil= affil-num=7 en-affil=Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine kn-affil= END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=1 article-no= start-page=e000772 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220927 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Association of one-point glucocorticoid-free status with chronic damage and disease duration in systemic lupus erythematosus: a cross-sectional study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective@It is still unclear how glucocorticoids (GCs) affect the long-term clinical course of patients with SLE. The objective of this study is to explore the factors associated with GC-free treatment status.
Methods@Using data from the lupus registry of nationwide institutions, GC dose at registration was compared between short, middle and long disease durations of <5, 5?20 and ?20 years, respectively. After excluding patients who never used GC, we evaluated the relationship between GC-free status and chronic damage using Systemic Lupus International Collaborating Clinics Damage Index.
Results@GC doses at enrolment of the 1019 patients were as follows: GC-free in 101 (10%); 0 Conclusion@Even in the patients with long disease duration, one-point GC-free treatment status might be related to no chronic damage accrual. en-copyright= kn-copyright= en-aut-name=SadaKen-ei en-aut-sei=Sada en-aut-mei=Ken-ei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatayamaYu en-aut-sei=Katayama en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AsanoYosuke en-aut-sei=Asano en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HayashiKeigo en-aut-sei=Hayashi en-aut-mei=Keigo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MiyawakiYoshia en-aut-sei=Miyawaki en-aut-mei=Yoshia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OhashiKeiji en-aut-sei=Ohashi en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KatsuyamaEri en-aut-sei=Katsuyama en-aut-mei=Eri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KatsuyamaTakayuki en-aut-sei=Katsuyama en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=Takano-NarazakiMariko en-aut-sei=Takano-Narazaki en-aut-mei=Mariko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MatsumotoYoshinori en-aut-sei=Matsumoto en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YoshimiRyusuke en-aut-sei=Yoshimi en-aut-mei=Ryusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ShimojimaYasuhiro en-aut-sei=Shimojima en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OhnoShigeru en-aut-sei=Ohno en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KajiyamaHiroshi en-aut-sei=Kajiyama en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=IchinoseKunihiro en-aut-sei=Ichinose en-aut-mei=Kunihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SatoShuzo en-aut-sei=Sato en-aut-mei=Shuzo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=FujiwaraMichio en-aut-sei=Fujiwara en-aut-mei=Michio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=YajimaNobuyuki en-aut-sei=Yajima en-aut-mei=Nobuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine kn-affil= affil-num=13 en-affil=Center for Rheumatic Diseases, Yokohama City University Medical Center kn-affil= affil-num=14 en-affil=Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University kn-affil= affil-num=15 en-affil=Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences kn-affil= affil-num=16 en-affil=Department of Rheumatology, Fukushima Medical University School of Medicine kn-affil= affil-num=17 en-affil=Department of Rheumatology, Yokohama Rosai Hospital kn-affil= affil-num=18 en-affil=Division of Rheumatology, Department of Medicine, Showa University School of Medicine kn-affil= en-keyword=systemic lupus erythematosus kn-keyword=systemic lupus erythematosus en-keyword=glucocorticoids kn-keyword=glucocorticoids en-keyword=outcome assessment kn-keyword=outcome assessment en-keyword=health care kn-keyword=health care en-keyword=epidemiology kn-keyword=epidemiology END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=11 article-no= start-page=e003134 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=202111 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background
Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples.

Methods
We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort.

Results
Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance.

Conclusions
The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer. en-copyright= kn-copyright= en-aut-name=KawashimaShusuke en-aut-sei=Kawashima en-aut-mei=Shusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InozumeTakashi en-aut-sei=Inozume en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KawazuMasahito en-aut-sei=Kawazu en-aut-mei=Masahito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UenoToshihide en-aut-sei=Ueno en-aut-mei=Toshihide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NagasakiJoji en-aut-sei=Nagasaki en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TanjiEtsuko en-aut-sei=Tanji en-aut-mei=Etsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HonobeAkiko en-aut-sei=Honobe en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OhnumaTakehiro en-aut-sei=Ohnuma en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KawamuraTatsuyoshi en-aut-sei=Kawamura en-aut-mei=Tatsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=UmedaYoshiyasu en-aut-sei=Umeda en-aut-mei=Yoshiyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NakamuraYasuhiro en-aut-sei=Nakamura en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KawasakiTomonori en-aut-sei=Kawasaki en-aut-mei=Tomonori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KiniwaYukiko en-aut-sei=Kiniwa en-aut-mei=Yukiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YamasakiOsamu en-aut-sei=Yamasaki en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FukushimaSatoshi en-aut-sei=Fukushima en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=IkeharaYuzuru en-aut-sei=Ikehara en-aut-mei=Yuzuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=ManoHiroyuki en-aut-sei=Mano en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SuzukiYutaka en-aut-sei=Suzuki en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=NishikawaHiroyoshi en-aut-sei=Nishikawa en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MatsueHiroyuki en-aut-sei=Matsue en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= affil-num=1 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=2 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=3 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=4 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=5 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=6 en-affil=Research Institute, Chiba Cancer Center kn-affil= affil-num=7 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=8 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=9 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=10 en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center kn-affil= affil-num=11 en-affil=Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center kn-affil= affil-num=12 en-affil=Department of Pathology, Saitama Medical University International Medical Center kn-affil= affil-num=13 en-affil=Department of Dermatology, Shinshu University School of Medicine kn-affil= affil-num=14 en-affil=Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University kn-affil= affil-num=16 en-affil=Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=18 en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo kn-affil= affil-num=19 en-affil=Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center kn-affil= affil-num=20 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=21 en-affil=Department of Tumor Microenvironment, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=10 article-no= start-page=e244861 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=202110 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Idiopathic combined adrenocorticotropin and growth hormone deficiency mimicking chronic fatigue syndrome en-subtitle= kn-subtitle= en-abstract= kn-abstract=A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI. Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue. A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy. Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics. en-copyright= kn-copyright= en-aut-name=TokumasuKazuki en-aut-sei=Tokumasu en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OchiKanako en-aut-sei=Ochi en-aut-mei=Kanako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Center for Education in Medicine and Health Sciences, Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END