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1.
J Vet Med Sci ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38839348

RESUMO

Immunoglobulin A (IgA) is notable for its broad specificity toward multiple bacteria. Phosphorylcholine (PC) plays a role in the infection of pathogenic bacteria carrying PC and in the induction of IgA responses in the host immune system. The commercially available mouse monoclonal IgA, TEPC15-IgA, is a distinctive antibody with specificity for PC, warranting further exploration of its response to PC-bearing enteric bacteria. In this study, using 17 different enteric bacteria, including 3 aerobic and 14 anerobic bacteria that could be cultured in vitro, we confirmed that TEPC15-IgA recognizes 4 bacterial species: Lactobacillus taiwanensis, Limosilactobacillus frumenti, Streptococcus infantis, and Escherichia coli, although reactivity varied. Interestingly, TEPC15-IgA did not react with four of six Lactobacillus species used. Moreover, distinct target molecules associated with PC in L. taiwanensis and L. frumenti were evident, differing in molecular weight. These findings suggest that the natural generation of PC-specific IgA could prevent PC-mediated infections and potentially facilitate the formation of a microflora rich in indigenous bacteria with PC, particularly in the gastrointestinal tract.

2.
Nat Commun ; 15(1): 3027, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637505

RESUMO

More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers.


Assuntos
Toxinas Botulínicas , Epilepsia , Humanos , Anticonvulsivantes/metabolismo , Microscopia Crioeletrônica , Levetiracetam/uso terapêutico , Epilepsia/tratamento farmacológico , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo
4.
In Vivo ; 38(2): 923-927, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38418128

RESUMO

BACKGROUND/AIM: Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV) infection. Concomitant therapy with bendamustine and rituximab or obinutuzumab intensifies immunosuppression, potentially affecting CMV onset. This study aimed to assess CMV onset differences between bendamustine monotherapy and combination therapy with rituximab or obinutuzumab using the Japanese Adverse Drug Event Report database (JADER). PATIENTS AND METHODS: A JADER analysis dataset (April 2004 to September 2022) defined CMV infection using 31 preferred term (PT) words from MedDRA 25.1J HLT "Cytomegalovirus infection (10011827)". Reporting odds ratios (ROR) calculated CMV infection signals for bendamustine monotherapy, rituximab, obinutuzumab, bendamustine+rituximab (BR), and bendamustine+obinutuzumab (GB). ROR confidence intervals exceeding 1 indicated a CMV signal. Days of CMV infection were calculated based on adverse event onset and administration start. RESULTS: CMV signals were confirmed for monotherapy and combination therapies. CMV infection durations (median, interquartile range) were 41.0 days (23.5-69.5) for bendamustine monotherapy, 63.5 days (35.2-95.0) for BR, and 61.0 days (33.0-102.5) for GB, with cases exceeding 200 days. CONCLUSION: JADER analysis detected significant CMV signals for rituximab, obinutuzumab, and bendamustine. Caution may be warranted 7-9 months post-bendamustine administration, necessitating further investigation, including cell-mediated immunity suppression assessment.


Assuntos
Infecções por Citomegalovirus , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Cloridrato de Bendamustina/efeitos adversos , Rituximab/efeitos adversos , Citomegalovirus , Preparações Farmacêuticas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Infecções por Citomegalovirus/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
5.
In Vivo ; 38(2): 767-773, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38418130

RESUMO

BACKGROUND/AIM: Renal dysfunction necessitates S-1 dose reduction. However, decreased dihydropyrimidine dehydrogenase (DPD) activity may lead to adverse events due to 5-FU. The guidelines provided by pharmaceutical companies state that total bilirubin (T-Bil) should be ≤upper limit of normal (ULN)×1.5 as a reference value for safely taking S-1. Nevertheless, the relationship between the degree of liver dysfunction and S-1 dose reduction has not been clearly established. PATIENTS AND METHODS: This study focused on patients who received S-1 monotherapy for various types of cancer. The primary outcome was defined as the variation between blood sampling results on the test day and the subsequent test. The variation data were categorized based on the difference in T-Bil: Low T-Bil group (≤2.25) and High T-Bil group (>2.25). RESULTS: The number of patients that underwent S-1 monotherapy was 883 and the running number was 7,511; Low T-Bil group included 7,245 and High T-Bil group included 266. Examination of the effect of the T-Bil Group on clinical outcomes revealed a correlation with red blood cell (RBC) count, platelet (PLT) count, and T-Bil level. When the impact of the interaction between the T-Bil Group and any of the clinical outcomes, such as the RBC count, PLT count, and T-Bil level, was determined, each outcome showed a significant decrease in the High T-Bil group compared with the Low T-Bil group. CONCLUSION: S-1 administration in patients with liver dysfunction accompanied by elevated T-Bil levels may cause thrombocytopenia.


Assuntos
Hepatopatias , Humanos , Estudos Retrospectivos , Bilirrubina , Testes de Função Hepática
7.
J Intensive Care ; 12(1): 1, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195590

RESUMO

BACKGROUND: Patients in intensive care units (ICUs) often require quality palliative care for relief from various types of suffering. To achieve quality palliative care, specific goals need to be identified, measured, and reported. The present study aimed to develop quality indicators (QIs) for palliative care in ICUs, based on a systematic review and modified Delphi method, and test their feasibility by reviewing electronic medical record (EMR) data. METHODS: The current study was performed in two phases: the development of QIs using the modified Delphi method, and pilot-testing the quality of palliative care in ICUs based on EMR review. The pilot test included 262 patients admitted to the general or emergency ICU at a university hospital from January 1, 2019, to June 30, 2019. RESULTS: A 28-item QI set for palliative care in ICUs was developed based on the consensus of 16 experts. The Delphi process resulted in low measurability ratings for two items: "Assessment of the patient's psychological distress" and "Assessment of the patient's spiritual and cultural practices." However, these items were determined to be important for quality care from the perspective of holistic assessment of distress and were adopted in the final version of the QI set. While the pilot test results indicated the feasibility of the developed QIs, they suggested that the frequency of care performance varied, and certain aspects of palliative care in ICUs needed to be improved, namely (1) regular pain assessment, (2) identification of the patient's advance directive and advance care planning for treatment, (3) conducting an interdisciplinary family conference on palliative care, and (4) assessment of psychological distress of family members. CONCLUSIONS: The QI set, developed using the modified Delphi method and tested using EMR data, provided a tool for assessing the quality of palliative care in ICUs. In the two ICUs considered in this study, aspects of the palliative care process with a low performance frequency were identified, and further national surveys were recommended. It is necessary to conduct ongoing surveys at more facilities to improve the quality of palliative care in ICUs.

8.
Sci Rep ; 14(1): 1672, 2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-38243054

RESUMO

Numerous COVID-19 diagnostic imaging Artificial Intelligence (AI) studies exist. However, none of their models were of potential clinical use, primarily owing to methodological defects and the lack of implementation considerations for inference. In this study, all development processes of the deep-learning models are performed based on strict criteria of the "KAIZEN checklist", which is proposed based on previous AI development guidelines to overcome the deficiencies mentioned above. We develop and evaluate two binary-classification deep-learning models to triage COVID-19: a slice model examining a Computed Tomography (CT) slice to find COVID-19 lesions; a series model examining a series of CT images to find an infected patient. We collected 2,400,200 CT slices from twelve emergency centers in Japan. Area Under Curve (AUC) and accuracy were calculated for classification performance. The inference time of the system that includes these two models were measured. For validation data, the slice and series models recognized COVID-19 with AUCs and accuracies of 0.989 and 0.982, 95.9% and 93.0% respectively. For test data, the models' AUCs and accuracies were 0.958 and 0.953, 90.0% and 91.4% respectively. The average inference time per case was 2.83 s. Our deep-learning system realizes accuracy and inference speed high enough for practical use. The systems have already been implemented in four hospitals and eight are under progression. We released an application software and implementation code for free in a highly usable state to allow its use in Japan and globally.


Assuntos
COVID-19 , Aprendizado Profundo , Humanos , COVID-19/diagnóstico por imagem , Inteligência Artificial , Tomografia Computadorizada por Raios X/métodos , Software , Teste para COVID-19
11.
Am J Hosp Palliat Care ; 41(4): 424-430, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37216960

RESUMO

CONTEXT: While in-person workshops on serious illness communication skills using VitalTalk pedagogy have been shown to have a long-lasting impact, whether changing the format into virtual would maintain its enduring impact is unknown. Objectives. To examine long-term impacts of a virtual VitalTalk communication workshop. METHODS: Physicians in Japan who participated in our virtual VitalTalk workshop were asked to complete a self-assessment survey at 3 time points: before, immediately after, and 2 months after the workshop. We examined self-reported preparedness in 11 communication skills on a 5-point Likert scale at 3 time points, as well as self-reported frequency of practice on 5 communication skills at the pre- and 2-month time points. RESULTS: Between January 2021 and June 2022, 117 physicians from 73 institutions across Japan completed our workshop. Seventy-four participants returned the survey at all the 3 time points. Their skill preparedness significantly improved upon the completion of the workshop in all 11 skills (P < .001 for all items). The improvement remained at the same level at 2 months in 7 skills. In 4 of the 11 skills, there was further improvement at the 2-month point. The frequency of self-directed skill practice also increased significantly in the 2-month survey for all 5 skills. CONCLUSION: A virtual workshop of VitalTalk pedagogy improved self-reported preparedness of communication skills, and the impact was long-lasting in a non-U.S. setting as it likely induced self-practice of skills. Our findings encourage the use of a virtual format in any geographical location considering its enduring impact and easy accessibility.


Assuntos
Médicos , Humanos , Inquéritos e Questionários , Autorrelato , Comunicação , Japão
12.
BMJ Case Rep ; 16(12)2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38050387

RESUMO

This is a report of an anticoagulated patient with septic shock caused by an infected chronic expanding haematoma (CEH) that required hip disarticulation as a means of definitive surgical source control. As far as we know, we did not find any report of an infected giant CEH in the lower extremity as large as in the present patient.


Assuntos
Desarticulação , Extremidade Inferior , Humanos , Hematoma/complicações , Hematoma/diagnóstico por imagem , Hematoma/cirurgia
13.
RMD Open ; 9(4)2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37945284

RESUMO

OBJECTIVES: The goal of this study was to identify protein and transcriptional biomarkers and pathways associated with baseline disease state, the effect of filgotinib (FIL) treatment on these biomarkers, and to investigate the mechanism of action of FIL on clinical improvement in patients with active psoriatic arthritis (PsA). METHODS: The phase II EQUATOR (NCT03101670) trial evaluated the efficacy of FIL, a Janus kinase 1-preferential inhibitor, in patients with PsA. Peripheral protein and gene expression levels in association with clinical state at baseline and post-treatment were assessed in 121 patients using linear mixed effects models for repeated measures analyses. Mediation analysis and structural equation modelling (SEM) were performed to investigate the mechanism of action of FIL at week 4 on downstream clinical improvement at week 16. RESULTS: Baseline analyses showed that markers of inflammation were significantly associated with multiple PsA clinical metrics, except for Psoriasis Area and Severity Index (PASI), which corresponded to Th17 markers. FIL treatment resulted in sustained transcriptional inhibition of immune genes and pathways, a sustained increase in B-cell fraction and mature B-cells in circulation, and a transient effect on other cell fractions. Mediation analysis revealed that changes in B cells, systemic inflammatory cytokines and neutrophils at week 4 were associated with changes in clinical metrics at week 16. SEM suggested that FIL improved PASI through reduction of IL-23 p19 and IL-12 p40 proteins. CONCLUSIONS: Our results revealed that FIL treatment rapidly downregulates inflammatory and immune pathways associated with PsA disease activity corresponding to clinical improvement in PsA. TRIAL REGISTRATION NUMBER: NCT03101670.


Assuntos
Artrite Psoriásica , Inibidores de Janus Quinases , Psoríase , Humanos , Artrite Psoriásica/tratamento farmacológico , Resultado do Tratamento , Piridinas/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Biomarcadores
14.
Clin Geriatr Med ; 39(4): 575-597, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37798066

RESUMO

Three-quarters of patients over the age of 65 visit the emergency department (ED) in the last six months of their lives. Approximately 20% of hospice residents have ED visits. These patients must decide whether to receive emergency care that prioritizes life support, which may not achieve their desired outcomes and might even be futile. The patients in these end-of-life stages could benefit from early palliative care or hospice consultation before they present to the ED. Furthermore, early integration of palliative care at the time of ED visits is important in establishing the goals of the entire treatment.


Assuntos
Serviço Hospitalar de Emergência , Cuidados Paliativos , Humanos , Encaminhamento e Consulta , Morte
15.
J Intensive Care ; 11(1): 34, 2023 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-37488591

RESUMO

BACKGROUND: The efficacies of fresh frozen plasma and coagulation factor transfusion have been widely evaluated in trauma-induced coagulopathy management during the acute post-injury phase. However, the efficacy of red blood cell transfusion has not been adequately investigated in patients with severe trauma, and the optimal hemoglobin target level during the acute post-injury and resuscitation phases remains unclear. Therefore, this study aimed to examine whether a restrictive transfusion strategy was clinically non-inferior to a liberal transfusion strategy during the acute post-injury phase. METHODS: This cluster-randomized, crossover, non-inferiority multicenter trial was conducted at 22 tertiary emergency medical institutions in Japan and included adult patients with severe trauma at risk of major bleeding. The institutions were allocated a restrictive or liberal transfusion strategy (target hemoglobin levels: 7-9 or 10-12 g/dL, respectively). The strategies were applied to patients immediately after arrival at the emergency department. The primary outcome was 28-day survival after arrival at the emergency department. Secondary outcomes included transfusion volume, complication rates, and event-free days. The non-inferiority margin was set at 3%. RESULTS: The 28-day survival rates of patients in the restrictive (n = 216) and liberal (n = 195) strategy groups were 92.1% and 91.3%, respectively. The adjusted odds ratio for 28-day survival in the restrictive versus liberal strategy group was 1.02 (95% confidence interval: 0.49-2.13). Significant non-inferiority was not observed. Transfusion volumes and hemoglobin levels were lower in the restrictive strategy group than in the liberal strategy group. No between-group differences were noted in complication rates or event-free days. CONCLUSIONS: Although non-inferiority of the restrictive versus liberal transfusion strategy for 28-day survival was not statistically significant, the mortality and complication rates were similar between the groups. The restrictive transfusion strategy results in a lower transfusion volume. TRIAL REGISTRATION NUMBER: umin.ac.jp/ctr: UMIN000034405, registration date: 8 October 2018.

16.
Acute Med Surg ; 10(1): e866, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37387799

RESUMO

Background: Abdominal compartment syndrome (ACS) is a known complication of severe acute pancreatitis. It is typically secondary to visceral edema and aggressive fluid resuscitation, but rarely caused by a retroperitoneal hematoma due to ruptured visceral pseudoaneurysms. Case Presentation: A 49-year-old man presented in shock with a history of heavy alcohol use and was transferred to the intensive care unit with a diagnosis of severe acute pancreatitis. Computed tomography scan on hospital day 2 revealed a large retroperitoneal hematoma due to ruptured gastroduodenal artery pseudoaneurysms. Despite adequate resuscitation, the patient developed ACS, which required decompressive laparotomy on hospital day 10. Open abdominal management was continued until multiorgan failure resolved. He was eventually discharged to a rehabilitation hospital 3 months after presenting. Conclusion: We report a patient with severe acute pancreatitis who underwent decompressive laparotomy for ACS secondary to a large retroperitoneal hematoma due to ruptured gastroduodenal artery pseudoaneurysms.

17.
Molecules ; 28(11)2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37298887

RESUMO

A total of 147 oral Kampo prescriptions, which are used clinically in Japan, were evaluated for their anti-glycation activity. Kakkonto demonstrated significant anti-glycation activity, prompting further analysis of its chemical constituents using LC-MS, which revealed the presence of two alkaloids, fourteen flavonoids, two but-2-enolides, five monoterpenoids, and four triterpenoid glycosides. To identify the components responsible for its anti-glycation activity, the Kakkonto extract was reacted with glyceraldehyde (GA) or methylglyoxal (MGO) and analyzed using LC-MS. In LC-MS analysis of Kakkonto reacted with GA, the peak intensity of ephedrine was attenuated, and three products from ephedrine-scavenging GA were detected. Similarly, LC-MS analysis of Kakkonto reacted with MGO revealed two products from ephedrine reacting with MGO. These results indicated that ephedrine was responsible for the observed anti-glycation activity of Kakkonto. Ephedrae herba extract, which contains ephedrine, also showed strong anti-glycation activity, further supporting ephedrine's contribution to Kakkonto's reactive carbonyl species' scavenging ability and anti-glycation activity.


Assuntos
Medicamentos de Ervas Chinesas , Efedrina , Efedrina/farmacologia , Efedrina/análise , Cromatografia Líquida , Óxido de Magnésio , Espectrometria de Massas em Tandem , Aldeído Pirúvico , Produtos Finais de Glicação Avançada/análise
18.
Int J Clin Oncol ; 28(8): 1054-1062, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37261583

RESUMO

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Bevacizumab/efeitos adversos , Incidência , Neoplasias Colorretais/patologia , Camptotecina/efeitos adversos , Neoplasias do Colo/patologia , Fluoruracila/efeitos adversos , Estudos de Coortes , Leucovorina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteinúria/induzido quimicamente , Ramucirumab
19.
J Trauma Acute Care Surg ; 95(2): e3-e5, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37125818

RESUMO

BACKGROUND: Acute care surgery has recently been recognized as a field of surgery in Japan, but no well-organized nontrauma emergency surgery education system exists. The American Association for the Surgery of Trauma-European Society of Trauma and Emergency Surgery Emergency Surgery Course (AAST-ESTES ESC) course gives surgeons the knowledge and skills to make daily decisions about nontrauma emergency surgery. We held an AAST-ESTES ESC course in Japan from October 2 to 3, 2022. METHODS: Thirty-two Japanese participants were asked to rate the following items using a 5-point Likert scale from 1 to 5: overall assessment, program subjects, content, instructional style, and activity. In addition, we also inquired about topics that participants intended to change as a result of what they had learned in the course. RESULTS: All items were rated highly (4.1-4.7) by the participants. Participants reported intending to implement changes concerning mesenteric ischemia, colorectal crises, and acute pancreatitis after taking the course. CONCLUSION: Japanese surgeons gave the AAST-ESTES ESC course excellent ratings, suggesting its crucial role in Japan, where there has been no development of nontrauma emergency surgery education courses.


Assuntos
Cirurgia Geral , Pancreatite , Cirurgiões , Humanos , Estados Unidos , Japão , Doença Aguda , Cirurgia Geral/educação
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