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This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig.
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Abatacepte , Antirreumáticos , Artrite Reumatoide , Interleucina-6 , Inibidores do Fator de Necrose Tumoral , Humanos , Artrite Reumatoide/tratamento farmacológico , Feminino , Masculino , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Pessoa de Meia-Idade , Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Antirreumáticos/farmacologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Idoso , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Articulação do Joelho/efeitos dos fármacos , Adulto , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
BACKGROUND: Medical care is impacted by uncertainty caused by various factors. The uncertainty that exists in medical care can cause patient distrust and lead to conflict. This study compared the tolerance of uncertainty in medical care between non-medical professionals and nurses. METHODS: We conducted a cross-sectional Internet-based survey. Participants included 2,100 individuals (600 nurses and 1,500 non-medical professionals; aged ≥ 20 years) from different parts of Japan. Of these, we excluded 70 participants who were classified as non-medical professionals but were registered nurses. Finally, we analyzed data from 2,030 participants (600 nurses and 1,430 non-medical professionals). Three registered nurses and nursing researchers developed an original questionnaire on tolerance of uncertainty in medical care. Data regarding participants' characteristics (age, sex, education level, marital status, having children, population size of the residential area, medical care usage, and occupation) were obtained. We performed a one-way analysis of variance (ANOVA) to compare the data between non-medical professionals and nurses. Additionally, we employed a multiple regression model to investigate factors related to tolerance of uncertainty in medical care scores. RESULTS: A significant portion of participants (36.7%) were aged 40-50 years (n = 745). Most were women (n = 1,210, 59.6%), and a considerable percentage were medical care users (n = 1,309, 64.5%). Non-medical professionals were less tolerant of uncertainty than nurses, and uncertainty scores were associated with medical care usage, occupation, and population size of the residential area. CONCLUSIONS: Our findings revealed variations in perceptions of uncertainty in medical care between non-medical professionals and medical care providers. To mitigate conflicts related to medical issues, medical care providers should enhance non-medical professionals' education regarding perceptions of uncertainty in medical care.
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Importance: Although the cognitive components of behavioral therapy for overactive bladder (OAB) are widely recognized, there is a lack of studies evaluating the effectiveness of multicomponent interventions that include cognitive components as a treatment for OAB. Objective: To examine the efficacy of a multicomponent intervention in improving health-related quality of life (HRQOL) for women with moderate to severe OAB. Design, Setting, and Participants: This multicenter, open-label, randomized clinical trial was conducted in Japan among women aged 20 to 80 years who had moderate to severe OAB. Participants were recruited from 4 institutions between January 16, 2020, and December 31, 2022, through self-referral via advertisement or referral from the participating institutions. Interventions: Participants were randomized 1:1 by minimization algorithm using an internet-based central cloud system to four 30-minute weekly sessions of a multicomponent intervention or waiting list. Both groups continued to receive baseline treatment throughout the study period. Main Outcomes and Measures: The primary outcome was the least-squares mean changes from baseline through week 13 in HRQOL total scores of the OAB questionnaire between 2 groups. Secondary outcomes included OAB symptom score and frequency volume chart. Results: A total of 79 women were randomized to either the intervention group (39 participants; mean [SD] age, 63.5 [14.6] years) or the waiting list control group (40 participants; mean [SD] age, 63.5 [12.9] years). One participant from each group dropped out from the allocated intervention, while 5 participants in the intervention group and 2 in the control group dropped out from the primary outcome assessment at week 13. Thirty-six participants (92.3%) in the intervention group and 35 (87.5%) in the control group had moderate OAB. The change in HRQOL total score from baseline to week 13 was 23.9 points (95% CI, 18.4-29.5 points) in the intervention group and 11.3 points (95% CI, 6.2-16.4 points) in the waiting list group, a significant difference of 12.6 points (95% CI, 6.6-18.6 points; P < .001). Similar superiority of the intervention was confirmed for frequency of micturition and urgency but not for OAB symptom score. Conclusions and Relevance: These findings demonstrate that a multicomponent intervention improves HRQOL for women with moderate to severe OAB and suggest that the cognitive component may be an effective treatment option for women with OAB. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000038513.
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Bexiga Urinária Hiperativa , Humanos , Feminino , Pessoa de Meia-Idade , Qualidade de Vida , Grupos Controle , Algoritmos , Terapia ComportamentalRESUMO
BACKGROUND: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment. PATIENTS AND METHODS: This multicenter, retrospective, observational study, conducted across 4 medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio. RESULTS: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival period was 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% CI, 0.70-2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61-2.47). Consistent results were obtained for subgroups receiving palbociclib (nâ =â 177) and abemaciclib (nâ =â 63) without propensity score matching. Adverse event incidence and severity were similar in both groups. CONCLUSION: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.
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Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores da Bomba de Prótons , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Piperazinas/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Piperazinas/administração & dosagem , Aminopiridinas/uso terapêutico , Aminopiridinas/farmacologia , Aminopiridinas/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/uso terapêutico , Piridinas/farmacologia , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Benzimidazóis/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/efeitos adversos , Adulto , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: Lung transplantation (LT) recipients are at risk of bone mineral density (BMD) loss. Pre- and post-LT BMD loss has been reported in some cross-sectional studies; however, there are limited studies regarding the serial BMD change in LT recipients. The aim of this study was to investigate the serial BMD changes and the clinical characteristics associated with BMD decline. METHODS: This was a single-center, retrospective observational study. BMD was serially measured in thoracic vertebral bodies (Th4, 7, 10) using computed tomography (CT) before and 3 and 12 months after LT. The frequency of osteoporosis and factors associated with pre-LT osteoporosis and post-LT BMD loss were evaluated. The frequency of post-LT compression fracture and its associated factors were also analyzed. RESULTS: This study included 128 adult LT recipients. LT recipients had decreased BMD (151.8 ± 42.2 mg/mL) before LT compared with age-, sex-, and smoking index-matched controls (176.2 ± 35.7 mg/mL). The diagnosis of COPD was associated with pre-LT osteoporosis. LT recipients experience further BMD decline after transplantation, and the percentage of recipients classified as exhibiting osteoporosis increased from 20% at baseline to 43% at 12 months. Recipients who had been taking no or small doses of glucocorticoids before LT had rapid BMD loss after LT. Early bisphosphonate use (within 3 months) after LT attenuated BMD loss and decreased new-onset compression fracture. CONCLUSION: LT recipients are at high risk for BMD loss and compression fracture after LT. Early bisphosphonate use may decrease BMD loss and compression fracture.
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Fraturas por Compressão , Osteoporose , Adulto , Humanos , Densidade Óssea , Estudos Transversais , Difosfonatos , Pulmão , Osteoporose/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Transplantados , Estudos RetrospectivosRESUMO
Objective To clarify both the histologic changes in primary viral pneumonia other than COVID-19 and whether patients with severe lung injury (SLI) on biopsy specimens progress to severe respiratory insufficiency. Methods Patients with primary viral pneumonia other than COVID-19, who underwent lung tissue biopsy, were retrospectively studied. Patients Forty-three patients (41 living patients and 2 autopsied cases) were included in the study. Results Nine patients had SLI, whereas most of patients who recovered from primary viral pneumonia showed a nonspecific epithelial injury pattern. One patient underwent a biopsy under mechanical ventilation. Two of 8 (25.0%) patients on ambient air or low-flow oxygen therapy progressed to a severe respiratory condition and then to death, while only 1 (3.1%) of 32 patients without SLI progressed to a severe respiratory condition and death (p=0.096). The proportion of patients who required O2 treatment for ≥2 weeks was higher in patients with SLI than in those without SLI (p=0.033). The 2 autopsy cases showed a typical pattern of diffuse alveolar damage, with both showing hyaline membranes. Non-specific histologic findings were present in 32 patients without SLI. Conclusion Some patients with SLI progressed to severe respiratory insufficiency, whereas those without SLI rarely progressed to severe respiratory insufficiency or death. The frequency of patients progressing to a severe respiratory condition or death did not differ significantly between those with and without SLI. The proportion of patients who required longer O2 treatment was higher in SLI group than in those without SLI.
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COVID-19 , Pneumonia Viral , Insuficiência Respiratória , Humanos , COVID-19/patologia , Estudos Retrospectivos , SARS-CoV-2 , Pneumonia Viral/terapia , Pneumonia Viral/tratamento farmacológico , Pulmão/patologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Insuficiência Respiratória/patologia , Progressão da DoençaRESUMO
OBJECTIVES: In anticancer clinical trials, particularly open-label trials, central reviewers are recommended to evaluate progression-free survival (PFS) and objective response rate (ORR) to avoid detection bias of local investigators. However, it is not clear whether the bias has been adequately identified, or to what extent it consistently distorts the results. Therefore, the objective of this study was to evaluate the detection bias in oncological open-label trials by confirming whether local investigators overestimate the PFS and ORR compared with the findings of central reviewers. DESIGN: Meta-epidemiological study. DATA SOURCES: MEDLINE via PubMed from 1 January 2010 to 30 June 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Open-label, parallel-group superiority, randomised trials of anticancer drugs that adjudicated PFS or ORR by both central reviewers and local investigators. REVIEW METHODS: We assessed the values for the same outcome (PFS and ORR) adjudicated by both central reviewers and local investigators. A random-effects model was used to estimate the ratio of HR (RHR) for PFS and the ratio of OR (ROR) for ORR between central reviewers and local investigators. An RHR lower than 1 and an ROR higher than 1 indicated an overestimation of the effect estimated by local investigators. RESULTS: We retrieved 1197 records of oncological open-label trials after full-text screening. We identified 171 records (PFS: 149 records, ORR: 136 records) in which both central reviewers and local investigators were used, and included 114 records (PFS: 92 records, ORR: 74 records) for meta-analyses. While the RHR for PFS was 0.95 (95% CI 0.91 to 0.98), the ROR of ORR was 1.00 (95% CI 0.91 to 1.09). The results remained unchanged in the prespecified sensitivity analysis. CONCLUSIONS: This meta-epidemiological study found that overestimation of local investigators has a small impact on evaluating PFS and ORR in oncological open-label trials. However, a limitation of this study is that it did not include data from all trials; hence, the results may not fully evaluate detection bias. The necessity of central reviewers in oncological open-label trials needs to be assessed by further studies that overcome this limitation. TRIAL REGISTRATION NUMBER: CTR-UMIN000044623.
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Antineoplásicos , Humanos , Antineoplásicos/uso terapêutico , Estudos Epidemiológicos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: Association between baseline medications plus neutrophil-to-lymphocyte ratio (NLR) and the effectiveness of immune checkpoint inhibitor (ICI) plus platinum doublet remains unknown, despite several reported prognostic models. We used real-world data to investigate whether baseline medications plus NLR predict survival outcomes in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICI plus platinum doublet. Methods: This multicenter, retrospective, observational study conducted in Japan between December 2018 and March 2021 used real-world data of consecutive patients with advanced NSCLC who received ICI (pembrolizumab or atezolizumab) plus platinum doublet as first-line treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The prognostic score for baseline medications plus NLR was weighted by regression ß coefficients and used to categorize patients into good, intermediate, and poor prognoses groups. In addition, time-dependent receiver operating characteristic curve analyses and univariable and multivariable Cox proportional hazards models were constructed. Results: Overall, 241 patients were included. Poor prognosis was significantly associated with worse PFS (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.08-2.94; P = 0.025) and OS (HR: 3.59; 95% CI: 2.05-6.28; P < 0.001) than good prognosis. Harrell's C-index for this prognostic model was 0.648. Conclusions: Baseline medication plus NLR could predict progressively worse survival outcomes in patients with advanced NSCLC receiving ICI plus platinum doublet and could be used as a prognostic index for poor outcomes.
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BACKGROUND: Patients with rheumatoid arthritis (RA) are prone to muscle atrophy due to inflammatory cytokines and corticosteroid use and immobility due to joint pain and deformity. Although resistance training is effective and safe in reversing muscle atrophy in RA, some patients are unable to perform a conventional high-load exercise program due to disease-related limitations. This study aims to examine the efficacy of individualized exercise therapy on physical function in elderly patients with RA who are at a high risk for sarcopenia. METHODS: This study is a single-center, parallel-group, two-arm, healthcare provider- and outcome assessor-blinded, superiority randomized controlled trial with a 1:1 allocation ratio. A total of 160 participants with RA between 60 and 85 years of age with a positive screening test for sarcopenia will be included. The intervention group will receive nutritional guidance and a four-month individualized exercise program in addition to the usual treatment. The control group will receive nutritional guidance in addition to the usual care. The primary endpoint will be physical function assessed using the Short Physical Performance Battery (SPPB) at 4 months. The data on outcome measures will be collected at baseline and at the two- and four-month follow-ups. Linear mixed-effects models for repeated measures will be conducted using the modified intention-to-treat analysis population. DISCUSSION: This study will provide evidence on whether a personalized exercise program can improve physical function and quality of life in elderly patients with RA. Some limitations include limited generalizability due to the single-center study and lack of blinding of the patients to the intervention assignment because of the nature of the exercise. Physical therapists may use this knowledge in their daily practice to improve RA treatment. Tailored exercise may enhance the health outcomes of the RA population and contribute to a reduction in healthcare costs. TRIAL REGISTRATION: The study protocol was retrospectively registered at the University hospital Medical Information Network-Clinical Trial Repository (UMIN-CTR) (registration number: UMIN000044930, https://www.umin.ac.jp/ctr/index-j.htm ) on January 4, 2022.
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Artrite Reumatoide , Sarcopenia , Humanos , Idoso , Qualidade de Vida , Resultado do Tratamento , Terapia por Exercício/métodos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND/PURPOSE: This prospective study aimed to investigate the dynamic changes in the gut microbiota (GM) and associated intestinal environment, which were assessed by measuring fecal organic acid (OA) concentrations, during the early period after liver transplantation (LT). To understand the fundamental characteristics of the human GM, data obtained from living donors were also analyzed. METHODS: Fixed-point observation was performed in 23 recipients and 21 donors for up to 2 weeks after LT. The GM and OA concentrations were investigated using ribosomal RNA-targeted reverse-transcription quantitative polymerase chain reaction and high-performance liquid chromatography, respectively. RESULTS: Before LT, the recipients exhibited remarkable dysbiosis and OA depletion, which were proportional to the model for end-stage liver disease score. Correlations between the abundances of some specific strains and OA concentrations were observed. After LT, while donor lobectomy caused only slight, transient and reversible changes in the GM and OA concentrations, recipients exhibited delayed recovery in these factors. However, no clear evidence of causality was observed between the GM or OA concentrations and LT outcomes. CONCLUSIONS: The GM and intestinal environment in LT recipients exhibited characteristics that were clearly different from those in donors. LT did not normalize but rather disrupted the GM during the early post-LT period, but its negative clinical impact could be minimized with perioperative management.
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Doença Hepática Terminal , Microbioma Gastrointestinal , Transplante de Fígado , Humanos , Doadores Vivos , Doença Hepática Terminal/cirurgia , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. Methods: An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1-3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. Findings: Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg-400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. Interpretation: This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required. Funding: AMED and iPS Cell Research Fund.
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Radiation therapy (RT) can enhance the abscopal effect of immune checkpoint blockade. This phase I/II study investigated the efficacy and safety of nivolumab plus RT in HER2-negative metastatic breast cancer requiring palliative RT for bone metastases. Cohort A included luminal-like disease, and cohort B included both luminal-like and triple-negative disease refractory to standard systemic therapy. Patients received 8 Gy single fraction RT for bone metastasis on day 0. Nivolumab was administered on day 1 for each 14-day cycle. In cohort A, endocrine therapy was administered. The primary endpoint was the objective response rate (ORR) of the unirradiated lesions. Cohorts A and B consisted of 18 and 10 patients, respectively. The ORR was 11% (90% CI 4-29%) in cohort A and 0% in cohort B. Disease control rates were 39% (90% CI 23-58%) and 0%. Median progression-free survival was 4.1 months (95% CI 2.1-6.1 months) and 2.0 months (95% CI 1.2-3.7 months). One patient in cohort B experienced a grade 3 adverse event. Palliative RT combined with nivolumab was safe and showed modest anti-tumor activity in cohort A. Further investigations to enhance the anti-tumor effect of endocrine therapy combined with RT plus immune checkpoint blockade are warranted.Trial registration number and date of registration UMIN: UMIN000026046, February 8, 2017; ClinicalTrials.gov: NCT03430479, February 13, 2018; Date of the first registration: June 22, 2017.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Nivolumabe/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Progressão , Metástase NeoplásicaRESUMO
The impact of T cell-mediated rejection (TCMR) after liver transplantation (LT) on the alterations in the gut microbiota (GM) and associated intestinal environment represented by fecal organic acids (OAs) require further elucidation. A rat allogeneic LT model was prepared without immunosuppressants or antibiotics, and a syngeneic model was used as a control. Qualitative and quantitative analyses of fecal samples at fixed time points were performed. Correlation analyses were also performed between liver function and GMs and OA levels. In the allogeneic TCMR group, the number of predominant obligate anaerobes decreased as liver function declined. Clostridioides difficile, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus were significantly increased. Regarding fecal OA concentration, short-chain fatty acid (SCFA) concentrations were depleted as liver function declined. In contrast, in the syngeneic group, GM and OAs exhibited only slight, transient, and reversible disturbances. In addition, alanine aminotransferase and total bilirubin were positively correlated with the number of Enterobacteriaceae and Enterococcus, and negatively correlated with the fecal concentration of SCFAs. The allogeneic TCMR model demonstrated distinct dysbiosis and depletion of fecal OAs as TCMR progressed after LT. The degree of graft injury was closely related to the number of specific bacterial strains and the concentrations of fecal SCFAs.
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Disbiose , Transplante de Fígado , Alanina Transaminase , Animais , Antibacterianos , Bilirrubina , Disbiose/microbiologia , Ácidos Graxos Voláteis/análise , Imunossupressores , Transplante de Fígado/efeitos adversos , RatosRESUMO
Background: The association between the effectiveness of capecitabine and the concomitant administration of gastric acid suppressants remains controversial. We aimed to clarify whether the effectiveness of capecitabine is affected by the co-administration of histamine H2 receptor antagonists (H2RAs) in early-stage colorectal cancer (CRC) patients using real-world data. Methods: This multicenter, retrospective, observational study included consecutive patients with stage II-III CRC who received either capecitabine monotherapy or the CapeOX regimen (capecitabine and oxaliplatin) as adjuvant therapy between January 2009 and December 2014 in Japan. Relapse-free survival (RFS) and overall survival were estimated using the Kaplan-Meier method. Additionally, multivariable Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting analyses were performed. Results: In total, 552 patients were included in this study, of which 30 were co-administered H2RAs. RFS at five years was 76.7% (95% confidence interval [CI]: 57.2-88.1%) and 79.8% (95% CI: 76.0-83.0%) in the H2RA and non-H2RA groups, respectively. Multivariable Cox proportional hazards model and propensity score-adjusted analyses showed that the co-administration of H2RAs was associated with a poor RFS among those receiving capecitabine monotherapy (hazard ratio [HR], 2.01; 95% CI: 0.86-4.70 and HR, 1.81; 95% CI: 0.77-4.22, respectively). In contrast, these results were inconsistent with the group receiving the CapeOX regimen. Conclusions: The study findings suggest that the co-administration of H2RAs may not reduce the effectiveness of capecitabine therapy in patients with early-stage CRC. To confirm this relationship, a prospective study with a pharmacokinetic approach is needed.
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INTRODUCTION: The nonexposed variant of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) presents with nonspecific clinical findings. The diagnosis of nonexposed ARONJ poses a critical challenge, and there is little evidence regarding its treatment and outcomes. This study aimed to examine the clinical outcomes in patients with nonexposed antiresorptive agent-related osteomyelitis of the jaw (AROMJ). The terms ARONJ and AROMJ were used separately in this study. MATERIALS AND METHODS: We enrolled patients with nonexposed AROMJ (osteomyelitis of the jaw without bone exposure associated with antiresorptive agents) with partial reference to an existing position paper on ARONJ. The initiating event of osteomyelitis was limited to periodontitis. Based on the findings of bone scintigraphy, panoramic radiography, computed tomography, and histopathological examination, we also used the hierarchical diagnostic criteria (HDC) for osteomyelitis of the jaw. RESULTS: There were 58 confirmed cases of nonexposed AROMJ based on the HDC. All patients had sufficient clinical findings to be diagnosed with nonexposed AROMJ as osteomyelitis underwent extraction with bone debridement. The healing rate was 93.1% (54/58). Univariable analysis showed a strong association between the healing status and malignant disease, while multivariable analysis showed no strong association between them. CONCLUSIONS: The present study had a relatively large sample size of patients with nonexposed AROMJ. The primary disease in patients with nonexposed AROMJ may not have a strong association with the healed status of the lesion. Based on its high healing rate, extraction with bone debridement in confirmed nonexposed AROMJ may prevent progression.
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Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Osteomielite , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico por imagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Conservadores da Densidade Óssea/efeitos adversos , Estudos de Coortes , Difosfonatos/efeitos adversos , Humanos , Arcada Osseodentária , Osteomielite/induzido quimicamente , Osteomielite/tratamento farmacológico , Radiografia PanorâmicaRESUMO
The association between capecitabine efficacy and proton pump inhibitors (PPIs) is controversial. Here, we determined whether co-administration of PPIs affects the real-world effectiveness of capecitabine. This retrospective observational study included consecutive patients with stage II-III colorectal cancer (CRC) who received adjuvant capecitabine monotherapy or CapeOX (capecitabine and oxaliplatin) between January 2009 and December 2014 at nine participating institutions. The primary endpoint was the difference in relapse-free survival (RFS) between patients who received PPIs and those who did not and was estimated using the Kaplan-Meier method. Overall survival (OS) was the secondary endpoint. Multivariable analysis of RFS and OS was performed using a Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting (IPTW) analyses. Data from 606 patients were evaluated, 54 of whom had received a PPI. PPI-treated patients tended to have poorer RFS and OS than patients treated without PPIs. The hazard ratio for RFS with capecitabine monotherapy was 2.48 (95% confidence interval: 1.22-5.07). These results were consistent with sensitivity analyses performed using propensity score adjustment and IPTW methods. Co-administration of PPIs may reduce the effectiveness of capecitabine and negatively impact patients with stage II-III CRC.
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Neoplasias Colorretais , Inibidores da Bomba de Prótons , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Fluoruracila/uso terapêutico , Humanos , Recidiva Local de Neoplasia , Inibidores da Bomba de Prótons/uso terapêutico , Estudos RetrospectivosRESUMO
Objective Phosphate is a fundamental element involved in a number of physiological pathways. A previous study showed abnormal laboratory findings and a higher mortality in hypophosphatemic patients than in normophosphatemic patients with pneumonia. Sporadic cases of pneumonia due to Legionella spp., Streptococcus pneumoniae, and viruses have been reported; however, the significance of hypophosphatemia in patients with pneumonia has not been adequately studied. We determined whether or not hypophosphatemia in patients with community-acquired pneumonia (CAP) was associated with specific pathogens, patient factors, disease severity, and mortality. Method We retrospectively analyzed 600 patients with CAP who were admitted to our hospital between January 1, 2010, and December 31, 2019. Results Hypophosphatemia was found in 72 (12.0%) of the 600 patients. The most frequent causative microbial agents of CAP in patients with hypophosphatemia were S. pneumoniae, Legionella spp., and influenza virus, whereas in severely ill patients with hypophosphatemia, influenza virus was the most common. Legionella spp., diabetes mellitus, and severe pneumonia were the independent factors for hypophosphatemia in the multivariable analysis. An impaired performance status, severe status on admission, interstitial pneumonia, bacteremia, and guideline-discordant therapy were the independent factors associated with mortality in the multivariable analysis. Hypophosphatemia was not significantly associated with mortality but showed a trend towards higher mortality in the multivariable analysis. Conclusion Hypophosphatemia was not associated with the prognosis in patients with CAP. However, the significance of hypophosphatemia for clinicians lies in the laboratory findings that predict abnormal glucose metabolism, Legionella infection, and severe disease.
Assuntos
Infecções Comunitárias Adquiridas , Hipofosfatemia , Pneumonia , Infecções Comunitárias Adquiridas/complicações , Humanos , Hipofosfatemia/complicações , Pneumonia/etiologia , Estudos Retrospectivos , Streptococcus pneumoniaeRESUMO
Choking can lead to mortality and residual impairments. This study aimed to determine the factors associated with choking among acute hospital patients and examine error-producing conditions to suggest choking-prevention policies. Among 36,364 cases reported by hospital staff at an acute university hospital from 2012 to 2018 were examined using a retrospective study, 35,440 were analysis as the number of cases analysed for the study. We used descriptive statistics to present patient characteristics and conducted univariable and multivariable logistic regression analyses to identify factors associated with choking. Additionally, we conducted content analysis (root cause analysis) to examine error-producing conditions and prevention policies. Sixty-eight cases were related to choking injuries; of these, 43 patients (63.2%) were male, and 38 (55.9%) were aged 65 years and older. Choking cases had a high percent of adverse outcomes involving residual impairment or death (n = 23, 33.8%). Mental illness (adjusted odds ratio [95% confidence interval]: 3.14 [1.39-7.08]), and hospitalisation in the general wards (adjusted odds ratio [95% confidence interval]: 3.13 [1.70-5.76]) were associated with an increased probability of choking. Error production was caused by food (n = 25, 36.8%) and medical devices or supplies (n = 13, 19.1%). Almost all contributory factors were associated with inadequate checking (n = 66, 97.1%) and misperception of risk (n = 65, 95.6%). Choking poses a highly significant burden on patients, and hospital administrators should minimise the risk of choking to prevent related injuries. Hospital administrators should provide training and education to their staff and develop adequate protocols and procedures to prevent choking.
Assuntos
Obstrução das Vias Respiratórias , Obstrução das Vias Respiratórias/etiologia , Feminino , Alimentos/efeitos adversos , Hospitais , Humanos , Japão/epidemiologia , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy. METHODS: Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching. RESULTS: The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0-120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine. CONCLUSIONS: The findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.
Assuntos
Carboplatina , Náusea , Antagonistas dos Receptores de Neurocinina-1 , Antagonistas do Receptor 5-HT3 de Serotonina , Vômito , Carboplatina/efeitos adversos , Dexametasona/uso terapêutico , Humanos , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Náusea/prevenção & controle , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Olanzapina/uso terapêutico , Pontuação de Propensão , Estudos Prospectivos , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/prevenção & controleRESUMO
Post-radiation fibrosis of the vocal folds is thought to cause vocal impairment. However, the mechanism by which this occurs has been poorly documented, probably because of the lack of an appropriate experimental animal model. The purpose of this study was to establish a simple and reproducible mouse model of laryngeal radiation to investigate the development of vocal fold fibrosis over time. C57BL/6 mice individually placed in a lead shield were irradiated with a single dose of 20 Gy. At 1, 2, and 6 months after irradiation, larynges were harvested and subjected to histological examination and gene expression analysis. Irradiated vocal folds showed time-dependent tissue contraction and increased collagen deposition, with no significant difference in the changes in hyaluronic acid levels. Transcriptional analysis revealed upregulated expressions of TGF-ß1 and iNOS at 6 months, but downregulated expressions of Acta2, Col1a1, Col3a1, and MMP8. Moreover, elevated TGF-ß1 and reduced downstream gene expression levels indicated the existence of an inhibitory factor over the TGF-ß/Smad pathway. Discrepancies in histological and transcriptional studies of collagen might suggest that radiation-induced vocal fold fibrosis could be caused by the elongated turnover of collagen. Overall, we established a mouse model of radiation-induced vocal fold fibrosis using a simple protocol. Further investigations are warranted to elucidate the pathogenesis of irradiation-induced fibrosis in vocal folds.