IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand.

BACKGROUND: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses. METHODS: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP- treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis. RESULTS: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase. CONCLUSIONS: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.

IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand.

BACKGROUND: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses. METHODS: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP-treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis. RESULTS: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase. CONCLUSIONS: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.

The role of critical care nurses in shared decision-making for patients with severe heart failure: A qualitative study.

AIM: Patients with severe heart failure undergo highly invasive and advanced therapies with uncertain treatment outcomes. For these patients, shared decision-making is necessary. To date, the nursing perspective of the decision-making process for patients facing difficulties and how nurses can support patients in this process have not been fully elucidated. This study aimed to clarify the perceptions of critical care nurses regarding situations with patients with severe heart failure that require difficult decision-making, and their role in supporting these patients. METHODS: Individual semi-structured interviews were conducted with 10 certified nurse specialists in critical care nursing at nine hospitals in Japan. A qualitative inductive method was used and the derived relationships among the themes were visually structured and represented. RESULTS: The nurses' perceptions on patients' difficult situations in decision-making were identified as follows: painful decisions under uncertainties; tense relationships; wavering emotions during decision-making; difficulties in coping with worsening medical conditions; patients' wishes that are difficult to realize or estimate; and difficulties in transitioning from advanced medical care. Critical care nurses' roles were summarized into six themes and performed collaboratively within the nursing team. Of these, the search for meaning and value was fundamental. Two positions underpin the role of critical care nurses. The first aims to provide direct support and includes partnerships and rights advocacy. The second aims to provide a holistic perspective to enable necessary adjustments, as indicated by situation assessments and mediation. By crossing various boundaries, co-creating, and forming a good circular relationship in the search for meaning and values, the possibility of expanding treatment and recuperation options may be considered. CONCLUSIONS: Patients with severe heart failure have difficulty participating in shared decision-making. Critical care nurses should collaborate within the nursing team to improve interprofessional shared decision-making by providing decisional support to patients that focuses on values and meaning.

Return-to-Work Prevalence Among COVID-19 Patients After Receiving Intensive Care: A Systematic Review and Meta-Analysis.

Returning to work can be a serious issue for patients who have undergone intensive care. Previous studies have reported a relatively low return-to-work prevalence among such patients. Some patients with coronavirus disease 2019 (COVID-19) experience severe pneumonia and require intensive care, including mechanical ventilation. However, little is known about the return-to-work prevalence among such patients. Therefore, we conducted a systematic review and meta-analysis of the literature describing the return-to-work prevalence among COVID-19 patients who received intensive care. The eligibility criteria were determined based on the medical condition, context, and population framework of each study, as follows: (1) full-text observational studies, (2) context: COVID-19 patients admitted to ICU, (3) condition: return-to-work prevalence after ICU discharge, and (4) population: critically ill patients who are 18 years and older. Eligible studies included randomized controlled trials (RCTs) and observational studies. Review articles, case reports, letters to the editor, and comments without data involving return-to-work prevalence were excluded. We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE, via PubMed), the Cumulated Index to Nursing and Allied Health Literature (CINAHL, via EBSCOhost), and the International Clinical Trials Registry Platform (ICTRP) databases from their inception till July 26, 2022, and updated the search on June 14, 2023. Specifically, we collected studies reporting data on the return-to-work prevalence among COVID-19 patients after receiving intensive care. Data extraction and quality assessment were performed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Prevalence Studies. Pre-developed standard forms were used for data collection, and pooled prevalence for return-to-work was calculated. Out of the 2221 available records, 42 full texts were reviewed, 20 of which were included in the qualitative synthesis. The number of return-to-work cases reported at 0-3 months, 4-6 months, and 7-12 months were three, 11, and nine, respectively. At 0-3 months, the pooled prevalence was 0.49 (three trials; n = 73; 95% CI: 0.15-0.84; I2 = 82%). At 4-6 months, the pooled prevalence was 0.57 (11 trials; n = 900; 95% CI: 0.40-0.73; I2 = 92%). Finally, at 7-12 months, the pooled prevalence was 0.64 (nine trials; n = 281; 95% CI: 0.50-0.77; I2 = 80%). However, the overall quality of the included studies was low. Based on the results, approximately one-third of COVID-19 patients did not return to work 12 months after receiving intensive care. Given the quality and limitations of the studies, a more detailed and extensive cohort study is required; also, concerned authorities should implement adequate measures in terms of providing integrated job support for this patient population.

Adverse Effects of Personal Protective Equipment Among Intensive Care Unit Healthcare Professionals During the COVID-19 Pandemic: A Scoping Review.

INTRODUCTION: To avoid exposure to SARS-COV-2, healthcare professionals use personal protective equipment (PPE) while treating COVID-19 patients. Prior studies have revealed the adverse effects (AEs) of PPE on healthcare workers (HCWs); however, no review has focused on the AEs of PPE on HCWs in intensive care units (ICUs). This review aimed to identify the AEs of PPE on HCWs working in ICUs during the COVID-19 pandemic. METHODS: A scoping review was conducted. MEDLINE, CINAHL, the World Health Organization (WHO) global literature on COVID-19, and Igaku-chuo-zasshi (a Japanese medical database), Google Scholar, medRxiv, and Health Research Board (HRB) open research were searched from January 25-28, 2021. The extracted data included author(s) name, year of publication, country, language, article title, journal name, publication type, study methodology, population, outcome, and key findings. RESULTS: The initial search identified 691 articles and abstracts. Twenty-five articles were included in the analysis. The analysis comprised four key topics: studies focusing on PPE-related headache, voice disorders, skin manifestations, and miscellaneous AEs of PPE. The majority of AEs for HCWs in ICUs were induced by prolonged use of masks. CONCLUSION: The AEs of PPE among HCWs in ICUs included heat, headaches, skin injuries, chest discomfort, and dyspnea. Studies with a focus on specific diseases were on skin injuries. Moreover, many AEs were induced by prolonged use of masks.

[Cryotherapy is useful and safe in the prevention of oral mucositis after high-dose melphalan (L-PAM)].

We prospectively assessed the effectiveness of cryotherapy after high-dose L-PAM to prevent oral mucositis. Cryotherapy with ice tips was commenced 15 minutes before L-PAM administration, and continued until the end of administration. Twenty-six patients were enrolled in this study. Thirteen patients with myeloma were treated with 200 mg/m2 L-PAM followed by autologous peripheral blood stem cell transplantation, and 13 patients (4 AML, 4 MDS, 2 ALL, 2 lymphoma and 1 CML) were treated with 140 mg/m2 L-PAM followed by allogeneic stem cell transplantation. Grade 1 mucositis occurred in four of 13 patients (31%) with 200 mg/m2 L-PAM, and 2 of 13 patients (16%) with 140 mg/m2 L-PAM. Only one patient had grade 2 mucositis, and no grade 3 mucositis were observed. The procedure was well tolerated in all patients. These data suggest that cryotherapy is effective to minimize L-PAM-induced oral mucositis.

Relationship between dietary pattern and cognitive function in elderly patients with type 2 diabetes mellitus.

OBJECTIVE: To analyse the relationships between dietary patterns and cognitive function in elderly patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM completed a 3-day dietary record and Mini-mental State Examination (MMSE). Dietary patterns were identified by factor analysis. RESULTS: The study included 73 patients and identified five dietary patterns, one of which was characterized by high loading for vegetables and fish. A higher consumption of vegetables and fish was significantly associated with improved MMSE score (unadjusted model, model adjusted for age and sex, and model adjusted for age, sex, education, diabetic nephropathy and alcohol consumption), and decreased prevalence of suspected mild dementia (unadjusted model, model adjusted for age and sex). CONCLUSIONS: A high score in the vegetables and fish dietary pattern was associated with high MMSE score and low prevalence of suspected mild dementia in elderly patients with T2DM.

Prognostic impact of the mean platelet volume/platelet count ratio in terms of survival in advanced non-small cell lung cancer.

BACKGROUND: Mean platelet volume (MPV) is a platelet volume index. Classically, MPV was recognized as a hallmark of platelet activation. Recent studies have revealed that the MPV and MPV/platelet count (PC) ratio can predict long-term mortality in patients with ischemic cardio-vascular disease. In addition, these indices were correlated with the pathophysiological characteristics of patients with various disorders, including malignant tumors. PATIENTS AND METHODS: We retrospectively analyzed various hematological indices of patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the contribution of platelet volume indices to survival in these patients. RESULTS: A total of 268 patients were enrolled in the study. The median age of the patients was 68 years (range: 31-87 years). We compared various hematological indices between the NSCLC group and an age- and sex-matched comparator group. MPV was significantly decreased in the NSCLC group compared to the comparator group. In contrast, the PC was significantly increased in the NSCLC group. Consequently, the MPV/PC ratio was also decreased in the NSCLC group (0.397 vs. 0.501). In receiver operating characteristics (ROC) curve analysis, the MPV/PC ratio was associated with a sensitivity of 62.3% and a specificity of 74.6% at a cutoff value of 0.408730 (area under the curve [AUC], 0.72492)]. Univariate analysis revealed that overall survival (OS) was significantly shorter in the group with a low MPV/PC ratio than in the other group (median survival time [MST]: 10.3 months vs. 14.5 months, log-rank, P=0.0245). Multivariate analysis confirmed that a low MPV/PC ratio was an independent unfavorable predictive factor for OS (hazard ratio [HR]: 1.668, 95% confidence interval [CI]: 1.235-2.271, P=0.0008). CONCLUSION: These data clearly demonstrate that the MPV/PC ratio was closely associated with survival in patients with advanced NSCLC.

Phase II study of pemetrexed and carboplatin plus bevacizumab, followed by maintenance pemetrexed and bevacizumab in Japanese patients with non-squamous non-small cell lung cancer.

The present study evaluated the efficacy and safety of pemetrexed, carboplatin and bevacizumab, followed by maintenance pemetrexed and bevacizumab, in chemotherapy-naïve patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). The patients were administered pemetrexed (500 mg/m2), carboplatin (area under the concentration-time curve, 6.0 mg/ml × min) and bevacizumab (15 mg/kg) intravenously every three weeks for up to six cycles. Patients who did not experience tumor progression remained on maintenance pemetrexed and bevacizumab until disease progression or unacceptable toxicity occurred. The primary endpoint was the overall response rate. Of the 26 patients enrolled between March 2010 and April 2011, three were excluded due to brain metastases, therefore the intention-to-treat (ITT) population consisted of 23 patients. The median age was 64 years (range, 40-74 years) and 15 patients were male. In total, six patients had a performance status of 0, and 20 had stage IV tumors. The response rate was 69.6% [95% confidence interval (CI), 47.1-86.8], the disease control rate was 100% and the time to response was 1.2 months (95% CI, 0.72-1.93). The median progression-free survival time was 8.6 months (95% CI, 5.9-10.9) and the median overall survival time was 18.6 months (95% CI, 12.9-24.8). There were no grade 3 or worse hemorrhagic events and the feasibility was modest. Overall, pemetrexed and carboplatin plus bevacizumab, followed by maintenance pemetrexed and bevacizumab, was effective and tolerable in the patients with non-squamous NSCLC, and the time to response was relatively short.

Primary intrahepatic malignant mesothelioma with multiple lymphadenopathies due to non-tuberculous mycobacteria: A case report and review of the literature.

Primary intrahepatic malignant mesothelioma (PIHMM) is an extremely rare tumor with clinicopathological characteristics that remain to be elucidated. The current study presents the case of a 68-year-old female with PIHMM and multiple lymphadenopathies due to non-tuberculous mycobacteria. The patient presented with an intrahepatic tumor, 70 mm in diameter, in the right lobe of the liver. An ultrasound-guided fine-needle aspiration biopsy of the liver tumor revealed findings that were consistent with an intrahepatic malignant mesothelioma. The systemic lymph node swellings were due to epithelioid granulomas that were caused by non-tuberculous mycobacteria. However, a hepatic rupture occurred due to the rapid growth of the liver tumor and consequently, a surgical resection was not performed. A review of the literature revealed that the clinicopathological characteristics of PIHMM are similar to those of non-occupational mesothelioma. However, PIHMM is usually a solitary tumor and is rarely associated with cavity effusion in contrast with conventional mesothelioma. Therefore, surgical resection with curative intent is often recommended for patients with PIHMM.

Comparative analysis of carboplatin and paclitaxel combination chemotherapy schedules in previously untreated patients with advanced non-small cell lung cancer.

The combination of carboplatin and paclitaxel is one of the most commonly used regimens for the treatment of non-small cell lung cancer (NSCLC). We aimed to compare the standard tri-weekly and weekly schedules of this treatment, while considering treatment-related hematological toxicities. We retrospectively analyzed the weekly [paclitaxel, 70 mg/m(2)/week on days 1, 8 and 15, and carboplatin, area under the curve (AUC)=6, every 4 weeks] and standard tri-weekly (paclitaxel, 200 mg/m(2), and carboplatin, AUC=6, on day 1 every 3 weeks] schedules in patients with previously untreated advanced NSCLC. A total of 167 patients were enrolled in this study. The median age of the patients was 65 years (range, 31-79 years). The weekly and standard arms included 73 and 94 patients, respectively. The incidence of grade 3 or 4 neutropenia and neuropathy was significantly decreased in the weekly arm compared with the standard arm (37.0 vs. 70.2%). The median survival and progression-free survival times were 11.8 and 4.2 months, respectively, in the weekly arm and 11.6 and 3.1 months, respectively, in the standard arm. The results of the multivariate analysis indicated that the weekly schedule [hazard ratio (HR)=0.634, P=0.0262] and grade 3 or 4 neutropenia (HR=0.372, P=0.0007) were independent favorable prognostic factors for overall survival time. In conclusion, the weekly schedule of carboplatin and paclitaxel was less toxic than and potentially superior to the standard tri-weekly schedule. However, further optimization of the dose and schedule is warranted.

Nail alterations as a surrogate marker for the efficacy of low-dose metronomic chemotherapy.

Docetaxel is a well-known causative agent of nail alterations. The aim of this study was to reveal the impact of nail alterations associated with low-dose metronomic (LDM) docetaxel chemotherapy on the survival of non-small cell lung cancer (NSCLC) patients. Clinical information, survival data and nail alterations in patients treated with LDM docetaxel chemotherapy (docetaxel 15 mg/m2 per week) were retrospectively reviewed. Forty-nine patients were included in this study. Various nail alterations were observed in 17 of the 49 patients (34.7%). Onycholysis and subungual hyperkeratosis were observed in 22.4% and 10.2% of patients, respectively. The number of docetaxel administration cycles was correlated with the incidence and severity of nail alterations. Univariate and multivariate analysis clearly demonstrated that the occurrence of nail alterations was an independent favorable prognostic factor for overall survival. Nail alterations associated with treatment may act as a surrogate marker for the efficacy of low-dose metronomic docetaxel chemotherapy.

Multivariate analysis of factors influencing oral mucositis in allogeneic hematopoietic stem cell transplantation.

Little information is available regarding the effect of oral intervention on the outcome of hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the incidence of oral mucositis after allogeneic HSCT with or without oral intervention among 96 consecutive patients in our hospital between January 1988 and March 2006. We combined two oral intervention strategies: cryotherapy and oral health care. The former was applied beginning in 2003 for patients being treated with melphalan, and the latter, which was the study's main strategy, was applied to all HSCT recipients beginning in 2004. Oral mucositis was evaluated according to NCI CTCAE v3.0. The incidence of oral mucositis was 30.9% (17/55) in reduced-intensity stem cell transplantation (RIST), which was significantly lower than the 90.2% (37/41) in conventional stem cell transplantation (CST; P < 0.001). Among these 96 patients, severe oral mucositis was observed in 19 (46.3%) CST cases and in 6 (10.9%) RIST cases (P < 0.001). The occurrence of oral mucositis apparently decreased after oral health care instructions were given. Multiple logistic analysis revealed that the conditioning regimen and oral health care were independent risk factors for the incidence of oral mucositis. The cryotherapy did not exert enough potency to prevent oral mucositis in patients who had undergone CST or RIST. We concluded that oral health care improved tissue damage due to an overall upgrade in oral hygiene during chemotherapy.

Efficacy and safety of modified Yale insulin infusion protocol in Japanese diabetic patients after open-heart surgery.

To our knowledge, there is currently no insulin infusion protocol for critically ill patients especially designed for Asian diabetics although many such protocols are used in Western countries. In this study, we modified the Yale insulin infusion protocol taking into consideration the characteristics of Japanese diabetics and hospital environment. We tested the modified protocol in 40 type 2 diabetic patients after elective open-heart surgery (MY group) comparing with 35 type 2 diabetic patients under empirical blood glucose control (EC group). Analyses of 1656 blood glucose measurements during insulin infusion revealed that percentage of samples that showed achievement of target blood glucose level (80-140 mg/dl) was higher under MY (78+/-15%, n=870) than EC (57+/-23%, n=786, p<0.0001). On the other hand, the percentage of samples in which blood glucose was less than 60 mg/dl was comparable in the two groups (MY: 0.5+/-5.9 per thousand, EC: 5.1+/-18.5 per thousand). None of the patients with hypoglycemia showed significant clinical adverse effects. In conclusion, our modified Yale insulin infusion protocol is effective and safe for tight blood glucose control in Japanese diabetic patients after open-heart surgery.