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Background: Critical care ultrasonography (CCUS) has become a daily diagnostic tool for intensivists. While the effective training measures for ultrasound novices are discussed widely, the best curriculum for the novices to retain a long-term proficiency is yet to be determined., Methods: Critical care medicine fellows who underwent an introductory CCUS workshop were randomly allocated into the standard training (ST) or the intensive training (IT) group. The IT group received an 8-h training besides the standardized fellowship education that the ST group received. Participant improvement in CCUS proficiency tests (maximum score, 200) after a 6-month training intervention was compared between the groups. CCUS examinations performed in patient care were observed over 2 years., Results: Twenty-one fellows were allocated into the ST (n = 10) or the IT (n = 11) group. No statistically significant difference was observed in the median (interquartile range [IQR]) improvement in CCUS proficiency tests between the ST group and the IT group: 18 (3.8-38) versus 31 (21-46) (P = .09). Median (IQR) test scores were significantly higher in postintervention than preintervention for both groups: ST, 103 (87-116) versus 124 (111-143) (P = .02), and IT, 100 (87-113) versus 143 (121-149) (P < .01). Participating fellows performed 226 examinations over the 2 years of observation., Conclusions: Fellows improved their CCUS proficiency significantly after 6-month training intervention. However, an additional 8-h training did not provide further benefits., (© 2022. The Author(s).)

Background: Orthokeratinized odontogenic cyst (OOC) is a rare developmental odontogenic cyst of the jaw. It was originally believed to be a variant of odontogenic keratocyst (OKC) but is now considered to be a distinct entity. OOC usually presents as a single lesion and recurs infrequently. On the other hand, OKC often presents with multiple lesions and displays locally aggressive behavior and a high recurrence rate associated with the protein patched homolog 1 (PTCH1) gene mutation. Multiple OOC cases are extremely rare and seem to be aggressive, but their pathogenesis is not fully understood. This study aimed to determine the clinical, pathological, and genetic characteristics of multiple OCC., Methods: Three cases of multiple OOC were evaluated for clinical and histological findings, and immunohistochemical expression of Ki-67 and Bcl-2. Furthermore, PTCH1 mutations were analyzed by next-generation sequencing using a custom panel to cover the entire exon of PTCH1., Results: The three cases of multiple OOC included two men and one woman with a mean age of 25.3 years old (range, 18-38 years old). Each case had two or three OOCs (total of seven OOCs), all of which were simultaneously detected. Of the seven OOCs that manifested as multiple jaw cysts, seven (100%) occurred in the posterior regions, four (57.1%) occurred in the mandible, and four (57.1%) were associated with an impacted tooth. Histological examination revealed cysts lined by orthokeratinized stratified squamous epithelium. Immunohistochemistry showed a low Ki-67 labeling index and no Bcl-2 expression in the seven OOCs. No pathogenic PTCH1 mutations were detected in any of the seven OOCs. None of the patients had any other symptoms or signs of recurrence at the last follow-up (6-60 months)., Conclusion: Multiple OOCs appeared to occur more often in younger patients than solitary OOC. Both multiple and solitary OOCs may be related diseases within the entity of odontogenic cysts. Multiple OOCs are clinicopathologically and genetically distinct from OKC., (© 2022. The Author(s).)

The antitumor effect of antibody-drug conjugates (ADC) is the main factor in achieving cures. Although the mechanism of tumor resistance to treatment is multifaceted, tumor-derived extracellular vesicles (T-EVs) have been implicated as contributing to the attenuation of ADC therapeutic efficacy. Thus, strategies to eliminate T-EVs are highly promising for overcoming drug resistance. Here we demonstrate plasma exchange therapy to remove T-EVs, decreasing their amount in vitro by 75%. Although trastuzumab emtansine (T-DM1) treatment alone was effective in our rat tumor model, the combination therapy of T-DM1 and T-EV filtration achieved early tumor shrinkage. Our results indicate that T-EV filtration plus ADC is a promising strategy for overcoming drug resistance.

Life-space activities are a measure of daily activity level. Here, we examined the association between life-space activities and prognosis in 129 cardiovascular diseases (CVD) patients 65 years of age or older (average age, 79.2 ± 7.6 years; mean left ventricular ejection fraction, 56.7 ± 13.2%) who had been admitted to our hospital for worsening CVD. Subjects were followed, and the primary endpoints were cardiovascular hospitalization and cardiovascular death. Receiver operating characteristic analysis produced a cutoff value for life-space assessment (LSA) score for increased risk of cardiovascular hospitalization for two years of 53.0 points (sensitivity, 55.9%; specificity, 82.1%). Kaplan−Meier analysis using this cutoff value revealed that the rates of cardiovascular hospitalization and cardiovascular death were significantly higher in subjects with an LSA score below the cutoff than in those with a score above the cutoff (both p < 0.001). Cox proportional analysis revealed that low LSA score was independently associated with cardiovascular hospitalization (HR, 2.540; 95% CI, 1.135−5.680; p = 0.023) and cardiovascular death (HR, 15.223; 95% CI, 1.689−137.180; p = 0.015), even after adjusting for age, sex, left ventricular ejection fraction, and log-transformed brain natriuretic peptide level. Thus, life-space activities are associated with prognosis in older adults with CVD.

In a previous report, we proposed a method for decellularizing porcine aortas by removing lipids from the aortas using liquefied dimethyl ether (DME) instead of the conventional sodium dodecyl sulfate (SDS). This is followed by DNA fragmentation with DNase. In the current work, the physical properties of porcine aortas decellularized using the DME method are evaluated by tensile strength tests. Conventional SDS decellularized aortas are typically swollen, rupture very easily, and have poor elasticity. By contrast, DME-treated samples are found to be less elastic. However, the maximum stress required for rupture is greater than that for the original aorta. These results indicate that decellularization with DME and DNase increases the maximum stress that can be withstood. Reduction of elasticity may derive from the appearance of temporary C=N bonds due to Schiff-base reactions that occur during the lipid removal process by liquefied DME, and methods to avoid this are desirable., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Objective: The objective of this survey was to identify areas where doctors have divergent practices in pharmacological treatment for hyperactive delirium in terminally ill patients with cancer., Methods: We conducted a survey of Japanese palliative care physicians and liaison psychiatrists. Inquiries were made regarding: (i) choice of drug class in the first-line treatment, (ii) administration methods of the first-line antipsychotic treatment, (iii) starting dose of antipsychotics in the first line treatment and maximum dose of antipsychotics in refractory delirium, and (iv) choice of treatment when the first-line haloperidol treatment failed. Respondents used a five-point Likert scale., Results: Regarding choice of drug class in the first-line treatment, more doctors reported that they 'frequently' or 'very frequently' use antipsychotics only than antipsychotics and benzodiazepine (oral: 73.4 vs. 12.2%; injection: 61.3 vs. 11.6%, respectively). Regarding administration methods of the first-line antipsychotic treatment, the percentage of doctors who reported that they used antipsychotics as needed and around the clock were 55.4 and 68.8% (oral), 49.2 and 45.4% (injection), respectively. There were different opinions on the maximum dose of antipsychotics in refractory delirium. Regarding the choice of treatment when the first-line haloperidol treatment failed, the percentage of doctors who reported that they increased the dose of haloperidol, used haloperidol and benzodiazepines, and switched to chlorpromazine were 47.0, 32.1 and 16.4%, respectively., Conclusions: Doctors have divergent practices in administration methods of the first-line antipsychotic treatment, maximum dose of antipsychotics, and choice of treatment when the first-line haloperidol treatment failed. Further studies are needed to determine the optimal treatment., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The perspective toward hypoactive delirium in the last days of life could be different among physicians., Objectives: To clarify the attitudes, beliefs, and opinions of palliative care physicians and liaison psychiatrists toward hypoactive delirium in the last days of life and to explore the association among these factors., Methods: A nationwide cross-sectional questionnaire survey was conducted among 1667 physicians who were either certified palliative care specialists or liaison psychiatrists. Physicians' agreement with the appropriateness of pharmacological management (e.g., antipsychotics) (one item), their beliefs (11 items), and their opinions (four items) were measured., Results: 787 (47%) physicians responded. 481 (62%) agreed to use of medications for hypoactive delirium in the last days of life, whereas 296 (38.1%) disagreed. More than 95% agreed with "hypoactive delirium at the end of life can be considered as a part of natural dying process." Multivariate analysis identified two belief subscales of "hypoactive delirium at the end of life is a natural dying process" and "antipsychotics are futile and harmful in managing hypoactive delirium" had a significant negative correlation with the use of medications. On the other hand, one belief subscale of "hypoactive delirium can be distressing even if patients' consciousness is impaired" had significant positive correlations with the use of medications., Conclusion: Pharmacological management of hypoactive delirium in the last days of life differs depending on physicians' beliefs. Future research is needed to clarify the efficacy and safety of pharmacological management of hypoactive delirium., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a fatal disease, which is characterized by occlusive pulmonary vascular disease (PVD) in small pulmonary arteries. It remains unknown whether perinatal insults aggravate occlusive PVD later in life. We tested the hypothesis that perinatal hypoxia aggravates PVD and survival in rats. PVD was induced in rats with/without perinatal hypoxia ( embryonic day 14 to postnatal day 3 ) by injecting SU5416 at 7 wk of age and subsequent exposure to hypoxia for 3 wk (SU5416/hypoxia). Hemodynamic and morphological analyses were performed in rats with/without perinatal hypoxia at 7 wk of age (baseline rats, n = 12) and at 15 wk of age in 4 groups of rats: SU5416/hypoxia or control rats with/without perinatal hypoxia ( n = 40). Pulmonary artery smooth muscle cells (PASMCs) from the baseline rats with/without perinatal hypoxia were used to assess cell proliferation, inflammation, and genomic DNA methylation profile. Although perinatal hypoxia alone did not affect survival, physiological, or pathological parameters at baseline or at the end of the experimental period in controls, perinatal hypoxia decreased weight gain and survival rate and increased right ventricular systolic pressure, right ventricular hypertrophy, and indices of PVD in SU5416/hypoxia rats. Perinatal hypoxia alone accelerated the proliferation and inflammation of cultured PASMCs from baseline rats, which was associated with DNA methylation. In conclusion, we established the first fatal animal model of PAH with worsening hemodynamics and occlusive PVD elicited by perinatal hypoxia, which was associated with hyperproliferative, proinflammatory, and epigenetic changes in cultured PASMCs. These findings provide insights into the treatment and prevention of occlusive PVD.

In Saccharomyces cerevisiae , mating type of haploid cells is determined by the presence or absence of the MAT α idiotype containing MATα1 and MATα2 , which encode the transcription factors. These proteins are characterized by rapid turnover, but the physiological relevance of this property remains unclear. Here, we show a direct link between their intracellular levels and sexual stability. Polyploid cells with fewer MAT α copies had unstable sexual phenotypes, causing morphological changes and an increase in cell death; these effects were mediated by hyperactivation of the mating pheromone response pathway. Thus, the MATα1 and MATα2 genes are haploinsufficient genes, and the reduction in their product levels causes sex fluctuation. Chromosome III harboring the mating type locus is the most prone to loss in diploids. We propose that the haploinsufficiency of MAT α compensates for the drop-out prone nature of chromosome III, thereby suppressing speciation through increased genome size via polyploidization., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Objective: Research on the association between circumstances of death in advanced cancer patients and depression in their bereaved caregivers is limited., Methods: A longitudinal study was performed on patients admitted to 21 inpatient hospices/palliative care units (PCUs) in Japan. Patient symptoms were assessed at admission and in the last 3 days of life. Data on distressing events (unexpected death, bleeding) and received treatments (morphine prescriptions, continuous deep sedation, cardiopulmonary resuscitation) were also obtained. Bereaved caregiver depression was assessed 6 months or more after patient death via mail survey using the Patient Health Questionnaire-9 (PHQ-9). A multivariable logistic regression analysis was used to explore variables predicting bereaved caregiver depression., Results: Of 1324 deceased patient-bereaved caregiver dyads, data were finally analyzed for 711 dyads. The proportion of probable depression (PHQ-9 scores ≥10) in bereaved caregivers was 13.6% (91/671; 95% confidence interval: 11.0-16.2). The multivariable logistic regression analysis showed that patient hyperactive delirium at PCU admission was significantly associated with the development of bereaved caregiver depression (odds ratio: 2.2, 95% CI: 1.2-3.8). Bereaved caregiver perceived low social support (OR: 4.7, 95% CI: 2.2-10.0) and low preparedness for death (OR: 4.5, 95% CI: 2.6-7.8) were also significantly associated with the development of depression. Other patient and bereaved caregiver variables had no association with depression., Conclusions: Hyperactive delirium in terminally ill cancer patients was associated with bereaved caregiver depression. The development of effective strategies to reduce delirium-related agitation and to provide educational interventions for caregivers may be needed., (© 2022 John Wiley & Sons Ltd.)

Clear cell carcinoma (CCC) is a rare epithelial malignant tumor of the salivary glands. It is characterized by tumor cells with clear cytoplasm, hyalinized stroma, and most importantly the fusion genes EWSR1-ATF1, EWSR1-CREM, and EWSR1-PLAG1. Break-apart FISH has been performed for multiple CCC cases, but direct sequencing analysis has been performed in relatively few. Herein, we report an interesting case of CCC harboring three EWSR1-ATF1 translocations: EWSR1 exon 8-ATF1 exon 4, EWSR1 exon 7-ATF1 exon 4, and EWSR1 exon 7-ATF1 exon 5. This case indicates the possibility of independent EWSR1-ATF1 gene translocations, and could provide insight into CCC tumorgenesis., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Although class III beta-tubulin (TUBB3) is not expressed in normal epithelium, its expression in cancers of some organs has been reported. Herein, we investigated the expression pattern and expression levels of TUBB3 in oral squamous cell carcinoma (SCC), and assessed whether TUBB3 immunostaining could improve the diagnostic accuracy of oral scraping liquid-based cytology (LBC)., Methods: Paraffin sections of biopsies from 107 patients with primary SCC and 30 patients with squamous papilloma of the tongue or gingiva were immunostained for TUBB3. In addition, 15 LBC samples obtained from the study participants with SCC were immunostained for TUBB3. Seven LBC samples were false-negative. The TUBB3 expression level in each sample was evaluated and classified as 3+, 2+, 1+, or 0., Results: TUBB3 expression was confirmed in 91.6% of paraffin-embedded SCC specimens. Clear and diffuse positivity (2+ or above) was observed in 77.6% of the total cases. In the well-differentiated type, tumour cells in the middle layer of the parenchyma specifically expressed TUBB3. In almost LBC samples, cancerous intermediate cells showed immunopositivity similar to that of paraffin samples, even if cellular atypia was not clear in Papanicolaou staining., Conclusions: TUBB3 immunostaining is useful for diagnosing oral SCC in scraping LBC, especially when samples consist of intermediate cells with little morphological change. Moreover, TUBB3 immunostaining could improve the diagnostic accuracy of oral scraping LBC by reducing false-negatives., (© 2022 John Wiley & Sons Ltd.)

Background: Informing families of a patient's death is one of the most challenging responsibilities of clinicians who provide care for terminally ill patients. Although death pronouncement can be a highly stressful event for clinicians, no previous study has reported qualitative characteristics of the burden experienced by clinicians related to death pronouncements. Moreover, no scale has been developed to assess this burden., Objective: This study sought to develop a scale to evaluate clinicians' burden related to death pronouncement (Death Pronouncement Burden Scale for oncology practice [DPBS-oncol]) and examine its reliability and validity in Japan., Methods: We presented the DPBS-oncol to clinicians involved in oncology practice and examined its reliability and discriminant validity. To investigate the test-retest reliability of the scale, the DPBS-oncol was presented a second time to a subsample of the clinicians., Results: Factor analysis required a grouping of the 15 DPBS-oncol items into one factor. Cronbach's α coefficient of the total score of DPBS-oncol was 0.94, and the intraclass correlation coefficient of the total score of DPBS-oncol was 0.89. Regarding discriminant validity, DPBS-oncol total score was moderately correlated with other available scales for assessing clinicians' attitudes to end-of-life care., Conclusion: This study was the first to develop a scale to evaluate clinicians' burden related to death pronouncement. The DPBS-oncol, which includes 15 items, was validated and shown to have sufficient reliability., Competing Interests: The authors declare that there is no conflict of interest., (© Yusuke Hiratsuka et al., 2022; Published by Mary Ann Liebert, Inc.)

Background: Patients with pulmonary arterial hypertension (PAH) carrying bone morphogenetic protein receptor type 2 (Bmpr2) mutations present earlier with severe hemodynamic compromise and have poorer survival outcomes than those without mutation. The mechanism underlying the worsening clinical phenotype of PAH with Bmpr2 mutations has been largely unaddressed in rat models of pulmonary hypertension (PH) because of the difficulty in reproducing progressive PH in mice and genetic modification in rats. We tested whether a clinically-relevant Bmpr2 mutation affects the progressive features of monocrotaline (MCT) induced-PH in rats., Methods: A monoallelic single nucleotide insertion in exon 1 of Bmpr2 (+/44insG) was generated in rats using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9, then PH, pulmonary vascular disease (PVD) and survival after MCT injection with or without a phosphodiesterase type 5 inhibitor, tadalafil, administration were assessed., Results: The +/44insG rats had reduced BMPR2 signalling in the lungs compared with wild-type. PH and PVD assessed at 3-weeks after MCT injection were similar in wild-type and +/44insG rats. However, survival at 4-weeks after MCT injection was significantly reduced in +/44insG rats. Among the rats surviving at 4-weeks after MCT administration, +/44insG rats had increased weight ratio of right ventricle to left ventricle plus septum (RV/[LV + S]) and % medial wall thickness (MWT) in pulmonary arteries (PAs). Immunohistochemical analysis showed increased vessels with Ki67-positive cells in the lungs, decreased mature and increased immature smooth muscle cell phenotype markers in the PAs in +/44insG rats compared with wild-type at 3-weeks after MCT injection. Contraction of PA in response to prostaglandin-F2α and endothelin-1 were significantly reduced in the +/44insG rats. The +/44insG rats that had received tadalafil had a worse survival with a significant increase in RV/(LV + S), %MWT in distal PAs and RV myocardial fibrosis compared with wild-type., Conclusions: The present study demonstrates that the Bmpr2 mutation promotes dedifferentiation of PA smooth muscle cells, late PVD and RV myocardial fibrosis and adversely impacts both the natural and post-treatment courses of MCT-PH in rats with significant effects only in the late stages and warrants preclinical studies using this new genetic model to optimize treatment outcomes of heritable PAH., (© 2022. The Author(s).)

Background: The appropriate delivery of death pronouncements potentially affects bereaved families' wellbeing positively. Although younger physicians need to learn the competencies and entrustable professional activities (EPAs) to conduct death pronouncement independently, both of which have not been clarified. Therefore, this study aimed to develop a list of competencies and EPAs necessary for death pronouncement practice, which resident physicians need to acquire by the end of their residency training (postgraduate year 2)., Methods: An anonymous modified Delphi study was conducted with a panel of 31 experts. The experts were invited online from general wards in hospitals with resident physicians across Japan to participate in the study using the purposive and snowball sampling method. A non-anonymous web conference was held with three additional external evaluators to finalize the item list. The consensus criterion was defined as a mean response of at least 4 points on a 5-point Likert scale for each competency and EPA item and a rating of 4 or 5 points by at least 80% of the participants., Results: Consensus was achieved, with consistently high levels of agreement across panel members, on 11 competencies and 9 EPA items. Additionally, a correspondence matrix table between competencies and EPAs was developed., Conclusions: This study clarified the standardized educational outcomes as competencies in death pronouncement practice and the unit of professional practice of physicians who can perform this independently (EPAs), serving as a blueprint to aid the development of an educational model and evaluation method for clinical educational institutions and developers of medical school curriculums., (© 2022. The Author(s).)

Objectives: The present study aims were (1) to identify the proportion of terminally ill cancer patients with desire for hastened death (DHD) receiving specialized palliative care, (2) to identify the reasons for DHD, and (3) to classify patients with DHD into some interpretable subgroups., Methods: Advanced cancer patients admitted to 23 inpatients hospices/palliative care units in 2017 were enrolled. Data were prospectively obtained by the primarily responsible physicians. The presence/absence of DHD and reasons for DHD were recorded. A cluster analysis was performed to identify patterns of subgroups in patients with DHD., Results: Data from 971 patients, whose Richmond Agitation-Sedation Scale score at admission was zero and who died in palliative care units, were analyzed. The average age was 72 years, common primary cancer sites were the gastrointestinal tract (31%) and the liver/biliary ducts/pancreas (19%). A total of 174 patients (18%: 95% confidence interval, 16-20) expressed DHD. Common reasons for DHD were dependency (45%), burden to others (28%), meaninglessness (24%), and inability to engage in pleasant activities (24%). We identified five clusters of patients with DHD: cluster 1 (35%, 61/173): "physical distress," cluster 2 (21%, 37/173): "dependent and burdensome," cluster 3 (19%, 33/173): "hopelessness," cluster 4 (17%, 30/173): "profound fatigue," and cluster 5 (7%, 12/173): "extensive existential suffering.", Conclusions: A considerable number of patients expressed DHD and could be categorized into five subgroups. These findings may contribute to the development of therapeutic strategies.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma characterized by an alveolar or organoid arrangement of polygonal tumour cells separated by fibrovascular septa. A specific fusion gene [ASPS critical region 1 (ASPSCR1)-TFE3] was detected in ASPS. Despite being a slow-growing tumour without pain and dysfunction, ASPS is characterized by early metastasis, which leads to poor prognosis. Herein, we report a rare case of primary ASPS of the cheek harbouring ASPSCR1 (exon 7)-TFE3 (exon 5) fusion gene in a 21 year-old woman. This tumour was a well-circumscribed, smooth, round mass that was clinically suspected as a benign tumour. However, histologically, it was observed that the polygonal tumour cells were arranged in solid and alveolar growth patterns. Post-operative examination of the whole body excluded the possibility of metastasis at other sites. Thus, careful immunohistochemical and genetic analyses, as well as whole-body examination, demonstrated that the tumour was a primary ASPS of the cheek., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To investigate the efficacy of two types of palliative sedation: proportional and deep sedation, defined by sedation protocols., Methods: From a multicenter prospective observational study, we analyzed the data of those patients who received the continuous infusion of midazolam according to the sedation protocol. The primary endpoint was goal achievement at 4 hours: in proportional sedation, symptom relief (Integrated Palliative care Outcome Scale: IPOS ≤ 1) and absence of agitation (modified Richmond Agitation-Sedation Scale: RASS ≤ 0); in deep sedation, the achievement of deep sedation (RASS ≤ -4). Secondary endpoints included deep sedation as a result of proportional sedation, communication capacity (Communication Capacity Scale item 4 ≤ 2), IPOS and RASS scores, and adverse events., Results: A total of 81 patients from 14 palliative care units were analyzed: proportional sedation (n = 64) and deep sedation (n = 17). At 4 hours, the goal was achieved in 77% (n = 49; 95% confidence interval: 66-87) with proportional sedation; and 88% (n = 15; 71-100) with deep sedation. Deep sedation was necessary in 45% of those who received proportional sedation. Communication capacity was maintained in 34% with proportional sedation and 10% with deep sedation. IPOS decreased from 3.5 to 0.9 with proportional sedation, and 3.5 to 0.4 with deep sedation; RASS decreased from +0.3 to -2.6, and +0.4 to -4.2, respectively. Fatal events related to the treatment occurred in 2% (n = 1) with proportional and none with deep sedation., Conclusion: Proportional sedation achieved satisfactory symptom relief while maintaining some patients' consciousness, and deep sedation achieved good symptom relief while the majority of patients lost consciousness., (Copyright © 2021. Published by Elsevier Inc.)

Context: Patients with malignant ascites often suffer from distressing symptoms, especially in their end-of-life stage. Although paracentesis is the most common treatment modality to alleviate such symptoms, the optimal volume of paracentesis is not known., Objectives: To explore the efficacy and safety of paracentesis by the drainage volume for terminally ill cancer patients with malignant ascites., Methods: This was part of a multicenter prospective observational study (EASED study). Consecutive adult patients with advanced cancer admitted to 23 participating palliative care units were eligible. We analyzed patients with malignant ascites who received paracentesis. We compared paracentesis-free survival (PFS) using Cox regression among three groups with different paracentesis volumes: minimum: ≤ 1500 mL, small: 1500-2500 mL, and moderate: > 2500 mL. Trends of the difference in the numerical rating scale of abdominal distension (0-10) and adverse events were compared among the 3 groups., Results: Of the 1926 patients enrolled, 673 developed ascites (symptomatic, n = 374 and asymptomatic, n = 299). Finally, we analyzed 87 patients with paracentesis. Median PFS was 7 days. Compared with a moderate volume, small-volume paracentesis was not a significant risk for shorter PFS (HR: 1.14, 95% CI: 0.69-1.93), while a minimum volume was a significant risk (HR: 2.34). The abdominal distension intensity significantly decreased after paracentesis (median: 7.5 to 4.0), while the difference did not significantly increase as the volume of paracentesis rose (P = 0.61). No severe adverse event was observed., Conclusion: Even small-volume paracentesis could alleviate abdominal distension of terminally ill cancer patients with malignant ascites without shortening the paracentesis interval compared with moderate-volume paracentesis. Small-volume paracentesis was a well-balanced treatment for these patients., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: For cancer patients nearing death, the prediction of their prognosis by physicians is crucial. This study examined the usefulness of the 1-Day Surprise Question (1DSQ)., Methods: This study was conducted as part of a multicenter prospective observational study. The physicians answered the 1DSQ "Would I be surprised if this patient died in the next 1 day?" when patients have palliative performance scale (PPS) ≤20. We calculated the sensitivity and specificity of the 1DSQ. Moreover, using multivariate analysis, we evaluated the characteristics of patients who died among those whose physicians answered the 1DSQ as "not surprised"., Results: Overall, 1,896 patients were enrolled, and 1,411 (74.4%) were analyzed between January and December 2017. Among these, 847 (60.0%) patients were placed in the "not surprised" group. The sensitivity, specificity, and positive and negative predictive values of the 1DSQ were 82.0% [95% confidence interval (CI): 77.5-85.8%], 45.5% (95% CI: 44.4-46.4%), 27.4% (95% CI: 25.9-28.7%), and 91.0% (95% CI: 88.9-92.9%), respectively. Multivariate analysis revealed that urine output over last 12 hours <100 mL, decreased response to visual stimuli, respiration with mandibular movement, pulselessness of radial artery, and saturation of percutaneous oxygen <90% were characteristics of patients who died as predicted by the physicians., Conclusions: The 1DSQ is a helpful screening tool for identifying cancer patients with impending death.

Objective: There are only a few treatment algorithms for first-episode schizophrenia. Moreover, all the algorithms apply to acute treatment, but not maintenance treatment. Therefore, we aimed to develop acute and maintenance treatment algorithms for first-episode schizophrenia., Methods: The algorithm committee of the Japanese Society of Clinical Neuropsychopharmacology developed pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia., Results: The acute treatment algorithm focuses on drug-naïve patients with first-episode schizophrenia who are not old or very agitated and recommends first-line treatment with aripiprazole, second- or third-line treatment with risperidone/paliperidone or olanzapine, and fourth-line treatment with clozapine. Long-acting injection of the current antipsychotic agent can be used for poor medication adherence or based on patient preference. The agitation treatment algorithm recommends first-line treatment with lorazepam and second- or third-line treatment with quetiapine or levomepromazine and clearly instructs that the medication used for agitation should be reduced and then discontinued after remission of agitation. The maintenance treatment algorithm recommends the gradual reduction of antipsychotics to the minimum effective dose after remission of positive symptoms., Conclusions: We hope that our unique algorithms will be used broadly and will contribute to minimizing patients' burden related to antipsychotic treatment., (© 2021 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.)

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8 + T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8 + T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

Clear cell carcinoma (CCC) is a rare low-grade malignant salivary gland carcinoma. EWSR1-ATF1 fusion has been characterized as a consistent finding in CCC, with breakpoints described between EWSR1 exon 11 and ATF1 exon 3. So far, over 100 cases of CCC harboring EWSR1 rearrangement arising from salivary gland of the oral cavity have been reported. Although EWSR1 involvement in these cases was confirmed by EWSR1 break-apart FISH indicating the translocation, sequence analysis for EWSR1-ATF1 fusion type has been reported only in three cases of CCC so far. Herein, we report a CCC case with novel EWSR1-ATF1 fusion (EWSR1 exon 15 and ATF1 exon 5) arising in minor salivary gland and review the role of the chimeric variants in some malignancies with EWSR1-ATF1 rearrangement. Current tumor was composed of the small nests of clear tumor cells and hyalized fibrous stroma. Immunohistochemically, the tumor was positive for AE1/AE3, CK5/6 and p63, negative for S100, Melan-A, SMA and CD10. After 8 months of follow-up, there are no evidence of recurrence.

Introduction: Abdominal pain and distention are common in ovarian tumours. When the ovarian tumour grows too large, the tumour can cause these symptoms. Percutaneous drainage from ovarian tumours, which can alleviate symptoms, is traditionally discouraged for its potential risk of peritoneal tumour seeding., Case: A 73-year-old woman with a multilocular ovarian tumour reporting abdominal fullness and pain was referred to the palliative care outpatient department. The multilocular tumour occupied most of the intra-abdominal space, which was determined to cause her symptoms. To alleviate her symptoms, we performed intermittent percutaneous drainage for 1.5 years. A clinical autopsy revealed the tumour was an ovarian mucinous carcinoma. Despite iterative tumour drainage, we observed no feature of peritoneal dissemination., Conclusion: Intermittent percutaneous drainage of ovarian tumours could reduce tumour-related abdominal symptoms without pathological evidence of peritoneal dissemination. This procedure can be a new palliative treatment option for ovarian tumour-related abdominal symptoms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although many Japanese patients wish to take a bath in their last days, the safety of bathing for patients with a prognosis of a few days is not known. Objective: To examine whether taking a bath affects the survival of advanced cancer patients with prognoses of a few days. Design: A single-center prospective cohort study. Setting/Subject: Advanced cancer patients in their last days of life in a palliative care unit of a Japanese hospital. We compared patients who took baths with those who did not. The primary endpoint was 24-hour survival rate. Result: Among 110 patients eligible for this prospective study, 89 (72%) met the inclusion criteria. Forty-eight patients (43%, 223 person-days) were eligible for analysis. A total of 28 patient-days were classified into the bathing group, and 192 patient-days were classified into the nonbathing group. After propensity score matching, the 24-hour death rate was 10.7% in the bathing group and 8.0% in the nonbathing group, respectively (mean difference 2.8% with 95% confidence interval of -11.2% to 16.8%, p  = 0.65). Conclusion: Taking a bath does not appear to bear a significant association with shortening of life among advanced cancer patients in their last days of life., Competing Interests: No competing financial interests exist., (© Kiyofumi Oya et al., 2021; Published by Mary Ann Liebert, Inc.)

Background: Hyperactive delirium is known to increase family distress and the burden on health care providers. We compared the prevalence and associated factors of agitated delirium in advanced cancer patients between inpatient palliative care and palliative home care on admission and at 3 days before death., Methods: This was a post hoc exploratory analysis of two multicenter, prospective cohort studies of advanced cancer patients, which were performed at 23 palliative care units (PCUs) between Jan and Dec 2017, and on 45 palliative home care services between July and Dec 2017., Results: In total, 2998 patients were enrolled and 2829 were analyzed in this study: 1883 patients in PCUs and 947 patients in palliative home care. The prevalence of agitated delirium between PCUs and palliative home care was 5.2% (95% CI: 4.2% - 6.3%) vs. 1.4% (0.7% - 2.3%) on admission (p < 0.001) and 7.6% (6.4% - 8.9%) vs. 5.4% (4.0% - 7.0%) 3 days before death (p < 0.001). However, multivariate logistic regression analysis revealed that the place of care was not significantly associated with the prevalence of agitated delirium at 3 days before death after adjusting for prognostic factors, physical risk factors, and symptoms., Conclusions: There was no significant difference in the prevalence of agitated delirium at 3 days before death between inpatient palliative care and palliative home care after adjusting for the patient background, prognostic factors, symptoms, and treatment., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The study aimed to clarify the efficacy of the "3-Day Surprise Question (3DSQ)" in predicting the prognosis for advanced cancer patients with impending death., Patients and Methods: This study was a part of multicenter prospective observational study which investigated the dying process in advanced cancer patients in Japan. For patients with a Palliative Performance Scale ≤20, the 3DSQ "Would I be surprised if this patient died in the next 3 days?" was answered by their physicians. In addition to the sensitivity and specificity of the 3DSQ, the characteristics of patients who survived longer than expected were examined via multivariate analysis., Results: Among the 1896 patients enrolled, 1411 were evaluated. Among 1179 (83.6%) patients who were classified into the "Not surprised" group, 636 patients died within 3 days. Among 232 (16.4%) patients of "Yes surprised" group, 194 patients lived longer than 3 days. The sensitivity, specificity, positive predictive value, and negative predictive value of the 3DSQ were 94.3% (95% confidence interval [CI]: 92.7% to 95.8%), 26.3% (95% CI: 24.8% to 27.6%), 53.9% (95% CI: 53.0% to 54.7%), and 83.6% (95% CI: 78.7% to 87.7%), respectively. Multivariate analysis showed palpable radial artery, absent respiration with mandibular movement, SpO 2 ≥ 90%, opioid administration, and no continuous deep sedation as characteristics of patients who lived longer than expected., Conclusions: The 3-Day Surprise Question can be a useful screening tool to identify advanced cancer patients with impending death., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We report a 46-year-old male patient with functional liver damage due to hepatitis B virus infection. A 12 cm hepatocellular carcinoma (HCC) in the left lobe and portal venous tumor thrombosis (PVTT) with vp4 (portal vein tumor thrombosis in the main trunk) were detected by computed tomography (CT). He underwent hepatic arterial infusion chemotherapy (HAIC) with cisplatin 100 mg for HCC and received radiation therapy (39 Gy/13 Fr) for PVTT with vp4. Follow-up CT showed reduction of HCC and reduced PVTT volume after 1 month of treatment. He then initiated lenvatinib therapy at 12 mg/day. One month later, follow-up CT showed no change in HCC size and a reduction in PVTT volume. Two months after initiating lenvatinib, follow-up CT showed no change in HCC, but further reduction in contrast effect and volume of PVTT. Three months after HAIC, he underwent drug-eluting-bead transcatheter arterial chemoembolization (DEB-TACE) with 100 mg of cisplatin (CDDP) for the HCC. After DEB-TACE, he received 12 mg/day with 5-days-on/2-days-off due to vomiting. One month after DEB-TACE, blood evaluation showed decreased tumor markers, and CT revealed that the HCC had grown slightly with no change in PVTT. Five months after HAIC, he underwent DEB-TACE with 100 mg of cisplatin for the HCC. A total of 150 days have passed since the start of lenvatinib treatment, and his Child-Pugh A status has been maintained.

Fam20C, which phosphorylates many secretory proteins with S-x-E/pS motifs, is highly expressed in bone and tooth tissues, implying that Fam20C-mediated phosphorylation is critical for regulation of these mineralized tissues. Previous studies of Fam20C-deficient mice revealed that Fam20C plays important roles in bone formation and mineralization. However, Fam20C-deficient mice develop hypophosphatemia, a systemic factor that masks the local effect of Fam20C in the bone tissue; consequently, the local role of Fam20C remains unknown. To elucidate the local function of Fam20C in bone tissue, we studied osteoblast-specific Fam20C transgenic (Fam20C-Tg) mice, which have no alteration in serum calcium and phosphate levels. Fam20C-Tg mice had more highly phosphorylated proteins in bone tissue than wild-type mice. In cortical bone of Fam20C-Tg mice, bone volume, mineralization surface (MS/BS), and mineral apposition rate (MAR) were elevated; in addition, the transgenic mice had an elevated number of vascular canals, resulting in an increased cortical porosity. Osteocyte number was elevated in the transgenics, but osteoblast number was unchanged. The microstructure of bone matrix characterized by the preferential orientation of collagen and apatite, was degraded and thus the mechanical function of bone material was deteriorated. In trabecular bone of Fam20C-Tg mice, bone volume was reduced, whereas MS/BS and MAR were unchanged. Osteoclast number was elevated and eroded surface area was non-significantly elevated with an increased serum CTX-I level, whereas osteoblast number was unchanged. These findings indicated that Fam20C overexpression in osteoblasts promotes cortical bone formation by increasing MS/BS and MAR and promoting osteocyte differentiation, but does not affect trabecular bone formation. Furthermore, Fam20C overexpression indirectly promotes osteoclastic bone resorption in cortical and trabecular bones. Our findings show that osteoblastic Fam20C-mediated phosphorylation in bone tissue regulates bone formation and resorption, and bone material quality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest related to this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Aim: The most important prognostic factor for non-alcoholic steatohepatitis (NASH) is liver fibrosis. The aim of this study is to examine clinical parameters involved in pathological progression in NASH patients who underwent repeated liver biopsy and to analyze the response to treatment with respect to NASH-related single nucleotide polymorphisms (SNPs). We performed longitudinal analysis of genetic and clinical factors associated with progression of NASH., Methods: Eighty NASH patients who had undergone serial liver biopsies were enrolled in this retrospective cohort study. Histological exacerbation was determined based on non-alcoholic fatty liver disease activity score (NAS) and liver fibrosis., Results: About 22.5% had progression of fibrosis, 22.5% had improvement of fibrosis, and 55.0% had no change. NAS increased in 12.5%, decreased in 61.3%, and remained stable in the remaining 26.3%. We examined factors associated with histological progression versus non-progression. Poor response of alanine aminotransferase (ALT) levels, increase in HbA1c levels, and presence of the tumor necrosis factor risk allele in the rs1799964 SNP were identified as independent risk factors contributing to histological progression in NASH patients. In addition, we found that the histological progression rate varies with ALT response, HbA1c levels, and rs1799964 genotype., Conclusions: In this study, we clarified the serum ALT level and the clinical significance of HbA1c to evaluate the progression of fibrosis in Japanese NASH patients. Furthermore, the tumor necrosis factor SNP was more likely to be involved in the response than PNPLA3 SNP. By simultaneously evaluating three factors, it is possible to estimate the risk of histological progression more accurately., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Patients' demographic and epidemiological characteristics, local variations in clinicians' knowledge and experience and types of surgery can influence peri-operative transfusion practices. Sharing data on transfusion practices and recipients may improve patients' care and implementation of Patient Blood Management (PBM)., Materials and Methods: This was a multicentre, prospective, observational, cross-sectional study that included 61 centres. Clinical and transfusion data of patients undergoing major elective surgery were collected; transfusion predictors and patients' outcomes were analysed., Results: Of 6,121 patients, 1,579 (25.8%) received a peri-operative transfusion. A total of 5,812 blood components were transfused: red blood cells (RBC), fresh-frozen plasma and platelets in 1,425 (23.3%), 762 (12.4%) and 88 (1.4%) cases, respectively). Pre-operative anaemia was identified in 2,019 (33%) patients. Half of the RBC units were used by patients in the age group 45-69 years. Specific procedures with the highest RBC use were coronary artery bypass grafting (16.9% of all units) and hip arthroplasty (14.9%). Low haemoglobin concentration was the most common indication for intra-operative RBC transfusion (57%) and plasma and platelet transfusions were mostly initiated for acute bleeding (61.3% and 61.1%, respectively). The RBC transfusion rate in study centres varied from 2% to 72%. RBC transfusion was inappropriate in 99% (n=150/151) of pre-operative, 23% (n=211/926) of intra-operative and 43% (n=308/716) of post-operative RBC transfusion episodes. Pre-operative haemoglobin, increased blood loss, open surgery and duration of surgery were the main independent predictors of intra-operative RBC transfusion. Low pre-operative haemoglobin concentration was independently associated with post-operative pulmonary complications., Conclusions: These findings identified areas for improvement in peri-operative transfusion practice and PBM implementation in Turkey.

Human embryonic kidney 293T (HEK293T) cells are used in various biological experiments and researches. In this study, we investigated the effect of cell culture environments on morphological and functional properties of HEK293T cells. We used several kinds of dishes made of polystyrene or glass for cell culture, including three types of polystyrene dishes provided from different manufacturers for suspension and adherent cell culture. In addition, we also investigated the effect of culturing on gelatin-coated surfaces on the cell morphology. We found that HEK293T cells aggregated and formed into three-dimensional (3-D) multicellular spheroids (MCS) when non-coated polystyrene dishes were used for suspension culture. In particular, the non-coated polystyrene dish from Sumitomo bakelite is the most remarkable characteristic for 3-D MCS among the polystyrene dishes. On the other hand, HEK293T cells hardly aggregated and formed 3-D MCS on gelatin-coated polystyrene dishes for suspension culture. HEK293T cells adhered on the non- or gelatin-coated polystyrene dish for adherent culture, but they did not form 3-D MCS. HEK293T cells also adhered to non- or gelatin-coated glass dishes and did not form 3-D MCS in serum-free medium. These results suggest that HEK293T cells cultured on non-coated polystyrene dish may be useful for the tool to analyze the characteristics of 3D-MCS.

Object: The rupture risk of cerebral aneurysms is determined by various factors. However, it is not clear whether the thickness of the aneurysm wall also influences the rupture risk. In this study, under the assumption that thin-walled aneurysms have a higher rupture risk compared with thick-wall aneurysms, we evaluate the usefulness of computed fluid dynamics(CFD)to identify thin-walled cerebral aneurysms., Methods: Fifty-four unruptured middle cerebral aneurysms from 53 patients were analyzed using CFD before the operation. We divided these aneurysms into two groups: translucent-type aneurysms and others. To analyze the difference of these groups, individual elements(age, gender, volume, and aspect ratio)and hemodynamic factors(wall shear stress[WSS], flow coefficient, and flow coefficient per volume)were examined using CFD., Results: Univariate analysis detected significant relationships between the translucent-type aneurysms and gender, aspect ratio, WSS and flow coefficient per volume. Multiple logistics regression also identified a significant relationship with gender and flow coefficient per volume. The receiver operating characteristic curve demonstrated that the flow coefficient per volume could predict translucent-type aneurysms(area under the curve 0.84, cut-off value 1.32, sensitivity 76.2%, and specificity 87.9%)., Conclusion: Gender and the flow coefficient per volume could predict translucent-type aneurysms of the middle cerebral artery. CFD analysis might be a useful tool to predict translucent-type aneurysms.