日本の百寿者及び非百寿者における死亡前1年間に発生する医療費の比較

Importance: Although research has shown that centenarians tend to experience shorter periods of serious illness compared with other age groups, few studies have focused on the medical expenditures of centenarians as a potential indicator of the scale of medical resources used in their last year of life. Objective: To compare Japanese centenarians' and noncentenarians' monthly medical expenditures during the year before death according to age and sex. Design, setting, and participants: This retrospective cohort study used linked national health and long-term care insurance data collected from April 2013 to March 2018 in Nara Prefecture, Japan, for residents aged 75 years or older who were insured under the Medical Care System for older adults and died between April 2014 and March 2018. Data were analyzed from April 2013 to March 2018. Exposures: Age of 100 years or older (centenarians) vs 75 to 99 years (noncentenarians). Main outcomes and measures: The numbers of unique inpatients and outpatients and medical expenditures related to decedents' hospitalization and outpatient care were extracted and analyzed based on sex and age group. The Jonckheere-Terpstra test was used to identify trends in unadjusted medical expenditures by age group, and generalized estimating equations were used to estimate monthly median expenditures by age group with adjustment for comorbidity burden and functional status. Results: Of 34 317 patients aged 75 to 109 years (16 202 men [47.2%] and 18 115 women [52.8%]) who died between April 2014 and March 2018, 872 (2.5%) were aged 100 to 104 years (131 men [15.0%] and 741 women [85.0%]) and 78 (0.2%) were aged 105 to 109 years (fewer than 10 were men). The analysis of unadjusted medical expenditures in the last year of life showed a significant trend of lower expenditures for the older age groups; the median adjusted total expenditures during the 30 days before death by age group were $6784 (IQR,$4884-$9703) for ages 75 to 79 years,$5894 (IQR, $4292-$8536) for 80 to 84 years, $5069 (IQR,$3676-$7150) for 85 to 89 years,$4205 (IQR, $3085-$5914) for 90 to 94 years, $3522 (IQR,$2626-$4861) for 95 to 99 years,$2898 (IQR, $2241-$3835) for 100 to 104 years, and $2626 (IQR,$1938-$3527) for 105 to 109 years. The proportion of inpatients among all patients in the year before death also decreased with increasing age: 4311 of all 4551 patients aged 75 to 79 years (94.7%); 43 of all 78 patients aged 105 to 109 years (55.1%); 2831 of 2956 men aged 75 to 79 years (95.8%); 50.0% of men aged 105 to 109 years (the number is not reported owing to the small sample size); 1480 of 1595 women aged 75 to 79 years (92.8%); and 55.7% of women aged 105 to 109 years (the number of women is not reported to prevent back-calculation of the number of men). Specifically, 274 of 872 patients aged 100 to 104 years (31.4%) and 35 of 78 patients aged 105 to 109 years (44.9%) had not been admitted to a hospital in the year before death. Conclusions and relevance: This cohort study found that medical expenditures in the last year of life tended to be lower for centenarians than for noncentenarians aged 75 years or older in Japan. The proportion of inpatients also decreased with increasing age. These findings may inform future health care services coverage and policies for centenarians.博士（医学）・甲第801号・令和3年12月21日© 2021 Nakanishi Y. et al.JAMA Network Open. Open Access: This is an open access article distributed under the terms of the CC-BY License(https://creativecommons.org/licenses/by/4.0/)

Lenvatinib for Anaplastic Thyroid Cancer

Background: Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. Patients and methods: This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. Results: At data cutoff, 17 patients with ATC were enrolled. All experienced >= 1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%. Conclusion: In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC

Editorial: Conflicts

The Editorial Board reflects on the theme of 'conflict', as observed in the work published in this issue, and in the wider world

Comparison of 2D-and 3D-culture models as drug-testing platforms in breast cancer

markdownabstract__Abstract__ Multinomial choices of individuals are likely to be correlated. Nonetheless, econometric models for this phenomenon are scarce. A problem of multivariate multinomial choice models is that the number of potential outcomes can become very large which makes parameter interpretation and inference difficult. We propose a novel Multivariate Multinomial Logit specification, where (i) the number of parameters stays limited; (ii) there is a clear interpretation of the parameters in terms of odds ratios; (iii) zero restrictions on parameters result in independence between the multinomial choices and; (iv) parameter inference is feasible using a composite likelihood approach even if the multivariate dimension is large. Finally, these nice properties are also valid in a fixed-effects panel version of the model

Role of PSCs in Regeneration of Remnant Pancreas after PX

Background and objectives Mechanism of regeneration of remnant pancreas after partial pancreatectomy (PX) is still unknown. In this study, effect of siRNA against the collagen specific chaperone, HSP47, which inhibits collagen secretion from activated pancreas stellate cells (aPSCs), and induces their apoptosis, on regeneration of remnant pancreas was determined. Methods Pancreatectomy was performed according to established methods. Proliferation of cells was assessed by BrdU incorporation. Immunostaining of HSP47 was employed to identify PSCs. Progenitor cells were identified by SOX9 staining. Acinar cells were immunostained for amylase. Co-culture of acinar cells with aPSCs were carried out in a double chamber with a cell culture insert. siRNA HSP47 encapsulated in vitamin A-coupled liposome (VA-lip siRNA HSP47) was delivered to aPSCs by iv injection. Results In remnant pancreas of 90% PX rat, new areas of foci were located separately from duodenal areas with normal pancreatic features. After PX, BrdU uptake of acinar cells and islet cells significantly increased, but was suppressed by treatment with VA-lip siRNA HSP47. BrdU uptake by acinar cells was augmented by co-culturing with aPSCs and the augmentation was nullified by siRNA HSP47. BrdU uptake by progenitor cells in foci area was slightly enhanced by the same treatment. New area which exhibited intermediate features between those of duodenal and area of foci, emerged after the treatment. Conclusion aPSCs play a crucial role in regeneration of remnant pancreas, proliferation of acinar and islet cells after PX through the activity of secreted collagen. Characterization of new area emerged by siRNA HSP47 treatment as to its origin is a future task

A tripartite paternally methylated region within the Gpr1-Zdbf2 imprinted domain on mouse chromosome 1 identified by meDIP-on-chip

The parent-of-origin specific expression of imprinted genes relies on DNA methylation of CpG-dinucleotides at differentially methylated regions (DMRs) during gametogenesis. To date, four paternally methylated DMRs have been identified in screens based on conventional approaches. These DMRs are linked to the imprinted genes H19, Gtl2 (IG-DMR), Rasgrf1 and, most recently, Zdbf2 which encodes zinc finger, DBF-type containing 2. In this study, we applied a novel methylated-DNA immunoprecipitation-on-chip (meDIP-on-chip) method to genomic DNA from mouse parthenogenetic- and androgenetic-derived stem cells and sperm and identified 458 putative DMRs. This included the majority of known DMRs. We further characterized the paternally methylated Zdbf2/ZDBF2 DMR. In mice, this extensive germ line DMR spanned 16 kb and possessed an unusual tripartite structure. Methylation was dependent on DNA methyltransferase 3a (Dnmt3a), similar to H19 DMR and IG-DMR. In both humans and mice, the adjacent gene, Gpr1/GPR1, which encodes a G-protein-coupled receptor 1 protein with transmembrane domain, was also imprinted and paternally expressed. The Gpr1-Zdbf2 domain was most similar to the Rasgrf1 domain as both DNA methylation and the actively expressed allele were in cis on the paternal chromosome. This work demonstrates the effectiveness of meDIP-on-chip as a technique for identifying DMRs

Phylogenetic relationships of the suborder Notacanthoidei (Teleostei: Albuliformes) reassessed from osteological characters, with a proposed new classification

The phylogenetic relationships of Notacanthoidei were reassessed on the basis of osteological characters and the classification of the suborder reconstructed on the basis of inferred relationships. The monophyly of the suborder is supported by two synapomorphies commonly recognized in all included genera. The phylogenetic analysis also revealed support for the suborder by five synapomorphies characterized by reversals or character transformations. In addition, notacanthoids share five apomorphies, present also in Anguilliformes, which may prove to be valid synapomorphies for the former. A phylogenetic analysis based on characters in 30 transformation series resulted in a single most parsimonious tree, which indicated that Aldrovandia branched off initially from other notacanthoids, followed by Lipogenys, and Polyacanthonotus and Notacanthus, which share a sister relationship with each other. Based on the reconstructed relationships, Notacanthoidei is classified into two families, Holasauridae and Notacanthidae, the latter being separated into subfamilies Lipogenyinae and Notacanthinae. Such a classification of Notacanthoidei, recognizing Lipogeninae as a subfamily of Notacanthidae, has not been previously proposed