A topology optimization method is proposed for transient response problems involving thermoelastic models, where the objective is to optimize the structure considering time-dependent dynamic and ...thermal loads. The proposed method can be applied to problems involving thermal deformation and stress, which damage heated machine parts. This paper presents a transient response analysis of a thermoelastic model subjected to mechanical and thermal loads having arbitrary profiles with respect to time. This can be formulated as a multi-objective optimization problem to obtain a structure that minimizes the deformation and maximum stress. A sensitivity analysis was conducted by using the adjoint variable method and the discretize-then-differentiate approach. The proposed method was applied to numerical examples for validation.
•A topology optimization method considering transient response is presented.•The objective is to optimize the structure considering time-dependent loads.•The discretize-then-differentiate approach is used in the sensitivity analysis.
We assessed the feasibility of transplanting a sheet of retinal pigment epithelial (RPE) cells differentiated from induced pluripotent stem cells (iPSCs) in a patient with neovascular age-related ...macular degeneration. The iPSCs were generated from skin fibroblasts obtained from two patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. The RPE cells and the iPSCs from which they were derived were subject to extensive testing. A surgery that included the removal of the neovascular membrane and transplantation of the autologous iPSC-derived RPE cell sheet under the retina was performed in one of the patients. At 1 year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular edema was present. (Funded by Highway Program for Realization of Regenerative Medicine and others; University Hospital Medical Information Network Clinical Trials Registry UMIN-CTR number, UMIN000011929 .).
Summary
Using the nationwide health insurance claims database, we found that the age-standardized hip fracture incidence rates in Japan indicated significant increase in males but no significant ...change in females during 2012–2015. The fracture risk in subjects aged 75–84 years indicated decrease in females but no change in males.
Introduction
Nationwide registry data on hip fractures have not yet been established in Japan. Using the newly developed National Database of Health Insurance Claims (NDB), which covers the entire Japanese population, we investigated the incidence rates of hip fractures and the associated regional differences. We also assessed the frequency of osteoporosis prescriptions, bone turnover marker (BTM) level, and bone mineral density (BMD) measurements.
Methods
The annual numbers of hip fractures, osteoporosis prescriptions, and BTM level and BMD measurements by prefecture from 2012 to 2015 were obtained from NDB data. We calculated the standardized claims-data ratio (SCR) in each prefecture.
Results
The age-standardized incidence rates from 2012 to 2015 indicated no significant change in females and significant increase in males (
p
value for trend; 0.920, 0.002, respectively). The fracture risk decreased in females aged 75–84 years and indicated no increase in females aged 85–89 years during 2012–2015, while the fracture risk indicated no change in males aged 75–84 years and increased in males aged 85–89 years. The frequency of osteoporosis prescriptions, BTM level measurements, and BMD measurements in the general population in the corresponding period increased with statistical or marginal significance in females and males. West–east regional differences were observed in the incidence rates; the highest SCR values in the western prefectures were approximately double the lowest values in the eastern prefectures.
Conclusions
The age-standardized hip fracture incidence rates indicated no significant change in females and significant increase in males in Japan from 2012 to 2015.
In this study, we propose a new topology optimization problem for creep deformation minimization. It is a phenomenon in which deformation progresses even when the load is constant, and is a cause of ...damage to mechanical parts. Therefore, the results of this paper will be one of the solutions to the problem of creep deformation. We deal with a viscoelastic model assuming the generalized Maxwell model to account for creep deformation. In addition, we devise a new objective function that directly evaluate the creep deformation. Since sensitivity analysis of the objective function is necessary for topology optimization, we formulate the sensitivity of the viscoelastic model to accurately consider the time dependence. The relationship between the creep characteristics and the objective function is explained through a numerical example using a one-dimensional model. By examining a two-dimensional model, it is shown that the formulated sensitivity is validated and the proposed method derives the optimized configuration under which creep deformation is minimized.
•We propose a topology optimization for minimizing creep deformation.•We apply the generalized Maxwell model to simulate creep deformation.•A new optimization problem that enables creep deformation minimization is introduced.•We present a sensitivity analysis that considers the history dependency of deformation.
Expanded polyglutamine 72 repeat (polyQ72) aggregates induce endoplasmic reticulum (ER) stress-mediated cell death with caspase-12 activation and vesicular formation (autophagy). We examined this ...relationship and the molecular mechanism of autophagy formation. Rapamycin, a stimulator of autophagy, inhibited the polyQ72-induced cell death with caspase-12 activation. PolyQ72, but not polyQ11, stimulated Atg5-Atg12-Atg16 complex-dependent microtubule-associated protein 1 (MAP1) light chain 3 (LC3) conversion from LC3-I to -II, which plays a key role in autophagy. The eucaryotic translation initiation factor 2 alpha (eIF2alpha) A/A mutation, a knock-in to replace a phosphorylatable Ser51 with Ala51, and dominant-negative PERK inhibited polyQ72-induced LC3 conversion. PolyQ72 as well as ER stress stimulators upregulated Atg12 mRNA and proteins via eIF2alpha phosphorylation. Furthermore, Atg5 deficiency as well as the eIF2alpha A/A mutation increased the number of cells showing polyQ72 aggregates and polyQ72-induced caspase-12 activation. Thus, autophagy formation is a cellular defense mechanism against polyQ72-induced ER-stress-mediated cell death by degrading polyQ72 aggregates, with PERK/eIF2alpha phosphorylation being involved in polyQ72-induced LC3 conversion.
High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of ...genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.
The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the ...functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34(+) cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34(+) cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.
The biology, clinical phenotype and progression rate of chronic myelomonocytic leukemia (CMML) are highly variable due to diverse initiating and secondary clonal genetic events. To determine the ...effects of molecular features including clonal hierarchy in CMML, we studied whole-exome and targeted next-generation sequencing data from 150 patients with robust clinical and molecular annotation assessed cross-sectionally and at serial time points of disease evolution. To identify molecular lesions unique to CMML, we compared it to the related myeloid neoplasms (N=586), including juvenile myelomonocytic leukemia, myelodysplastic syndromes (MDS) and primary monocytic acute myeloid leukemia and discerned distinct molecular profiles despite similar pathomorphological features. Within CMML, mutations in certain pathways correlated with clinical classification, for example, proliferative vs dysplastic features. While most CMML patients (59%) had ancestral (dominant/co-dominant) mutations involving TET2, SRSF2 or ASXL1 genes, secondary subclonal hierarchy correlated with clinical phenotypes or outcomes. For example, progression was associated with acquisition of new expanding clones carrying biallelic TET2 mutations or RAS family, or spliceosomal gene mutations. In contrast, dysplastic features correlated with mutations usually encountered in MDS (for example, SF3B1 and U2AF1). Classification of CMML based on hierarchies of ancestral and subclonal mutational events may correlate strongly with clinical features and prognosis.
Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a ...thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements.
We studied 78 patients undergoing paediatric cardiac surgery with cardiopulmonary bypass (CPB) for the initial 12 h after operation. Stepwise multiple linear regression was used to develop an algorithm to guide blood product transfusions. Thereafter, we randomly assigned 100 patients to conventional or algorithm-guided blood product management, and assessed bleeding and red cell transfusion requirements.
CPB time, post-bypass rotational thromboelastometry (ROTEM®) EXTEM amplitude at 10 min (A10), and FIBTEM-A10 were independently associated with chest tube drainage volume during the initial 12 h after operation. Discriminative analysis determined cut-off values of 30 mm for EXTEM-A10 and 5 mm for FIBTEM-A10, and estimated optimal intraoperative fresh-frozen plasma and platelet concentrate transfusion volumes. Thromboelastometry-guided post-bypass blood product management significantly reduced postoperative bleeding (9 vs 16 ml kg−1, P<0.001) and packed red cell transfusion requirement (11 vs 23 ml kg−1, P=0.005) at 12 h after surgery, and duration of critical care stay (60 vs 71 h, P=0.014).
Rotational thromboelastometry-guided early haemostatic intervention by rapid intraoperative correction of EXTEM-A10 and FIBTEM-A10 reduced blood loss and red cell transfusion requirements after CPB, and reduced critical care duration in paediatric cardiac surgical patients.
UMIN Clinical Trials Registry UMIN000006832 (December 4, 2011).
6
He is known as two-neutron halo nuclei and has a Borromean structure in which there is no bound state in the binary subsystems. To explore resonances of unstable nuclei, the (
p
,
p
′
) reaction ...with the inverse kinematics has been often used. The
2
2
+
state has been investigated via various structural calculations and experimental studies. Unfortunately, the contribution of this state in the energy spectrum does not show a shape structure. Thus, the resonant energy and decay width of the
2
2
+
state have never been clear. To clarify the properties, it is required an accurate analysis of treating not only resonant contributions but also nonresonant contributions in energy spectra. In this study, we investigated the
2
2
+
resonant state via the analysis of
6
He(
p
,
p
′
) reaction by using the continuum-discretized coupled-channels method. To describe the resonant and nonresonant state components, we also applied the complex scaling method to the analysis.
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