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In Western countries, the ideal professional and ethical attributes of healthcare providers and the ideal patient-doctor relationship have been analysed in detail. Other cultures, however, may have different norms, arising in response to diverse healthcare needs, cultural values and offering alternative perspectives. In this paper, drawing a case study, we introduce the concept of Shinmi, used in Japan to describe a desirable approach to medical care. Shinmimeans kind or cordial in Japanese. In the medical context, it refers to doctors treating patients with a degree of emotional closeness as if they were the doctors’ own family. We analyse the concept of Shinmi, drawing on virtue ethics. We distinguish two different elements to a Shinmi-naattitude. As illustrated in our example, excessive Shinmican be problematic for patients and doctors. Furthermore, elements of Shinmimay conflict with existing Western values (for example, norms that encourage emotional detachment and discourage doctors’ treatment of family members). However, if pursued appropriately, we argue that a balanced Shinmi-na approach can be conducive to the goals of medicine. The concept of Shinmimay be valuable for medical students, in Japanese and potentially other health care systems, and help them to cultivate a virtuous approach to meeting the emotional needs of patients.

To gain insight into microscopic hydrogen bond networks, we measured ultraviolet photodissociation (UVPD) spectra of the phenol-methanol 1:3 cluster cation, [PhOH(MeOH)3]+trapped in a variable temperature ion trap. At low temperatures, an isomer with a ring-type hydrogen bond structure dominates, whereas at higher temperatures the chain-type isomers become dominant due to the flexibility of their hydrogen bond structures. We also found a clear temperature dependence of the spectral features, such as band position and width. In addition to the above measurement, we observed the infrared (IR) induced isomerization of [PhOH(MeOH)3]+to study the dynamical aspects of hydrogen bond networks. We succeeded in observing IR-induced isomerization from the ring to chain forms of [PhOH(MeOH)3]+at low temperature. The isomerization was clearly identified as a change in the UVPD spectra. The time evolution of the UVPD spectra after IR excitation indicated that the IR-induced isomerization occurs within a nanosecond. The chain-type isomers produced by the IR-induced isomerization are then converted back to the ring-type form by collisions with cold He buffer gas in the trap. This backward isomerization proceeds with a time constant of 100 μs under our experimental conditions. In this study, we evaluated the temperatures of the chain isomers during the backward isomerization on the basis of the spectral features.

Because exacerbation of severe asthma decreases patients’ quality of life, this study aimed to identify predictive factors for asthma exacerbation.

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013–2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1–65.5%) and CBT (46.2%, 95% CI: 33.2–58.1%; P= 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57–1.66], P= 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.

ABSTRACTIn this study, using a C(T) specimen for 12Cr steel used for a steam turbine rotor, crack growth tests under creep-fatigue conditions with and without overloading were conducted and the fundamental behaviours of deformation and crack growth were investigated experimentally. As a result, load line displacement was found to be suppressed under overload condition regardless of temperature and stress holding time. Crack initiation life under high temperature and low stress condition with overloading was delayed as compared with no overload condition. However, under low temperature and high stress condition with short stress holding time, crack initiation was accelerated remarkably. Furthermore, although crack growth life under creep-fatigue conditions with overloading was found to be shortened as compared with no overloading, the effect of overloading on crack growth life was decreased with an increase in stress holding time.

We determined intrinsic viscosity for polystyrene (PS) samples with a wide range of molecular weight in d-limonene, which attracts interest as an environmentally friendly solvent for PS. By analyzing the experimental data obtained in d-limonene using the helical wormlike chain model with and without the excluded-volume effect, solvent quality of d-limonene for PS was quantitatively evaluated. Consequently, it was concluded that d-limonene belongs to the category of medium solvent, which is intermediate between good solvents like toluene and poor solvents like cyclohexane, for PS.

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The multiport Cauer ladder network (CLN) method is an efficient and accurate model order reduction (MOR) method for multi-input/multi-output (MIMO) systems. This manuscript discusses a theoretical aspect of port reduction in multiport CLN to generate a further reduced system. An intuitively derived method is found to be inaccurate. A recurrence formula and its practical implementation are presented to generate an accurate reduced system, which is proven by computational examples.

Synovial mesenchymal stem cells (MSCs) are an attractive cell source for transplantation because of their high chondrogenic potential, especially in areas like the meniscus of the knee. A synovial MSC suspension placed onto the meniscus for 10 min promoted healing of repaired meniscal tears that generally do not heal. Here, we quantified the proportion of human synovial MSCs that adhered to a porcine abraded meniscus, clarified their morphological changes, and revealed the mechanism by which the synovial MSCs adhered to the meniscus. The numbers of adhering cells at immediately after 10, 60 min and 6, 24 h after suspension placement were calculated. The meniscus surface was examined by scanning electron microscopy, and 50 cells were randomly selected at each time period, classified, and quantified for each of the six donors. Approximately 28% of the synovial MSCs immediately adhered to the meniscus after placement and the proportion of adhered cells increased further with time. All cells maintained a round shape for 60 min, and then transformed to a mixture of round and semi-flattened cells. By 24 h, flattened cells covered the meniscus. Microspikes were observed in 36% of the floating synovial MSCs and in 76% of the cells on the meniscus shortly after placement on the meniscus, then the proportion of cells with pseudopodia increased. The bleb-dominant cell proportion significantly decreased, and the smooth-dominant cell proportion increased within 60 min. Microspikes or the bodies of synovial MSCs were trapped by meniscal fibers immediately after placement. The proportion of adhered cells increased with time, and the cell morphology changed dynamically for 24 h as the synovial MSCs adhered to the meniscus. The MSCs in the round morphological state had a heterogeneous morphology. The microspikes, and the subsequent development of pseudopodia, may play an important role in adhesion onto the meniscus.

Plants can rapidly respond to different stresses by activating multiple signaling and defense pathways. The ability to directly visualize and quantify these pathways in real time using bioorthogonal probes would have practical applications, including characterizing plant responses to both abiotic and biotic stress. Fluorescence-based labels are widely used for tagging of small biomolecules but are relatively bulky and with potential effects on their endogenous localization and metabolism. This work describes the use of deuterium- and alkyne-derived fatty acid Raman probes to visualize and track the real-time response of plants to abiotic stress within the roots. Relative quantification of the respective signals could be used to track their localization and overall real-time responses in their fatty acid pools due to drought and heat stress without labor-intensive isolation procedures. Their overall usability and low toxicity suggest that Raman probes have great untapped potential in the field of plant bioengineering.

The stratum corneum (SC), the outermost layer of the skin, has an important function to provide a barrier against dry environments. To evaluate the barrier function and the skin condition, it is crucial to investigate the ability of SC to absorb and retain water. In this study, we demonstrate stimulated Raman scattering (SRS) imaging of three-dimensional SC structure and water distribution when water is absorbed into dried SC sheets. Our results show that the process of water absorption and retention is dependent on the specific sample and can be spatially heterogeneous. We also found that acetone treatment leads to spatially homogeneous retention of water. These results suggest the great potential of SRS imaging in diagnosing skin conditions.

Detecting multiple enzyme activities simultaneously with high spatial specificity is a promising strategy to investigate complex biological phenomena, and Raman imaging would be an excellent tool for this purpose due to its high multiplexing capabilities. We previously developed activatable Raman probes based on 9CN-pyronins, but specific visualization of cells with target enzyme activities proved difficult due to leakage of the hydrolysis products from the target cells after activation. Here, focusing on rhodol bearing a nitrile group at the position of 9 (9CN-rhodol), we established a novel mechanism for Raman signal activation based on a combination of aggregate formation (to increase local dye concentration) and the resonant Raman effect along with the bathochromic shift of the absorption, and utilized it to develop Raman probes. We selected the 9CN-rhodol derivative 9CN-JCR as offering a suitable combination of increased stimulated Raman scattering (SRS) signal intensity and high aggregate-forming ability, resulting in good retention in target cells after probe activation. By using isotope-edited 9CN-JCR-based probes, we could simultaneously detect β-galactosidase, γ-glutamyl transpeptidase, and dipeptidyl peptidase-4 activities in live cultured cells and distinguish cell regions expressing target enzyme activity in Drosophilawing disc and fat body ex vivo.

Multifocal lymphangioendotheliomatosis with thrombocytopenia is a rare disease characterized by progressive multiple vascular lesions and is accompanied by thrombocytopenia. The precise diagnosis of this disease is frequently difficult because of the heterogeneity of the clinical symptoms. We report a case of a male infant who presented with severe thrombocytopenia induced by local inflammation. In addition, enlargement of the extremities with soft tissue and bone involvement without gastrointestinal bleeding was observed. The thrombocytopenia resolved after a combination therapy of sirolimus and prednisolone. Our finding that plasma angiopoietin-2 concentrations reflected the disease status suggests its utility as a biomarker of Multifocal lymphangioendotheliomatosis with thrombocytopenia.

Purpose: To evaluate the efficacy of the Active Seal technology employed in the AFX endovascular aortic aneurysm system (AFX), during endovascular aneurysm repair (EVAR) in patients with abdominal aortic aneurysms (AAAs) having a conical proximal neck.Materials and Methods: A retrospective analysis of the EVAR for AAA with a conical proximal neck using the AFX was performed at 17 Japanese hospitals between January 2016 and August 2020. The conical proximal neck was defined as a cone-shaped proximal neck, with more than 10% diameter increase within a 15 mm length at the proximal landing zone. All anatomical analyses were performed in the core laboratory, and cases with parallel walls within the proximal neck adequate for the landing zone were excluded from the study.Results: This study included 53 patients, but only 39 patients (mean age, 76.6 ± 6.7 years; 87.0% males; mean aneurysm diameter, 52.0 ± 8.0 mm) were analyzed after being characterized as having a pure conical neck by the core laboratory. The mean proximal neck diameters at the lower renal artery and proximal edge of the aneurysm were 20.0 ± 2.9 mm and 27.5 ± 4.9 mm, respectively. The mean proximal neck length was 21.5 ± 6.0 mm. Instructions for use violations other than the conical neck were observed in 15 patients (38.5%). The VELA cuff was used in all cases; however, additional proximal cuff was required in 9 more cases (23.1%). The Active Seal technology was able to significantly extend the proximal sealing zone from 21.5 ± 6.0 to 26.0 ± 12.2 mm (p= .047). Thirty-six patients completed the 12-month follow-up (one patient was lost to follow-up, and 2 patients died from causes unrelated to the aneurysm), and there were no type-1a and 3 endoleaks with only one reintervention (2.6%) related to type 1b endoleak in the 12-month period. Furthermore, there was no significant enlargement of the proximal neck diameter at 12 months (at 1 month: 20.6 ± 3.4 mm and at 12 months: 21.3 ± 3.8 mm; p= .420).Conclusion: The Active Seal technology of the AFX significantly extended the proximal seal zone and no type-1a endoleak and proximal neck dilation was observed in patients with conical proximal neck at 12 months.

ABSTRACTBackgroundMONONOFU, a multicenter, randomized, double-blind, placebo-controlled phase 2 study of Japanese patients with migraine, was pivotal for lasmiditan approval in Japan. However, treatment-emergent adverse events (TEAEs) were more common than in global studies. A detailed safety profile would assist patient management.Research design and methodsSafety assessments in MONONOFU included specific terms reported, frequency, severity, time to onset, duration, TEAE management, common TEAE risk factors, and TEAE–efficacy associations.ResultsOf 846 participants, 691 were assessed for safety. The proportion of participants reporting ≥1 TEAE was 23.4% with placebo and 70.9% with lasmiditan; 87.3% of TEAEs with lasmiditan were mild. The most frequent TEAEs with lasmiditan, dizziness (39.4%) and somnolence (19.3%), started ≤1 hour postdose (median durations: 2.5 and 3.3 hours, respectively). Higher lasmiditan dose, but not patient factors including body size, was identified as a clinically meaningful predictor of dizziness and somnolence. There were no adverse consequences of neurological TEAEs, which did not appear to adversely affect lasmiditan efficacy.ConclusionsIn the MONONOFU study, TEAEs appeared typically mild, transient, and self-limiting. Lasmiditan may represent a useful and well-tolerated acute treatment option for smaller (body mass index <30 kg/m2) patients and Asian patients with migraine.

Haematopoietic stem-cell transplantation (HSCT)-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with high mortality. Accumulating evidence suggests that complement dysregulation is potentially involved in the development of HSCT-TMA. We retrospectively analysed the clinical characteristics and outcomes of thirteen paediatric patients who were diagnosed with atypical haemolytic uremic syndrome and treated with eculizumab to manage HSCT-TMA during post-marketing surveillance in Japan. The median time from HSCT to TMA was 31 days (Interquartile range, IQR;21–58) and the median doses of eculizumab was three (IQR;2–5). Seven patients (54%) were alive at the last follow-up while six died due to complications related to HSCT. Six of seven survivors initiated eculizumab after insufficient response to plasma therapy. Following eculizumab treatment, median platelet counts and LDH levels in all survivors significantly improved and renal function improved in 4/7 patients. All survivors possessed potential risk factors of complement overactivation. During the follow-up period after eculizumab discontinuation (median;111.5 days, IQR;95–555), no TMA recurrence was observed. In this analysis, eculizumab showed benefit in over half of this paediatric patient population. Ongoing clinical studies are expected to optimize the treatment regimen of terminal complement pathway inhibitor, and it may become a therapeutic option for paediatric HSCT-TMA in the future.

A population pharmacokinetic (PopPK) analysis was conducted using data from 215 Japanese administered oral sirolimus (tablet and granule) including healthy subjects and patients with intractable vascular anomalies and other diseases. The analysis included neonates, infants, and adults, and identified covariates that influence sirolimus pharmacokinetics (PK). The final model was used to predict sirolimus trough concentrations for various dosing regimens and covariates of interest. The results showed that sirolimus trough concentrations were predicted to increase with higher levels of hemoglobin, and that the granule formulation had a 1.23-fold higher exposure than the tablet formulation. Coadministration of CYP3A4 inducers was found to decrease trough concentrations by 54 %. The PK simulations showed that administration of the granule formulation at doses of 0.02, 0.04, 0.06, and 0.08 mg/kg/day in ages <3 months, 3 to <6 months, 6 to <12 months, and ≥1 year, respectively, resulted in >70 % target attainment within the therapeutic trough concentration range (5–15 ng/mL). In conclusion, incorporation of time-varying covariates (body weight and age) into the PopPK model appropriately predicted sirolimus concentrations in Japanese subjects from infants to adult sub-populations. This PopPK model would therefore be able to provide a reference for clinical individualization of sirolimus dosing.

ABSTRACTBackgroundSome migraine treatments are contraindicated for patients with cardiovascular disease (CVD) or risk factors (CVRFs). We report safety and efficacy of lasmiditan, a new oral acute migraine treatment with no cardiovascular contraindication, in Japanese patients with CVRFs.Research design and methodsMONONOFU was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of Japanese patients with migraine (met International Headache Society criteria, Migraine Disability Assessment score ≥11, disabling migraine for ≥1 year). Eligible patients were randomized (7:3:7:6) to placebo or lasmiditan 50, 100, 200 mg. This prespecified analysis described CVDs, CVRFs, and cardiovascular treatment-emergent adverse events (TEAEs). Efficacy (proportion pain-free, experienced pain relief, most bothersome symptom-free, or disability-free 2 hours post-dose) was evaluated within CVRF subgroups (≤1, ≥2).ResultsOf 846 randomized patients, 691 were analyzed (CVRF≤1: 375; CVRF≥2: 316). The proportion of lasmiditan-treated patients with ≥1 TEAE was not related to CVRF numbers. Eighteen (3.8%) lasmiditan-treated and three (1.4%) placebo-treated patients reported likely cardiovascular TEAEs. Lasmiditan was more effective than placebo at relieving pain, symptoms, and disability in both CVRF subgroups. There was no consistent relationship between CVRF subgroups and efficacy.ConclusionsLasmiditan was well tolerated and effective in Japanese patients with migraine and CVRFs.Trial registrationClinicalTrials.gov: NCT03962738.